CN112034118A - Method for rapidly detecting dissolution rate of solid preparation - Google Patents
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Abstract
The invention provides a method for rapidly detecting dissolution rate of a solid preparation, which comprises the following steps: providing a solid formulation that is known to be dissolution-eligible; providing a dissolution medium; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate; placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the particle size of the particles in the dissolution liquid at a specified time to obtain the particle size of the solid preparation with the known qualified dissolution rate; providing a solid preparation to be tested; obtaining the particle size of the solid preparation to be measured according to the method same as the method for measuring the particle size of the solid preparation with the known dissolution rate qualification; and comparing the particle size of the solid preparation to be tested with the particle size of the solid preparation with known qualified dissolution rate. The rapid detection method for the dissolution rate of the solid preparation provided by the invention can rapidly, simply and conveniently realize the detection of the dissolution rate of the solid preparation.
Description
Technical Field
The invention relates to the detection of the dissolution rate of a solid preparation, in particular to a rapid detection method of the dissolution rate of the solid preparation.
Background
Solid formulations following oral administration, absorption of the drug depends on dissolution or release of the drug from the formulation, dissolution of the drug under physiological conditions, and permeation through the gastrointestinal tract. Since dissolution and dissolution of a drug have a significant impact on absorption, in vitro dissolution tests have the potential to predict its behavior in vivo.
At present, methods for evaluating the dissolution rate of oral solid preparations, such as the basket method and the paddle method, adopted by the existing methods, for example, the chinese pharmacopoeia (2020 edition), generally need to further measure the concentration of a drug in a dissolution liquid by analysis means such as ultraviolet spectrum and liquid chromatography, and the methods are complex, have long investigation period and are not intuitive enough for evaluating the dissolution process of the drug. In addition, in the processes of using ultraviolet spectrum and liquid chromatography, substances such as some organic solvents are inevitably used, and certain environmental pollution is caused.
Therefore, there is a need to provide a rapid method for detecting the dissolution rate of solid dosage forms.
Disclosure of Invention
The embodiment of the invention provides a method for rapidly detecting the dissolution rate of a solid preparation, which can rapidly, simply and conveniently detect the dissolution rate of the solid preparation.
The embodiment of the invention provides a method for rapidly detecting the dissolution rate of a solid preparation, which comprises the following steps:
providing a solid formulation that is known to be dissolution-eligible;
providing a dissolution medium; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate;
placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the particle size of the particles in the dissolution liquid at a specified time to obtain the particle size of the solid preparation with the known qualified dissolution rate;
providing a solid preparation to be tested;
obtaining the particle size of the solid preparation to be measured according to the method same as the method for measuring the particle size of the solid preparation with the known dissolution rate qualification;
and comparing the particle size of the solid preparation to be tested with the particle size of the solid preparation with known qualified dissolution rate.
Furthermore, the dissolution medium is prepared by taking the dissolution medium corresponding to the dissolution rate of the solid preparation with the known dissolution rate qualification, and then adding sodium dodecyl benzene sulfonate or sodium dodecyl sulfate.
Optionally, the dissolution medium has a sodium dodecylbenzene sulfonate or sodium dodecylsulfate content of 0.5 wt% to 5 wt%.
Optionally, the dissolution medium has a sodium dodecylbenzene sulfonate or sodium dodecylsulfate content of 1 wt% to 4 wt%.
Optionally, the method of determining the particle size of the particles in the dissolution fluid comprises: mixing the dissolution liquid with an inhibitor and then measuring the particle size of the particles; the inhibitor is preferably glycerol, propylene glycol, polyethylene glycol 400 or kerosene;
optionally, the volume ratio of the dissolution liquid to the inhibitor is 5-10:100-150, preferably 5-10: 100.
Optionally, the dissolution fluid samples are mixed after sampling from the upper, middle and lower positions in the dissolution medium.
Optionally, the method for rapidly detecting the dissolution rate of the solid preparation further comprises: placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the size of the solid preparation in the dissolution medium at a specified time to obtain the size of the solid preparation with known qualified dissolution rate; obtaining the size of the solid preparation to be measured according to the method which is the same as the method for measuring the size of the solid preparation with the known dissolution rate; comparing the size of the solid preparation to be tested with the size of the solid preparation with known qualified dissolution rate.
Optionally, in the method for rapidly detecting the dissolution rate of the solid preparation, a basket method or a paddle method is adopted for detection, and the rotating speed of a rotating basket or a stirring paddle is 150-200 rpm.
Optionally, in the method for rapidly detecting the dissolution rate of the solid preparation, the temperature of the dissolution medium is controlled to be 40-50 ℃, preferably 40-45 ℃.
The embodiment of the invention also provides a method for rapidly detecting the dissolution curve of the solid preparation, which comprises the following steps:
placing the control solid preparation in a dissolution medium, and measuring at different time points to obtain the particle sizes of the control solid preparation in the dissolution medium at different time points; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate; preferably, the content of sodium dodecylbenzene sulfonate or sodium dodecyl sulfate in the dissolution medium is 0.5 wt% -5 wt%, more preferably 1 wt% -4 wt%;
according to the same method, the particle sizes of the solid preparation to be tested at different time points in the dissolution medium are obtained;
and comparing the particle size and the particle size change of the preparation to be tested with the particle size change of the control preparation, and analyzing the dissolution behavior of the preparation to be tested and the control preparation.
Optionally, wherein the method of determining particle size comprises: mixing the dissolution liquid with an inhibitor and then measuring the particle size of the particles; the inhibitor is preferably glycerol, propylene glycol, polyethylene glycol 400 or kerosene;
optionally, the volume ratio of the dissolution liquid to the inhibitor is 5-10:100-150, preferably 5-10: 100.
Optionally, wherein the samples are taken from upper, middle and lower positions in the dissolution medium and mixed to form a dissolution fluid sample.
Optionally, the method for rapidly detecting a dissolution curve of a solid preparation further includes: measuring at different time points to respectively obtain the sizes of the control solid preparation and the solid preparation to be measured at different time points in the dissolution medium; and comparing the sizes of the test formulation and the control formulation, and analyzing the dissolution behavior of the two.
