CN112326838A - Determination method for improving dissolution curve of azithromycin capsule - Google Patents
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a determination method for improving a dissolution curve of an azithromycin capsule. The method is simple to operate and high in accuracy, can eliminate the phenomena of slow dissolution and nonuniform dissolution caused by capsule shell crosslinking in the determination of the azithromycin capsule dissolution curve, and is suitable for the development of preparation processes and the quality detection of samples on the market.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry, and particularly relates to a determination method for improving an azithromycin capsule dissolution curve.
Background
The main component of the azithromycin capsule is azithromycin (azithromycin), the chemical name of which is (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R) -13- [ (2, 6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-nuclear-hexopyranosyl) oxy ] -2-ethyl-3, 4, 10-trihydroxy-3, 5, 6, 8, 10, 12, 14-heptamethyl-11- [ [3, 4, 6-trideoxy-3- (dimethylamino) -beta-D-xylopyranosyl ] oxy ] -1-oxa-6-azacyclopentadecane-15-one, and the structural formula of the azithromycin capsule is as follows:
the Azithromycin capsule is a capsule preparation which is prepared by filling Azithromycin crystalline powder content into a gelatin capsule shell, is called Azithromycin capsule by English name, is produced by the former inventor of Crodipril tile company (PLIVA Croatia Ltd.), is mainly suitable for upper and lower respiratory tract infection, skin soft tissue infection, sexually transmitted diseases and the like caused by sensitive bacteria, and is a semi-synthetic fifteen-membered macrolide antibiotic. It has wide antibacterial spectrum, is widely used for various infectious diseases, has relatively definite curative effect, and is a common antibacterial medicament. The imitation research of the medicine is more at home and abroad, and particularly, the azithromycin capsule serving as the basic medicine of national medical insurance is a popular research medicine due to the evaluation of the consistency of imitation medicines which rise at home in recent years.
In the field of medicine, particularly in the process of evaluating the consistency of the imitation drugs, the importance of a dissolution test is undoubted, the in-vivo dynamic release of the preparation can be simulated and researched in vitro, the inherent excellent quality of the preparation is reflected, the process characteristics of different prescriptions of oral solid preparations can be analyzed, the screening of the prescription process of the preparation is convenient, and the method has important significance for quality supervision and inspection after the medicine is marketed.
The azithromycin capsule consists of a gelatin capsule shell and contents, and the dissolution and release of the capsule preparation need to pass through the process that the capsule shell is dissolved in a dissolution medium and then the contents are released, so the type and the property of the capsule shell have great influence on the determination of the dissolution rate of the medicine. Gelatin is a mixture of a series of water-soluble collagen derivatives, and is easy to generate a crosslinking reaction under the conditions of light, heat, oxygen, temperature and humidity, so that the dissolution of a capsule shell in a dissolution medium is slowed down and is not uniform, and the accuracy of the dissolution determination of a capsule preparation is directly influenced. The existing method for detecting the dissolution curve of the azithromycin capsule does not particularly provide a simple, accurate and reliable exact method for solving the problems of slow dissolution release and large dissolution RSD value caused by the cross-linking of a capsule shell. Therefore, it is very useful to develop an elution method which can solve this problem.
Disclosure of Invention
The invention aims to provide a determination method for improving the dissolution curve of an azithromycin capsule, which can effectively solve the problems of slow dissolution release and large dissolution RSD value caused by the crosslinking of a gelatin capsule shell.
Definition of terms
In the present invention, "%" means mass% unless otherwise specified.
In the present invention, unless otherwise indicated, whether or not "about" precedes a specific value means that the value may fluctuate within the scope of the art, specifically referring to the general examples of the chinese pharmacopoeia.
In the present invention, unless otherwise specified, the water used for the preparation of the buffer solution of the dissolution medium is used for the analysis in the field of analysis, and includes, but is not limited to, purified water, ultrapure water, deionized water, etc., and the water used for the liquid chromatography includes, but is not limited to, ultrapure water, etc.
In the present invention, unless otherwise indicated, dissolution medium buffers include, but are not limited to, phosphate buffers and the like.
In the present invention, proteases required for dissolution media include, but are not limited to, trypsin, unless otherwise indicated.
In the present invention, the absolute values of the pH of the dissolution medium buffer salt and the buffer salt in the mobile phase may fluctuate within. + -. 0.05, unless otherwise indicated.
Detailed Description
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for measuring the improved dissolution curve of azithromycin capsule, which follows the requirements of dissolution in the general oral solid preparation dissolution curve measurement and comparison guiding principle and Chinese pharmacopoeia, and adopts a dissolution measuring method (the second method of 0931 in the four parts of the 2015 edition of Chinese pharmacopoeia), a slurry method and a settling basket.
In the dissolution rate determination method provided by the invention, a dissolution medium is a buffer salt solution added with protease with a certain concentration. Specifically, the buffer salt solution can be a potassium salt or sodium salt buffer solution of phthalic acid, boric acid, citric acid, acetic acid and phosphoric acid with the pH value of 2.2-10.0, and the protease can be one or more of trypsin, papain, bromelain and pepsin. According to the common knowledge in the field of analysis, an ordinary analyst in the field can select other inorganic and organic salts and protease or other enzymes as dissolution media or other simulated intestinal fluid, gastric juice and the like to achieve the purpose of the invention based on the technical scheme of the invention according to the actual type of the capsule preparation and in order to better meet the actual working requirement and obtain better experimental effect.
More specifically, the invention provides a determination method for improving the dissolution curve of azithromycin capsules, which adopts a dissolution determination method (second method of 0931 in the four parts of the Chinese pharmacopoeia 2015 edition), a slurry method and a settling basket, takes 900ml of protease buffer salt solution with certain concentration as a dissolution medium, rotates at 75 revolutions per minute and has the temperature of 37 ℃, is operated according to the method, samples are taken for 10min, 15min, 20min and 30min, 5ml of solution is taken, and is filtered, and the subsequent filtrate is taken as a sample solution and is supplemented with the dissolution medium with the same volume and the same temperature. And precisely weighing 28mg of azithromycin reference substance, placing the reference substance in a 100ml volumetric flask, adding 14ml of ethanol for dissolving, quantitatively diluting to a scale by using a dissolution medium, and shaking up to obtain a reference substance solution. Precisely measuring the sample solution and the reference solution by 50 μ l each, injecting into a liquid chromatograph, recording chromatogram, and calculating the dissolution value of each sampling point of each capsule by peak area according to external standard method.
Compared with the traditional method of taking a buffered salt solution as a dissolution medium, the slow and uneven dissolution release and inaccurate measurement result of the capsule shell crosslinking agglomeration of the capsule preparation are easily caused, the problem of the crosslinking of the capsule shell can be well solved by adding protease into the buffered salt solution, the measurement accuracy is improved, the dissolution release behavior of the capsule preparation is reflected more truly, and the quality research of the medicine is better guided.
In some embodiments, the determination method for improving the dissolution curve of the azithromycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
In some embodiments, the determination method for improving the dissolution curve of the azithromycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.02g/L Trypsin
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
In some embodiments, the method for determining the dissolution curve of the azithromycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.05g/L Trypsin
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
In some embodiments, the method for determining the dissolution curve of the azithromycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.1g/L Trypsin
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
In some embodiments, the method for determining the dissolution curve of the azithromycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.2g/L Trypsin
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
In some embodiments, the method for determining the dissolution curve of the spectinomycin capsule comprises the following steps:
the dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.5g/L Trypsin
Dissolution volume: 900ml
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
The sample detection method comprises the following steps: HPLC method
Wherein, the sample detection method is an HPLC method.
A chromatographic column: waters
MS C18 150×4.6mm，5μm；
Mobile phase: acetonitrile-0.05M K2HPO4(pH8.2)＝55:45(V/V)；
Column temperature: 30 ℃;
wavelength: 210 nm;
sample introduction amount: 50 μ l;
flow rate: 1 ml/min;
the running time is 15 min.
The calculation method comprises the following steps: and (4) an external standard method.