Optionally, wherein the detecting is performed by a basket method or a paddle method, the rotating speed of the rotating basket or the stirring paddle is 150rpm-200 rpm.
Optionally, wherein the temperature of the dissolution medium is controlled to be in the range of 40-50 ℃, preferably 40-45 ℃.
Optionally, the pH value of the dissolution medium is adjusted to 1.0-6.8.
Optionally, wherein, when the control solid preparation and the solid preparation to be tested are capsules, the used dissolution medium is artificial gastric juice.
Detailed Description
The solid preparation includes tablets, capsules and the like. The dissolution process of tablets is generally classified as "disintegrating type", "dissolving type", or a combination of both. The disintegrating type is that the tablet is gradually disintegrated into granules from a complete tablet in a dissolution cup, and the medicine is gradually released and dissolved from small granules; the dissolution type is that the tablet keeps an intact state in a dissolution cup, the outer layer of the tablet is gradually stripped and the tablet core is gradually reduced along with the time, and the medicine is dissolved after being stripped from the tablet framework. The dissolution process of a capsule is usually such that after dissolution of the capsule shell, the contents are released from the capsule and the drug is gradually dissolved from the content particles/pellets.
The present inventors have found in practice that, for the above solid formulation, when measured according to a prescribed dissolution method (e.g., chinese pharmacopoeia 2020 edition); the particle size of the granules in the dissolution liquid gradually becomes smaller with the lapse of the measurement time, and the dissolution amount of the drug in the dissolution liquid has a correlation with the particle size of the granules in the dissolution liquid. The dissolution behavior of the drug in the dissolution medium can thus be reflected by determining the particle size of the particles in the dissolution fluid. Thus, the amount of the drug dissolved in the dissolution liquid does not need to be detected, thereby simplifying the detection method and saving the detection time.
Specifically, the embodiment of the invention provides a method for rapidly detecting the dissolution rate of a solid preparation, which comprises the following steps:
providing a solid formulation that is known to be dissolution-eligible;
providing a dissolution medium; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate;
placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the particle size of the particles in the dissolution liquid at a specified time to obtain the particle size of the solid preparation with the known qualified dissolution rate;
providing a solid preparation to be tested;
obtaining the particle size of the solid preparation to be measured according to the method same as the method for measuring the particle size of the solid preparation with the known dissolution rate qualification;
and comparing the particle size of the solid preparation to be tested with the particle size of the solid preparation with known qualified dissolution rate.
Furthermore, the dissolution medium is prepared by taking the dissolution medium corresponding to the dissolution rate of the solid preparation with the known dissolution rate qualification, and then adding sodium dodecyl benzene sulfonate or sodium dodecyl sulfate.
In some embodiments, if not specifically indicated, reference may be made to the chinese pharmacopoeia methods, e.g., the chinese pharmacopoeia 2020 edition.
In some embodiments, the dissolution medium used, the specified time, may be in accordance with the corresponding specification for the solid formulation being tested, e.g., the chinese pharmacopoeia 2020 edition.
In some embodiments, the dissolution medium used is water, acetate buffer solution (ph4.5), phosphate buffer solution (ph6.8), or phosphate buffer solution (ph7.2), and the dissolution medium further comprises sodium dodecylbenzenesulfonate or sodium dodecylsulfate.
In some embodiments, the particle size of the drug in the dissolution fluid can be detected by laser particle size distribution assay.
The inventors found in practice that when the particle size of the solid preparation is measured by simply using the dissolution medium corresponding to the dissolution rate of the solid preparation with the known dissolution rate, the particle aggregation occurs in the dissolution medium, so that the detection result on the particle size is higher, and the accuracy of the detection result is influenced. In order to solve the technical problem, the inventors surprisingly found that the addition of sodium dodecylbenzene sulfonate or sodium dodecyl sulfate to the corresponding dissolution medium can prevent the particles from agglomerating in the dissolution medium, thereby making the detection result more accurate.
In some embodiments, the amount of sodium dodecylbenzene sulfonate or sodium dodecyl sulfate in the dissolution medium may be determined by the particular dissolution medium and type of solid formulation; for example, typically the sodium dodecylbenzene sulfonate or sodium dodecyl sulfate is present in the dissolution medium in an amount of 0.5 wt% to 5 wt%, specifically, for example, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, or 5 wt%. In some embodiments, the sodium dodecylbenzene sulfonate or sodium dodecyl sulfate content of the dissolution medium is 1 wt% to 4 wt%
In some embodiments, the particle size is measured by removing an appropriate amount of dissolution fluid from the dissolution medium at a specified time point and measuring the particle size of the particles in the dissolution fluid. During the test, the particles in the dissolution medium or dissolution fluid are in the process of dynamic dissolution, and therefore need to be tested as soon as possible to prevent deviations. The inventors have further found that some inhibitor may be added to inhibit further dissolution of the particles. This further improves the accuracy of the detection results and also allows the particles to remain substantially undissolved for a longer period of time (e.g., at least 20min), ensuring adequate detection time and reducing detection errors. The optional inhibitor comprises glycerol, propylene glycol, polyethylene glycol 400, kerosene, wherein preferred is glycerol.
In some embodiments, an amount of dissolution fluid is removed from the dissolution medium at a specified time point and added to an amount of the inhibitor (preferably after mixing) to determine the particle size of the particles. The ratio of the dissolution liquid to the inhibitor may be determined depending on the specific dissolution medium (dissolution liquid), the type of the solid preparation, and the inhibitor used. For example, typically 5-10ml of the dissolution liquid can be taken and added to 100-150ml of the above-mentioned inhibitor before the particle size is determined. That is, the volume ratio of the dissolution liquid to the inhibitor can be 5-10:100-150, such as 5-10: 100.
The inventors have also made some studies to make the sampling representative, considering that the particles in the dissolution medium (dissolution cup) are not a homogeneous system per se.
In some embodiments, sampling may be from a specific location in the dissolution media (dissolution cup), which may reduce errors due to sampling.
In some embodiments, the samples can be taken from upper, middle, and lower positions in the dissolution media (dissolution cup) and mixed as a dissolution fluid sample, thereby reducing errors.
In some embodiments, the particle size of the solid preparation to be tested is compared with the particle size of the solid preparation with known qualified dissolution rate, and if the relative deviation does not exceed 30-50%, the solid preparation to be tested can be judged to be qualified in dissolution rate; otherwise, the dissolution rate of the solid preparation to be detected is judged to be unqualified.
The relative deviation, as described herein, is calculated as follows:
relative deviation% ([ (control sample detection value-sample detection value to be detected)/control sample detection value ] × 100%
The method for rapidly detecting the dissolution rate of the solid preparation provided by the embodiment is suitable for disintegrating tablets, and is also suitable for capsules and granules.
In some embodiments, if the solid preparation to be tested is an erosion type tablet or a combination of erosion type and disintegration type tablet, in order to further improve the accuracy of the dissolution test result, the test method further comprises: placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the size of the solid preparation in the dissolution medium at a specified time to obtain the size of the solid preparation with known qualified dissolution rate;
obtaining the size of the solid preparation to be measured according to the method which is the same as the method for measuring the size of the solid preparation with the known dissolution rate;
comparing the size of the solid preparation to be tested with the size of the solid preparation with known qualified dissolution rate.
In some embodiments, comparing the size of the solid preparation to be tested with the size of the solid preparation with known qualified dissolution rate, and if the relative deviation does not exceed 20-50%, determining that the dissolution rate of the solid preparation to be tested is qualified; otherwise, the dissolution rate of the solid preparation to be detected is judged to be unqualified.
In some embodiments, for a circular sheet, the dimensions include a diameter and a thickness; for a shaped sheet, the dimensions include length, width, and thickness.
In some embodiments, in determining the particle size and size of the solid formulation in the dissolution medium (dissolution liquid), the basket method or paddle method may be used, see in particular the chinese pharmacopoeia 2020 edition.
In determining the particle size of solid formulations in dissolution media (dissolution fluids), the pharmacopoeia generally requires a rotating basket/paddle speed of 50-100 rpm. In some embodiments, the rotation speed of the dissolution rotary basket/stirring paddle is suitably increased to 150rpm-200rpm, so that the drug dissolution speed can be increased, the detection period can be further shortened, and the detection efficiency can be improved. It was found that if the agitation speed is higher than 200rpm, it is easy to cause rapid drug release, which decreases the discrimination power of the method of the examples herein.
In the measurement of the particle size of a solid preparation in a dissolution medium (dissolution liquid), the dissolution medium temperature is required to be 37 ℃ in general pharmacopoeia. In some embodiments herein, it may be appropriate to increase the temperature of the dissolution medium to 40-50℃, preferably 40-45℃. Therefore, the dissolving speed of the medicine can be improved, the detection period is further shortened, and the detection efficiency is improved. It was found that temperatures above 50 ℃ tend to result in rapid drug release, reducing the discriminatory power of the methods of the examples herein.
In some embodiments, in determining the particle size of the solid formulation in the dissolution medium (dissolution liquid), it is suitable to adjust the dissolution medium to a pH value of 1.0 to 6.8.
In some embodiments, for capsule testing, the dissolution medium used is artificial gastric fluid. In some embodiments, diluted hydrochloric acid 16.4ml, water about 800ml and pepsin 10g are added, shaken up, and then diluted with water to 1000ml to prepare the artificial gastric juice.
In the production process of the solid preparation, the method for rapidly detecting the dissolution rate of the solid preparation provided by the embodiment can simply, conveniently and rapidly control the quality of the solid preparation.
The method for rapidly detecting the dissolution rate of the solid preparation provided by the embodiment can be used for evaluating the quality consistency among drug batches, guiding the research and development of new preparations and confirming the consistency of the quality and the curative effect of the drugs after certain changes (such as prescription, production process, production site change and production process amplification) of the drugs.
During the development of the imitation drug, it is necessary to establish a dissolution profile method and to make the dissolution behavior of the imitation preparation consistent with that of the control preparation. The whole research and development cost and the research and development period of the imitation drugs are greatly improved.
Sustained release preparations are preparations which can release the drug continuously over a long period of time after administration. Compared with the common preparation, the sustained-release preparation can prolong the duration of treatment action, reduce toxic and side effects, reduce the times of medication and improve the compliance of medication. Therefore, the in vitro release degree is an important index for the process screening of the sustained release preparation prescription.
How to comprehensively and rapidly evaluate the in-vitro dissolution behavior of the solid preparation in the research and development process needs a rapid, visual, cheap and simple detection method, shortens the research and development period of the imitation drugs, and reduces the research and development cost.
The embodiment of the invention also provides a method for rapidly detecting the dissolution curve of the solid preparation, which comprises the following steps:
placing the control solid preparation in a dissolution medium, and measuring at different time points to obtain the particle sizes of the control solid preparation in the dissolution medium at different time points; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate;
obtaining the particle sizes of the solid preparation to be tested at different time points in the dissolution medium according to the same method (namely, the same method for measuring the particle size of the control solid preparation);
and comparing the particle size and the particle size change of the preparation to be tested with the particle size change of the control preparation, and analyzing the dissolution behavior of the preparation to be tested and the control preparation.
Wherein, if the reference solid preparation and the solid preparation to be tested are dissolution type tablets or dissolution type and disintegration type combined tablets, the method preferably also comprises the steps of measuring at different time points, and respectively obtaining the sizes (tablet cores) of the reference solid preparation and the solid preparation to be tested at different time points in the dissolution medium; and comparing said sizes (tablet cores) of the test preparation and the control preparation, analyzing the dissolution behavior of both. This can further improve the accuracy of the detection result.
In some embodiments, the development of the imitation drug prescription and preparation process can be guided according to the dissolution behaviors of the preparation to be tested and the control preparation.
In some embodiments, when the particle size is measured, if the control preparation and the preparation to be tested are tablets or capsules, the detection time points for the quick release preparation are 5min, 10min, 15min, 20min, 30min, 45min, 60min and 120 min; the detection time points for the sustained release preparation are 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h and 24 h.