Concentration of sample
Wherein:
Csample (A): the concentration of azithromycin (mg/ml) in the test article at the nth time sampling point;
Cto pair: concentration of azithromycin control (mg/ml);
Asample (A): the peak area of azithromycin in the test sample at the nth time sampling point;
Ato pair: peak area of azithromycin in the control solution;
wherein:
q: the total dissolution (%) of the azithromycin capsules in the test article at the nth time sampling point;
cn: concentration of azithromycin (mg/ml) in the test article at the nth time sampling point.
Since the biological activity of proteases is closely related to the pH of the environment, we also consider the influence of the pH of the buffered saline solution on the protease activity when selecting a suitable dissolution medium, and select a suitable protease according to the pH.
After a plurality of experimental researches, the inventor finds that the azithromycin capsule is prepared by adding Na with pH of 6.82HPO4When the buffer salt solution is used as a dissolution medium, the dissolution release speed of the capsule is moderate, the rising of the dissolution curve is smooth, and the dissolution curve has better discrimination force. The dissolution curve with the distinguishing force has extremely important significance for quality analysis and process screening of the oral solid preparation and comparison of similarity of the dissolution curves. However, the dissolution and release of the capsule in the dissolution medium are not uniform, and the RSD value of the dissolution rate is large. When protease is added to the buffered salt solution at a concentration, the capsules are filledThe phenomena of slow dissolution and uneven dissolution can be greatly improved. Through a plurality of tests and screens, when the pH value is 6.8, the trypsin is added, and the concentration of the trypsin is 0.05g/L and 0.1g/L, the azithromycin capsule has a smaller dissolution rate RSD value, and the analysis and detection result is more accurate and reliable.
The method is simple, convenient and accurate, can greatly reduce the problems of slow dissolution release and uneven dissolution caused by capsule shell crosslinking, and provides an accurate and convenient method for process screening in the research and development stage and quality detection of samples produced commercially. Particularly, but not exclusively, for testing azithromycin capsule formulations.
Drawings
Figure 1 is a dissolution curve of azithromycin capsules in ph6.8 buffer with different concentrations of trypsin;
figure 2 is a dissolution rate RSD value versus time curve of azithromycin capsules in ph6.8 buffer with different concentrations of trypsin;
figure 3 is a dissolution RSD value versus time curve for azithromycin capsules in ph6.8 buffer with and without 0.05g/L trypsin.
Detailed Description
In order to enable those skilled in the art to better understand the technical solution of the present invention, the following further discloses some non-limiting embodiments for further detailed description of the present invention.
The acetonitrile used in the invention is a chromatographic pure reagent, the trypsin is bovine trypsin (batch number J1730028) produced by the Aladdin company, the sample is an azithromycin capsule (batch number 950056) produced by the Crodipy tile company, a filter membrane used for filtering a sample is a mixed cellulose membrane (the diameter is 25mm, the pore diameter is 0.45um) of Tianjin Fuchengda, a reference substance is an azithromycin working reference substance (self-made), and other reagents are analytical pure reagents. The mobile phase water for liquid chromatography is ultrapure water, and the rest is purified water.
Example 1
Chromatographic conditions
An Agilent 1260 II high performance liquid chromatography system and workstation; chromatographic columnAs Waters
MS C18150X 4.6mm, 5 μm; the column temperature is 30 ℃; the wavelength is 210 nm; the flow rate is 1 ml/min; the sample amount is 50 mul; the running time is 15 min;
0.05M K2HPO4solution: about 8.709g of dipotassium hydrogen phosphate was weighed out and dissolved in 1000ml of ultrapure water, the pH was adjusted to 8.2 with 20% phosphoric acid, shaken up and filtered through a 0.45 μm filter membrane.
Mobile phase: acetonitrile-0.05M K2HPO4(ph8.2) 55:45 (V/V); isocratic elution.
Dissolution conditions:
the dissolution instrument is a Tiandatianfa dissolution tester (model RC8MD)
The dissolution method comprises the following steps: second method of Chinese pharmacopoeia, pulp method and settling basket
Dissolution medium: pH6.8 Na2HPO4Buffered saline solution
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
Dissolution volume: 900ml X6 cup
Rotating speed: 75rpm
Dissolution medium temperature: 37 deg.C
Sampling time points are as follows: 10min, 15min, 20min, 30min
Sampling volume: 5ml of
Volume of fluid infusion: 5ml of
Solution preparation:
diluting liquid: dissolution media
Blank solution: adding 14ml of ethanol into a 100ml volumetric flask, then quantitatively diluting the mixture to a scale with a diluent, and shaking up.