In some embodiments, the detection time points for the immediate release formulation are 5min, 10min, 15min, 20min, 30min, 45min, 60min, 120min if the control formulation and the formulation to be tested are tablets when measuring the size; the detection time points for the sustained release preparation are 30min, 1h, 2h, 4h, 6h, 8h, 10h and 12 h.
Other conditions in the rapid detection method of the dissolution curve can be found in the rapid detection method of the dissolution rate of the solid preparation.
In some embodiments, the dissolution behavior of the dummy formulation can be determined to be consistent by comparing the particle size difference between the two formulations, or by further comparing the size difference between the two formulations.
In some embodiments, if the relative deviation of the particle sizes of the two initial and final time points of the preparation to be tested (e.g. the dummy preparation) and the control preparation exceeds 50%, and the relative deviation of the particle sizes of the middle time points exceeds 30%, it indicates that there is a difference in the dissolution behaviors of the control preparation and the preparation to be tested, and the prescription or process needs to be adjusted; otherwise, the dissolution behaviors of the two are judged to be basically consistent.
In some embodiments, if the relative size deviation of the test preparation (e.g., the dummy preparation) and the control preparation and the relative size deviation of the start time point and the end time point exceeds 50%, and the relative size deviation of the middle time point exceeds 20%, it indicates that the dissolution behavior of the dummy preparation and the control preparation is different, and the prescription or process needs to be adjusted; otherwise, the dissolution behaviors of the two are judged to be basically consistent.
In some embodiments, the solid formulation comprises temozolomide capsules, indomethacin sustained release tablets, megestrol acetate tablets, metoprolol succinate sustained release tablets.
The detection method provided by the embodiment evaluates the dissolution behavior of the product more quickly, simply, conveniently and intuitively by measuring the particle sizes of the solid preparation at different dissolution times or further combining with measuring the size change of the tablet core, and guides the development of the prescription process in the research and development process of the solid preparation imitation drugs. Meanwhile, the method of the embodiment can also be applied to the rapid monitoring of the production process of the solid preparation, thereby improving the production efficiency and reducing the inspection and production cost.
Further details are provided below in conjunction with specific embodiments for the understanding of those skilled in the art.
Hereinafter, unless otherwise specified, it is necessary to replenish the same dissolution medium at the same temperature and in the same volume in time after the dissolution liquid is taken out.
Example 1
1) Taking 1 temozolomide capsule batch, detecting dissolution according to the method of Chinese pharmacopoeia 2020, taking 500ml of water as dissolution medium, basket method, rotating speed 50rpm, operating according to the method, taking 10ml of dissolution liquid at 30min, filtering, taking subsequent filtrate as test solution, measuring absorbance at 330nm wavelength according to ultraviolet spectrophotometry, and calculating dissolution amount of each capsule, wherein the limit is 80% of labeled amount. The detection result is 91%, and the requirements of pharmacopoeia are met.
And taking temozolomide capsules of the same batch as the step, and detecting according to the method, wherein the difference is only that: dissolving medium water also contains 1.0 wt% sodium dodecyl benzene sulfonate, the rotating speed of the rotary basket is increased from 50rpm to 150rpm, the temperature of the dissolving medium is increased from 37 ℃ to 45 ℃, 10ml of dissolving liquid taken out from the bottom of the dissolving cup is added into 100ml of glycerin, the particle size is rapidly detected by adopting a laser particle size method, and the particle size (D) is obtained when the particle size is 15min90) Is 227 micrometers.
2) Taking batch 2 temozolomide capsules, detecting the dissolution rate according to a method of Chinese pharmacopoeia 2020, taking 500ml of water as a dissolution medium, basket method, rotating speed of 50rpm, operating according to the method, taking 10ml of dissolution liquid after 30min, filtering, taking subsequent filtrate as a test solution, measuring absorbance at a wavelength of 330nm by an ultraviolet spectrophotometry, and calculating the dissolution amount of each capsule, wherein the limit is 80% of the marked amount. The detection result is 71%, which does not meet the requirements of pharmacopoeia.
Then taking temozolomide capsules of the same batch as the step, detecting according to the method, wherein the difference is that the dissolution medium water also contains 1.0 wt% of sodium dodecyl benzene sulfonate, the rotating speed of a rotating basket is increased from 50rpm to 150rpm,the temperature of dissolution medium is increased from 37 deg.C to 45 deg.C, 10ml of dissolution liquid taken out from the bottom of dissolution cup is added into 100ml of glycerol, and the particle size is rapidly detected by laser particle size method to obtain particle size (D) at 15min90) Is 314 microns.
3) Compared with the results, the temozolomide capsules of the batch 1 in the step 1) meet the dissolution rate requirement of pharmacopoeia, and the particle size (D) of the particles in the dissolution liquid90) Is 227 microns; the temozolomide capsules of batch 2 in the step 2) do not meet the requirement of dissolution rate of pharmacopoeia, and the particle size (D) of particles in dissolution liquid90) Is 314 microns.
From this, it can be judged that the particle diameter (D) of the particles in the dissolution liquid was 15min90) When the dissolution rate of the product is more than 300 microns, the dissolution rate of the product for 30min does not meet the requirements of pharmacopoeia; the particle diameter of the granules in the solution is 15min (D)90) When the dissolution rate is not more than 250 microns, the dissolution rate of the product meets the requirements of pharmacopoeia. The result shows that the method of the embodiment is similar to the pharmacopoeia method, but the method of the embodiment is simpler and has shorter detection time.
Example 2
1) Taking batch 1 indomethacin sustained release tablets, detecting the dissolution rate according to the method of Chinese pharmacopoeia 2020, taking the product, according to the determination method of dissolution rate and release rate (general rule 0931 second method), taking 500ml of phosphate buffer solution (pH7.2) as dissolution medium, rotating at 100rpm, operating according to the method, taking 5ml of dissolution liquid after 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours respectively, filtering, and taking the subsequent filtrate of 2 hours, 4 hours, 6 hours and 8 hours as the test solution (I); precisely measuring 3ml of each of the subsequent filtrates for 12 hr and 20 hr, respectively placing into 10ml measuring bottles, diluting with dissolution medium to scale, and shaking to obtain sample solution (II); precisely weighing about 25mg of indomethacin reference substance, placing into a 100ml measuring flask, adding 0.5ml of tetrahydrofuran for dissolving, diluting with dissolution medium to scale, shaking, precisely weighing 5ml, placing into a 50ml measuring flask, diluting with dissolution medium to scale, and shaking to obtain reference substance solution. Taking the reference solution, the sample solution (I) and the sample solution (n), measuring absorbance at 320nm wavelength by ultraviolet-visible spectrophotometry (on 0401), and calculating the elution amount of each tablet at different time. The dissolution amount of each tablet of the product in 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours is respectively 15-30%, 30-50%, 40-65%, 50-80%, 70-95% and more than 80% of the marked amount, and the dissolution amount meets the requirements. The results are shown in Table 1 below.
Another batch of 1 indomethacin sustained release tablets is taken and tested according to the method of the pharmacopoeia, and the difference is that 1.0 wt% of sodium dodecyl benzene sulfonate is added into a phosphate buffer solution of a dissolution medium, 10ml of dissolution liquid is taken out from the bottom of the dissolution cup and added into 100ml of glycerol after 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours, the particle size is rapidly detected, and the result is shown in the following table 1.
2) Taking a batch of 2 indomethacin sustained-release tablets, and carrying out determination according to the method of the pharmacopoeia in the step 1), wherein the difference is only that 1.0% of sodium dodecyl benzene sulfonate is added into a phosphate buffer solution of a dissolution medium, 10ml of dissolution liquid is taken out from the bottom of a dissolution cup and added into 100ml of glycerol after 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours, the particle size is rapidly detected, and the result is shown in the following table 1.
TABLE 1
| Sample (I) | Detecting items | 2 hours | 4 hours | 6 hours | 8 hours | 12 hours | 20 hours |
| Batch 1 | Dissolution rate | 28％ | 55％ | 72％ | 88％ | 98％ | 98％ |
| Batch 1 | Particle size (D)90) | 44μm | 87μm | 123μm | 136μm | 98μm | 93μm |
| Batch 2 | Dissolution rate | 22％ | 43％ | 55％ | 74％ | 87％ | 96％ |
| Batch 2 | Particle size (D)90) | 36μm | 79μm | 90μm | 120μm | 116μm | 97μm |
3) Results compare the correlation between the particle size of insoluble particles in the dissolution medium and dissolution rate; with the increase of the elution amount, the particle size is increased and then decreased, and finally, the particle size is kept unchanged. The result shows that the method of the embodiment is similar to the pharmacopoeia method, but the method of the embodiment is simpler and has shorter detection time.
4) Another batch of 1 indomethacin sustained release tablets is taken and tested according to the method of the pharmacopoeia in the step 1), the difference is only that 1.0 wt% of sodium dodecyl benzene sulfonate is added into the phosphate buffer solution of the dissolution medium, and the tablet core size (diameter) is respectively measured after 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours, and the result is shown in the following table 2.
5) And detecting batches of 2 indomethacin sustained-release tablets by the same method as the step 4), and measuring the tablet core sizes of the indomethacin sustained-release tablets after 2 hours, 4 hours, 6 hours, 8 hours, 12 hours and 20 hours respectively, wherein the results are shown in the following table 2.
TABLE 2
| Sample (I) | Detecting items | 2 hours | 4 hours | 6 hours | 8 hours | 12 hours | 20 hours |
| Batch 1 | Dissolution rate | 28％ | 55％ | 72％ | 88％ | 98％ | 98％ |
| Batch 1 | Core diameter of the tablet | 8.5mm | 6.7mm | 4.8mm | 2.0mm | 0mm | 0mm |
| Batch 2 | Dissolution rate | 22％ | 43％ | 55％ | 74％ | 87％ | 96％ |
| Batch 2 | Core diameter of the tablet | 8.7mm | 7.7mm | 6.9mm | 4.7mm | 1.9mm | 0mm |
6) Results comparison, the decrease in tablet core diameter correlated with the increase in dissolution; the diameter of the tablet core is about 9mm, the drug dissolution is about 20%, the diameter of the tablet core is about 7mm, the drug dissolution is about 50%, the diameter of the tablet core is about 5mm, the drug dissolution is about 70%, and the diameter of the tablet core is about 2mm, the drug dissolution is about 90%. The result shows that the method of the embodiment is similar to the pharmacopoeia method, but the method of the embodiment is simpler and has shorter detection time.