Test solution: 5ml of sample is taken at each specific sampling time point of the dissolution test, filtered, 2ml of primary filtrate is discarded, and the subsequent filtrate is taken as a test solution.
Control solution: weighing azithromycin reference substance 28mg, precisely weighing, placing in a 100ml volumetric flask, adding ethanol 14ml for dissolving, quantitatively diluting with diluent to scale, and shaking up to obtain the final product.
Respectively taking the blank solution, the reference solution and the test solution, performing high performance liquid chromatography according to the chromatographic conditions, and recording the chromatogram. And calculating the dissolution value of each dissolution sampling point according to a reference external standard method, and drawing a dissolution-time curve according to the dissolution values of each time point to obtain the dissolution curve of the azithromycin capsule. According to the 'determination of dissolution curve and comparative guiding principle' of common oral solid preparation, the RSD value of dissolution rate at the 1 st sampling time point is not more than 20%, and the RSD value of dissolution rate from the 2 nd time point to the last time point is not more than 10%. Table 1 shows that the dissolution rate RSD value of the azithromycin capsule at the 1 st sampling time point exceeds 20 percent, and the dissolution rate RSD value of the azithromycin capsule at the 2 nd sampling time point exceeds 10 percent, so that the dissolution rate method needs to be improved to meet the requirement.
TABLE 1 dissolution Profile of Azithromycin capsules in dissolution media pH6.8
Example 2
The apparatus and chromatographic conditions were the same as in example 1
Dissolution conditions:
dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.02g/L Trypsin
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
pH6.8 Na2HPO4Buffered saline solution +0.02g/L trypsin: 120mg of trypsin is added into 6000ml of pH6.8 Na2HPO4Stirring, dissolving, mixing, and ultrasonic degassing for 30 min.
Other dissolution conditions, solution preparation methods and sample injection methods were the same as in example 1.
As a result, as shown in Table 2, the dissolution RSD value was not improved by adding 0.02g/L trypsin in pH6.8 buffered saline as a dissolution medium, probably due to insufficient enzyme concentration. For the capsule, the problems of slow dissolution release and uneven dissolution caused by capsule shell crosslinking can be well improved only after the concentration of the enzyme reaches the proper concentration.
TABLE 2 dissolution Profile of Azithromycin capsules in Trypsin dissolution Medium pH6.8+0.02g/L
Example 3
The apparatus and chromatographic conditions were the same as in example 1
Dissolution conditions:
dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.05g/L Trypsin
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
pH6.8 Na2HPO4Buffered saline solution +0.05g/L trypsin: adding 300mg of trypsin into 6000ml of pH6.8 Na2HPO4Stirring, dissolving, mixing, and ultrasonic degassing for 30 min.
Other dissolution conditions, solution preparation methods and sample injection methods were the same as in example 1.
As a result, as shown in Table 3, the pH6.8 buffered saline solution containing 0.05g/L trypsin as a dissolution medium showed no change in dissolution profile but showed a significantly reduced dissolution RSD value, compared to the condition without enzyme, and the conditions for comparison of the similarity of dissolution profiles in the dissolution guide rules were satisfied. Therefore, the trypsin with a certain concentration is added into the buffered saline solution to serve as a dissolution medium, the dissolution rate RSD value of the azithromycin capsule is reduced, the dissolution curve is accurate, and the method can be used for comparing the dissolution similarity in a preparation process so as to perform better preparation analysis and process screening.
TABLE 3 dissolution Profile of Azithromycin capsules in Trypsin dissolution Medium pH6.8+0.05g/L
Example 4
The apparatus and chromatographic conditions were the same as in example 1
Dissolution conditions:
dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.1g/L Trypsin
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
pH6.8 Na2HPO4Buffered saline solution +0.1g/L trypsin: 600mg of trypsin is added into 6000ml of pH6.8 Na2HPO4Stirring, dissolving, mixing, and ultrasonic degassing for 30 min.