Example 3
S1, megestrol acetate tablet control preparation particle size: taking a megestrol acetate tablet contrast preparation, taking 900ml of lauryl sodium sulfate aqueous solution containing 1 wt% as a dissolution medium according to a determined dissolution curve analysis method (2020 edition of Chinese pharmacopoeia), taking 10ml of dissolution liquid out of the bottom of a dissolution cup at the temperature of 37 ℃ and the rotating speed of 150rpm of a paddle method for 5min, 10min, 15min, 20min, 30min, 45min and 60min respectively, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by a laser particle size detection method;
s2, megestrol acetate tablet control formulation tablet core size: taking a megestrol acetate tablet control preparation, taking 900ml of aqueous solution containing 1 wt% of sodium dodecyl sulfate as a dissolution medium according to a determined dissolution curve analysis method (2020 edition) and measuring the size of the dissolution medium at 37 ℃ and 150rpm by a paddle method at 5min, 10min and 15min respectively, wherein the tablet is completely disintegrated at 20min and later, and is not measured any more;
s3, megestrol acetate tablet imitation preparation particle size: taking a megestrol acetate tablet contrast preparation, taking 900ml of lauryl sodium sulfate aqueous solution containing 1 wt% as a medium according to a determined dissolution curve analysis method (2020 edition of Chinese pharmacopoeia), taking 10ml of dissolution liquid out of the bottom of a dissolution cup at the temperature of 37 ℃ and the rotating speed of 150rpm by a paddle method for 5min, 10min, 15min, 20min, 30min, 45min and 60min respectively, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by a laser particle size detection method;
s4, megestrol acetate tablet imitation preparation core size: taking a megestrol acetate tablet imitation preparation, taking 900ml of lauryl sodium sulfate aqueous solution containing 1 wt% as a medium according to a determined dissolution curve analysis method (2020 edition of Chinese pharmacopoeia), measuring the size of the dissolution medium at 37 ℃ and 150rpm by a paddle method at the rotating speed of 20min for 5min, 10min, 15min and 20min respectively, and completely disintegrating the tablet at 30min and later time points without measuring;
s5, judging the result: comparing the particle size and the tablet core size of the megestrol acetate tablet imitation preparation and the control preparation, and analyzing the difference of the dissolution behaviors of the megestrol acetate tablet imitation preparation and the control preparation, wherein the difference is shown in the following tables 3 and 4:
TABLE 3 dissolution curves of two megestrol acetate tablets with different time particle diameters (D)90)
| Sample (I) | 5min | 10min | 15min | 20min | 30min | 45min | 60min |
| Control formulation | 10μm | 32μm | 75μm | 69μm | 58μm | 49μm | 20μm |
| Imitation preparation | 8μm | 29μm | 68μm | 72μm | 69μm | 60μm | 52μm |
| Relative deviation of | 20.0％ | 9.3％ | 9.3％ | 4.3％ | 19.0％ | 22.4％ | 160.0％ |
TABLE 4 dissolution curves of two megestrol acetate tablets at different time tablet core diameters
| Sample (I) | 5min | 10min | 15min | 20min |
| Control formulation | 9.1mm | 5.2mm | 2.3mm | / |
| Imitation preparation | 9.4mm | 6.5mm | 4.2mm | 1.9mm |
| Relative deviation of | -3.3％ | -25.0％ | -82.6％ | / |
It can be seen that the granules of the dummy preparation after disintegration at the same time point in the dissolution cup are different from the control preparation, and the diameters of the tablet cores are all larger than those of the control preparation. The disintegration time of the tablet core is delayed compared with that of the contrast preparation, and the dissolution speed of the imitation preparation is deduced to be slower than that of the contrast preparation. It is suggested that the dissolution behavior of the product should be improved by increasing the amount of disintegrant in the prescription or decreasing the core hardness during the development of the prescription process.
Comparative example 1
The control preparation and the imitation preparation of the example 3 are taken and detected according to the dissolution curve analysis method of the step S1 of the example 3, the samples are respectively sampled from the dissolution cup for 5min, 10min, 15min, 20min, 30min, 45min and 60min, and the content of the active ingredients in the liquid medicine is detected by an ultraviolet spectrophotometer, which is shown in the following table 5.
TABLE 5
The results show that the dissolution rate of the dummy formulation is slower than that of the control formulation. The detection result is basically consistent with that of the embodiment 3, but the method of the embodiment 3 is faster and simpler.
Example 4
S1, particle size of temozolomide capsule control preparation: taking a temozolomide capsule control preparation, taking 500ml of aqueous solution containing 1.0 wt% of sodium dodecyl sulfate as a medium according to a determined dissolution curve analysis method (2020 edition) and taking 10ml of dissolution liquid from the bottom of a dissolution cup at the temperature of 45 ℃ and the basket method rotating speed of 150rpm for 5min, 10min, 15min, 20min, 30min, 45min and 60min respectively according to the determined dissolution curve analysis method, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by adopting a laser particle size method;
s2, particle size of temozolomide capsule imitation preparation: taking a temozolomide capsule imitation preparation, taking 500ml of aqueous solution containing 1.0 wt% of sodium dodecyl sulfate as a medium according to a determined dissolution curve analysis method (2020 edition of Chinese pharmacopoeia), taking 10ml of dissolution liquid from the bottom of a dissolution cup at the temperature of 45 ℃, a basket method and the rotating speed of 150rpm respectively for 5min, 10min, 15min, 20min, 30min, 45min and 60min, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by adopting a laser particle size method;
s3, judging the result: the temozolomide capsule imitation preparation and the control preparation are subjected to particle size comparison, and the difference of the dissolution behaviors of the temozolomide capsule imitation preparation and the control preparation is analyzed, as shown in the following table 6:
TABLE 6 particle size (D) of two temozolomide capsules at different times of dissolution curve90)
| Sample (I) | 5min | 10min | 15min | 20min | 30min | 45min | 60min |
| Control formulation | 89μm | 137μm | 221μm | 214μm | 201μm | 132μm | 91μm |
| Imitation preparation | 82μm | 142μm | 228μm | 219μm | 219μm | 147μm | 79μm |
| Relative deviation of | 7.9％ | 3.6％ | 3.1％ | 2.3％ | 9.0％ | 11.4％ | 13.2％ |
As can be seen, the difference between the granules of the simulated preparation after the content of the dispensing capsule is disintegrated in the same time in the dissolution cup and the granules of the control preparation is within 15 percent. Suggesting that the dissolution behavior of the simulated preparation is basically consistent with that of the comparative preparation.
Example 5
S1, the particle size of the metoprolol succinate sustained-release tablet control preparation: taking a metoprolol succinate sustained-release tablet control preparation, taking 900ml of phosphate buffer solution containing 1.2 wt% of sodium dodecyl sulfate and having pH6.8 as a medium according to a determined dissolution curve analysis method (2020 edition), taking 5ml of dissolution liquid out of the upper part, the middle part and the lower part of a dissolution cup respectively at the temperature of 50 ℃ and the rotating speed of 200rpm of a paddle method for 30min, 1h, 2h, 4h, 6h, 8h, 10h and 12h, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by a laser particle size determination method;
s2, metoprolol succinate sustained release tablet control preparation core size: taking a metoprolol succinate sustained-release tablet control preparation, and measuring the size of the metoprolol succinate sustained-release tablet control preparation in 30min, 1h, 2h, 4h, 6h, 8h, 10h and 12h respectively by taking 900ml of phosphate buffer solution containing 1.2 wt% of sodium dodecyl sulfate and having pH6.8 as a medium according to a determined dissolution curve analysis method, wherein the temperature of the dissolution medium is 50 ℃, and the rotating speed of a paddle method is 200 rpm;
s3, the particle size of the metoprolol succinate sustained-release tablet imitation preparation is as follows: taking a metoprolol succinate sustained-release tablet control preparation, taking 900ml of phosphate buffer solution containing 1.2 wt% of sodium dodecyl sulfate and having pH6.8 as a medium according to a determined dissolution curve analysis method, taking 5ml of dissolution liquid from the upper part, the middle part and the lower part of a dissolution cup respectively at the temperature of 50 ℃ and the rotating speed of 200rpm of a paddle method for 30min, 1h, 2h, 4h, 6h, 8h, 10h and 12h, adding the dissolution liquid into 100ml of glycerol, keeping stirring, and rapidly detecting the particle size by a laser particle size measurement method;
s4, the tablet core size of the metoprolol succinate sustained-release tablet is as follows: taking a metoprolol succinate sustained-release tablet imitation preparation, and measuring the size of the metoprolol succinate sustained-release tablet imitation preparation in 30min, 1h, 2h, 4h, 6h, 8h, 10h and 12h respectively by taking 900ml of phosphate buffer solution containing 1.2 wt% of sodium dodecyl sulfate and having pH6.8 as a medium according to a determined dissolution curve analysis method, wherein the temperature of the dissolution medium is 50 ℃, and the rotation speed of a paddle method is 200 rpm;
s5, judging the result: the metoprolol succinate sustained-release tablet imitation preparation and the control preparation are compared in particle size distribution and tablet core size, and the difference of the dissolution behaviors of the metoprolol succinate sustained-release tablet imitation preparation and the control preparation is analyzed, as shown in the following tables 7 and 8:
TABLE 7 particle size of the particles (D) at different times in the dissolution curves of two metoprolol succinate sustained-release tablets90)
| Sample (I) | 30min | 1h | 2h | 4h | 6h | 8h | 10h | 12h |
| Control formulation | 34μm | 52μm | 81μm | 105μm | 184μm | 192μm | 236μm | 239μm |
| Imitation preparation | 49μm | 59μm | 73μm | 111μm | 209μm | 227μm | 253μm | 244μm |
| Relative deviation of | 44.1％ | 13.5％ | 9.9％ | 5.7％ | 13.6％ | 18.2％ | 7.2％ | 2.1％ |
TABLE 8 core diameters at different times of dissolution curves of two metoprolol succinate sustained-release tablets
| Sample (I) | 30min | 1h | 2h | 4h | 6h | 8h | 10h | 12h |
| Control formulation | 7.0mm | 6.2mm | 5.8mm | 4.5mm | 3.1mm | 2.0mm | 1.2mm | 0mm |
| Imitation preparation | 6.8mm | 6.1mm | 5.6mm | 4.4mm | 3.1mm | 1.9mm | 1.2mm | 0mm |
| Relative deviation of | 2.9％ | 1.6％ | 3.4％ | 2.2％ | 0 | 5.0％ | 0 | 0 |
It can be seen that the granules of the dummy preparation after disintegration at the same time point in the dissolution cup are substantially the same as the control preparation, and the diameter of the tablet core is also substantially the same as the control preparation. Therefore, the dissolution behaviors of the imitation preparation and the control preparation can be judged to be basically consistent.
Experimental example 1 Effect of sodium dodecylbenzenesulfonate on particle size
Taking temozolomide capsules, detecting the dissolution rate according to a method of Chinese pharmacopoeia 2020, taking 500ml of water as a dissolution medium, basket method, rotating speed of 150rpm, the temperature of the dissolution medium of 45 ℃, operating according to the method, taking 10ml of dissolution liquid at 15min, rapidly detecting the particle size by adopting a laser particle size method, and obtaining the particle size (D) at 15min90) And 332 microns.
Taking temozolomide capsules of the same batch, detecting according to the method, wherein the difference is that the dissolution medium water also contains sodium dodecyl benzene sulfonate, taking 10ml of dissolution liquid at 15min, rapidly detecting the particle size by adopting a laser particle size method, and obtaining the particle size (D) at 15min90) See table 9 below.
TABLE 9
| The content wt% | 0 | 0.5 | 1 | 2 | 3 | 4 |
| Particle size (. mu.m) | 332 | 309 | 221 | 220 | 218 | 225 |
Note: the "content" in the table refers to the content (wt%) of sodium dodecylbenzenesulfonate in the dissolution medium.
Experimental example 2 Effect of inhibitor on particle size
Taking temozolomide capsules, detecting the dissolution rate according to a method of Chinese pharmacopoeia 2020, taking 500ml of aqueous solution containing 1% sodium dodecyl benzene sulfonate as a dissolution medium, performing basket method at the rotating speed of 150rpm and the dissolution medium temperature of 45 ℃, operating according to the method, taking 10ml of dissolution liquid after 15min, adding the dissolution liquid into glycerol with different volumes for dispersion; particle size (D) detection by laser particle size method90) The results are shown in Table 10 below.
TABLE 10 volume vs. particle size (D) of various inhibitors90) Influence of assay result (. mu.m)
Experimental example 3 influence of sampling on particle size measurement results
Taking temozolomide capsules, detecting the dissolution rate according to a method of Chinese pharmacopoeia 2020, taking 500ml of aqueous solution containing 1% sodium dodecyl benzene sulfonate as a dissolution medium, performing basket method at a rotating speed of 150rpm, operating according to the method, and sampling 15min respectively according to the following modes:
1) taking 10ml of dissolution liquid from the upper part of the dissolution cup;
2) taking 10ml of dissolution liquid from the middle part of the dissolution cup;
3) taking 10ml of dissolution liquid from the lower part of the dissolution cup;
4) 3ml of the dissolution liquid is taken from the upper part, the middle part and the lower part of the dissolution cup respectively, and the mixture is used as a sample.
Adding the above dissolved solution into 100ml glycerol respectively, dispersing, and detecting particle diameter (D) by laser particle size method90) The results are shown in Table 11 below.