Other dissolution conditions, solution preparation methods and sample injection methods were the same as in example 1.
The results are shown in Table 4, and similar to example 3, the dissolution RSD value of the dissolution medium with 0.1g/L trypsin at each sampling point is reduced compared with the condition without enzyme, and the requirement of dissolution guiding principle is met. Therefore, 0.1g/L trypsin is added into the buffer salt solution to be used as a dissolution medium, so that the dissolution and release behaviors of the azithromycin capsule can be improved, and the method has important significance for solving the cross-linking problem of the capsule preparation. The concentration of the additive in the dissolution medium is preferably 0.05g/L, since the concentration is increased from low to high according to the general principle of adding the additive in the dissolution medium, and the concentration of trypsin is preferably 0.05g/L when both of the concentrations are suitable 0.05g/L and 0.1g/L in view of the cost.
TABLE 4 dissolution Profile of Azithromycin capsules in Trypsin dissolution Medium pH6.8+0.1g/L
Example 5
The apparatus and chromatographic conditions were the same as in example 1
Dissolution conditions:
dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.2g/L Trypsin
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
pH6.8 Na2HPO4Buffered saline solution +0.2g/L trypsin: adding 1200mg of trypsin into 6000ml of pH6.8 Na2HPO4Stirring, dissolving, mixing, and ultrasonic degassing for 30 min.
Other dissolution conditions, solution preparation methods and sample injection methods were the same as in example 1.
As a result, as shown in Table 5, it was found that the dissolution RSD value is rather increased by increasing the concentration of trypsin in the buffered salt solution as compared with the values in the dissolution medium to which 0.05g/L and 0.1g/L trypsin were added, and the dissolution release of azithromycin capsule becomes faster as compared with the dissolution medium to which no trypsin was added, which may affect the actual dissolution release behavior of the sample and be disadvantageous in the determination of the test results. Therefore, the concentration of trypsin is not as high as possible, and there is a suitable concentration range for the enzyme concentration in the dissolution medium at a certain pH.
TABLE 5 dissolution Profile of Azithromycin capsules in Trypsin dissolution Medium pH6.8+0.2g/L
Example 6
The apparatus and chromatographic conditions were the same as in example 1
Dissolution conditions:
dissolution medium: pH6.8 Na2HPO4Buffered saline solution +0.5g/L Trypsin
pH6.8 Na2HPO4Buffer salt solution: taking Na2HPO442.588g, 5.376g NaOH, 6000ml water, stirring, dissolving, mixing, and adding H3PO4Or NaOH solution to adjust the pH value to 6.8.
pH6.8 Na2HPO4Buffered saline solution +0.5g/L trypsin: adding 3000mg trypsin into 6000ml pH6.8 Na2HPO4Stirring, dissolving, mixing, and ultrasonic degassing for 30 min.
Other dissolution conditions, solution preparation methods and sample injection methods were the same as in example 1.
As a result, as shown in Table 6, it was found that the dissolution RSD value of the azithromycin capsule in the buffer solution added with 0.5g/L trypsin is higher than that of the dissolution medium added with 0.05g/L trypsin and 0.1g/L trypsin, and the requirement of the dissolution guiding principle on the dissolution RSD value is not met. Indicating that the added trypsin concentration is too high to make the dissolution medium at this concentration unsuitable for the determination of the dissolution curve of the present capsule. For the determination of the dissolution curve of the azithromycin capsule in the invention, trypsin is added at suitable concentrations of 0.05g/L and 0.1 g/L. The concentration of trypsin in the dissolution medium is therefore very important for the determination of the dissolution profile of the capsules.