TABLE 11 product vs. particle size (D) for different sampling regimes90) Influence of assay result (. mu.m)
| Sampling site | Upper part | Middle part | Lower part | Upper, middle and lower part |
| Particle size (. mu.m) | 122 | 166 | 219 | 189 |
The particles in the dissolving cup are in a suspension state heterogeneous system, most of the particles are deposited at the lower part, and the particle sizes of the particles at the upper part and the middle part are smaller. Therefore, the sampling from the upper, middle and lower three positions is mixed to be used as a sample, so that the result accuracy is higher, and the error caused by different sampling positions can be avoided.
In conclusion, the invention has at least the following beneficial effects:
1) instruments and reagents used by the method are simple and easy to obtain, and a test site has no special requirements, so that a research unit can conveniently carry out the test;
2) the rapid testing method for the dissolution curve of the embodiment of the invention has short time consumption, can be better applied to dissolution curve testing, and provides a basis for the adjustment of the prescription process of the imitation preparation;
3) the rapid testing method for the dissolution curve provided by the embodiment of the invention can judge the dissolution behavior of the tablet at different time points more intuitively, so that the adjustment direction of the prescription process is more definite and more targeted.
4) Compared with the traditional method, the rapid testing method for the dissolution curve of the embodiment of the invention has the advantages that the judgment trend is consistent, the problems that the existing testing method needs to test in a specific test field due to the special required instruments and the detection consumes long time are solved, and an effective and instant detection method is provided for the detection of the dissolution curve of the imitation preparation. And the method can also be applied to the rapid monitoring of the process of the tablet production.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (11)
1. A method for rapidly detecting the dissolution rate of a solid preparation comprises the following steps:
providing a solid formulation that is known to be dissolution-eligible;
providing a dissolution medium; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate; preferably, the content of sodium dodecylbenzene sulfonate or sodium dodecyl sulfate in the dissolution medium is 0.5 wt% -5 wt%, more preferably 1 wt% -4 wt%;
placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the particle size of the particles in the dissolution liquid at a specified time to obtain the particle size of the solid preparation with the known qualified dissolution rate;
providing a solid preparation to be tested;
obtaining the particle size of the solid preparation to be measured according to the method same as the method for measuring the particle size of the solid preparation with the known dissolution rate qualification;
and comparing the particle size of the solid preparation to be tested with the particle size of the solid preparation with known qualified dissolution rate.
2. The method for rapidly detecting the dissolution rate of the solid preparation according to claim 1, wherein the method for determining the particle size of the granules in the dissolution liquid comprises the following steps: mixing the dissolution liquid with an inhibitor and then measuring the particle size of the particles; the inhibitor is preferably glycerol, propylene glycol, polyethylene glycol 400 or kerosene;
more preferably, the volume ratio of the dissolution liquid to the inhibitor is 5-10:100-150, preferably 5-10: 100.
3. The method for rapidly detecting the dissolution rate of a solid preparation according to claim 1 or 2, wherein samples are taken from upper, middle and lower positions in the dissolution medium and then mixed to be used as a dissolution liquid sample.
4. The method for rapidly detecting the dissolution rate of the solid preparation according to claim 1, further comprising:
placing the solid formulation of known dissolution eligibility in the dissolution medium; measuring the size of the solid preparation in the dissolution medium at a specified time to obtain the size of the solid preparation with known qualified dissolution rate;
obtaining the size of the solid preparation to be measured according to the method which is the same as the method for measuring the size of the solid preparation with the known dissolution rate;
comparing the size of the solid preparation to be tested with the size of the solid preparation with known qualified dissolution rate.
5. The method for rapidly detecting the dissolution rate of the solid preparation according to any one of claims 1 to 4, wherein a basket method or a paddle method is adopted for detection, and the rotating speed of a rotating basket or a stirring paddle is 150rpm to 200 rpm; and/or the presence of a gas in the gas,
the temperature of the dissolution medium is controlled to be 40-50 deg.C, preferably 40-45 deg.C.
6. A method for rapidly detecting a dissolution curve of a solid preparation comprises the following steps:
placing the control solid preparation in a dissolution medium, and measuring at different time points to obtain the particle sizes of the control solid preparation in the dissolution medium at different time points; wherein the dissolution medium also contains sodium dodecyl benzene sulfonate or sodium dodecyl sulfate; preferably, the content of sodium dodecylbenzene sulfonate or sodium dodecyl sulfate in the dissolution medium is 0.5 wt% -5 wt%, more preferably 1 wt% -4 wt%;
according to the same method, the particle sizes of the solid preparation to be tested at different time points in the dissolution medium are obtained;
and comparing the particle size and the particle size change of the preparation to be tested with the particle size change of the control preparation, and analyzing the dissolution behavior of the preparation to be tested and the control preparation.
7. The method for rapidly testing the dissolution profile of a solid dosage form according to claim 6, wherein the method for measuring the particle size comprises: mixing the dissolution liquid with an inhibitor and then measuring the particle size of the particles; the inhibitor is preferably glycerol, propylene glycol, polyethylene glycol 400 or kerosene;
more preferably, the volume ratio of the dissolution liquid to the inhibitor is 5-10:100-150, preferably 5-10: 100.
8. The method for rapidly testing the dissolution profile of a solid preparation according to claim 6 or 7, wherein samples are taken from the upper, middle and lower positions in the dissolution medium and then mixed to obtain a dissolution liquid sample.
9. The method for rapidly testing the dissolution profile of a solid dosage form according to claim 6, further comprising: measuring at different time points to respectively obtain the sizes of the control solid preparation and the solid preparation to be measured at different time points in the dissolution medium; and comparing the sizes of the test formulation and the control formulation, and analyzing the dissolution behavior of the two.
10. The method for rapidly testing the dissolution profile of a solid preparation according to any one of claims 6 to 9, wherein the testing is carried out by a basket method or a paddle method, and the rotating speed of a rotating basket or a stirring paddle is 150rpm to 200 rpm; and/or the presence of a gas in the gas,
the temperature of the dissolution medium is controlled to be 40-50 deg.C, preferably 40-45 deg.C.
11. The method for rapidly testing the dissolution profile of a solid dosage form according to any one of claims 6 to 10, wherein the dissolution medium is adjusted to a pH of 1.0 to 6.8.
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