TABLE 6 dissolution Profile of Azithromycin capsules in Trypsin dissolution Medium pH6.8+0.5g/L
The names of the dissolution media in tables 1-6 represent the following meanings:
in summary of the embodiments described in the above,
FIGS. 1 and 2 show that when protease is added to a buffered salt solution at a certain concentration as a dissolution medium, the dissolution curve does not change much, and when the protease concentration is 0.05g/L and 0.1g/L, the RSD value of the dissolution rate is within the range of the dissolution guiding principle. And then the addition principle and the cost of the additive and the improvement degree of the dissolution rate RSD are comprehensively considered, the optimal protease concentration is considered to be 0.05g/L, and the dissolution rate RSD value of the dissolution medium without the protease is obviously reduced compared with the result that the dissolution rate RSD value is measured by the dissolution medium without the protease, such as the dissolution rate RSD value of a pH6.8 buffered salt solution added with 0.05g/L trypsin in the graph shown in figure 3. According to the experimental results of the implementation cases 1-6, the method for improving the dissolution curve of the azithromycin capsule provided by the invention can effectively solve the problems of drug wrapping, slow dissolution and release and uneven dissolution of the azithromycin capsule in dissolution measurement due to gelatin crosslinking. In order to optimize the effect of the protease, it is necessary to prepare an appropriate protease concentration according to the properties of the capsule preparation. The method is simple, accurate and reliable, and is suitable for quality analysis and process screening in capsule preparation development stage and quality control of product in industrial production.
While the methods of the present invention have been described in terms of specific embodiments, those skilled in the relevant art will recognize that the methods described herein can be practiced and applied to other embodiments, as appropriate, and with various modifications, additions, substitutions, and equivalents within the spirit and scope of the invention. The examples are provided for better illustration of the present invention, but the present invention is not limited to the examples.
Those skilled in the art can, with reference to the present disclosure, suitably modify the process parameters, and it is specifically noted that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the invention.
Claims (9)
1. A determination method for improving the dissolution curve of azithromycin capsules is characterized in that protease is added into a buffered salt solution as a dissolution medium.
2. The determination method for improving the dissolution curve of the azithromycin capsule as claimed in claim 1, wherein the buffered salt solution is a potassium salt or sodium salt solution of phthalic acid, boric acid, citric acid, acetic acid, phosphoric acid, preferably a disodium hydrogen phosphate buffered salt solution.
3. The determination method for improving the dissolution curve of the azithromycin capsule as claimed in claim 2, wherein the pH of the buffered saline solution is in the range of 2.2-10.0, preferably the pH is 6.8.
4. The method for determining the improved azithromycin capsule dissolution curve as claimed in claim 1, wherein the protease is one or more of trypsin, papain, bromelain or pepsin or other simulated intestinal fluid, gastric fluid and the like, preferably trypsin.
5. The determination method for improving the dissolution curve of the azithromycin capsule according to claim 4, wherein the concentration of the protease is 0.05g/L to 0.10g/L, preferably 0.05 g/L.
6. The assay method for improving the dissolution curve of azithromycin capsules as claimed in claim 1, wherein the method employs dissolution assay, slurry plus sedimentation basket, temperature 37 ℃.
7. An assay method for improving the dissolution curve of azithromycin capsules as claimed in claim 1, wherein the method further comprises: 900ml of dissolution medium.
8. An assay method for improving the dissolution curve of azithromycin capsules as claimed in claim 1, wherein the method further comprises: the rotation speed was 75 revolutions per minute.
9. The determination method for improving the dissolution curve of the azithromycin capsule as claimed in claim 1 or 6, wherein the detection method of the sample is high performance liquid chromatography, and the steps are as follows:
respectively sampling a test sample solution and an azithromycin reference solution, carrying out high performance liquid chromatography analysis, recording a chromatogram, and calculating the content of azithromycin in the test sample according to an external standard method so as to calculate the dissolution rate of the azithromycin capsule at each sampling time point;
the high performance liquid chromatography adopts octadecylsilane chemically bonded silica as stationary phase, the specification of the chromatographic column is 4.6 × 150mm, 5 μm, and acetonitrile-0.05M K2HPO4(pH8.2) 55:45 as a mobile phase, a column temperature of 30 ℃, a flow rate of 1.0ml/min, a detection wavelength of 210nm, a sample amount of 50. mu.l, and an analysis time of 15 min.
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| CN105078920A (en) * | 2014-05-16 | 2015-11-25 | 山东司邦得制药有限公司 | Azithromycin capsule and preparation method thereof |
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