Abnormal Analysis Of Drug Dissolution Test Data

Dissolution testing is a must for almost all non-true solution drug products. Dissolution testing is primarily used in the pharmaceutical industry as a quality control tool to monitor dosage form formulations and manufacturing processes. Most regulatory agencies consider dissolution to be a highly critical quality characteristic for most solid dosage forms.

Dissolution testing is used by regulatory agencies to provide a link in quality from critical biological batches to commercialized products. Therefore, the development and validation of dissolution tests is a key factor in ensuring the robustness and clinical relevance of the test. However, in actual work, abnormal data are often encountered. After studying the article “Specification of Drug Substances and Products __ Dissolution”, I combined the author’s own understanding to summarize the points that need attention. The following will explain from the following points.

Part 1 Instrument

In order for dissolution testing to be commonly used to control the consistency of pharmaceutical dosage forms, it is necessary to control the type of instrumentation used. USP <711> “Dissolution” describes several apparatus types used in dissolution testing. USP Apparatus 1 (basket) and Apparatus 2 (paddle) are currently the most commonly used devices for immediate-release and controlled-release dosage forms. Pharmacopoeias other than the USP, such as the Japanese Pharmacopoeia, the British Pharmacopoeia and the European Pharmacopoeia, and the Chinese Pharmacopoeia all contain Apparatus 1 and Apparatus 2 described in the USP. There are currently standard requirements for both devices. In 2016, China issued the “Guiding Principles for Mechanical Validation of Drug Dissolution Apparatus”, which shows that it is in line with international standards.

In the case of ensuring compliance with the “Guiding Principles for Mechanical Validation of Drug Dissolution Apparatus”, some special circumstances should also be paid attention to. The paddles are sometimes partially coated with Teflon. This coating can flake off and partially peel off the paddle, causing hydrodynamic flow disturbances within the vessel. The paddles may be rusted and chipped or dented; this can adversely affect the solution hydrodynamics and is a source of contamination. Some drugs have an effect on the dissolution rate in some media, such as amlodipine besylate tablets under the condition of pH 1.2, which also needs attention. Thorough cleaning of the paddles is very important to prevent contamination with drugs or media.

Baskets need careful inspection. With use, they may become worn, deformed or twisted. Screen size may change over time, especially when used in acidic media. These changes may affect dissolution results. Baskets are especially prone to accumulating gelatin or trimmings and causing contamination if not thoroughly washed immediately after use.

Vessels can become contaminated if they are not cleaned. Scratched and corroded containers after repeated cleaning should be discarded. The lid needs to be in place at all times during the dissolution process to prevent evaporation. Teacher Tang Lijuan Tang has an article “Introduction of dissolution error as a result of different openings in vessel covers” which describes in detail the influence of evaporation on dissolution rate. If you are interested, you can read it.

The vibration of the instrument should also be paid attention to. Pay attention to the maintenance and maintenance of the instrument at ordinary times to ensure smooth operation. External sources of vibration may include other equipment on the platform, such as shakers, centrifuges, or sonicators. Heavy footsteps and slamming doors should also be avoided.

Part 2 Sinker Basket

Dosage forms that tend to float or move during dissolution testing create issues with variability and biased results. Sinkers are commonly used to hold this dosage form during dissolution testing. There are many types of sinker baskets used in dissolution testing (see figure below), some homemade, some commercially available, and the type of sinker basket will affect the results. There are many settling baskets specified in USP, and various instrument companies also have commercially available settling baskets. Where sinkers are required, a detailed description of their use and the reason for their use must be submitted with the method and any regulations. When comparing different sinkers (or sinker vs. no sinker), the test must be performed simultaneously with each sinker. Each sinker type must be evaluated based on its ability to hold a dose at the bottom of the container without inhibiting drug release. The sinker will significantly affect the dissolution rate of the drug, and the comparison of different sinker types (or no sinker) should be verified in the early stage of dissolution method determination. The design of the sinker must be clearly stated in the method. When transferring methods, the sinkers must be replicated as closely as possible in any subsequent testing facility.

The use of settling baskets should meet some requirements:

Settlers should not inhibit or affect dissolution. Capsules or tablets should dissolve freely and no part of the dose should be trapped under or within the sinker.

Dosage forms should always fall to the bottom of the central dissolution container.

Results should be reproducible; variability should not be introduced by the shape of the sinker.

Shapes should be easy to define and make, preferably common.

Part 3 Robustness Of The Dissolution Method

Since dissolution testing is an integral part of drug product development, the robustness of the dissolution method is also critical. The key test parameters that determine the dissolution method are usually evaluated by making small changes to each dissolution parameter. Data evaluation will establish the necessary controls required for test parameters to maintain methodological consistency. This will facilitate any method transfer and minimize the need for troubleshooting. Robustness studies should include evaluation of the effects of different media pH, rotational speed, settling baskets (if applicable), media degassing, media surfactant levels, media temperature and filters, etc.

For drugs, the pH of the medium, the choice of medium type, and the level of surfactant in the medium are the targets that need to be investigated. Yaoshi Zongheng introduced in detail how to select the appropriate pH value, surfactant concentration, and rotational speed to ensure the robustness of the method in the article “Understand how to develop dissolution methods for new drugs to make generic drugs”. Another article “Etoricoxib as an Example: Development and Validation of Dissolution Method with Moderate Discrimination Power” is also a rare and good article to confirm the robustness of the dissolution method. It is worth learning more and applying it in practical work.

Part 4 Medium

Dissolved gases in the medium may affect dissolution rates. Air bubbles adhering to the tablet surface or to the basket screen prevent media contact and can slow down dissolution. Particles will attach to air bubbles on the glass surface of the container or shaft.

Attention should also be paid to the temperature of the medium. Some instruments can display the temperature of the liquid in each dissolution vessel. If not, it is necessary to check the temperature of the cup liquid before conducting the experiment.

If the dissolution medium contains surfactants, care should be taken when using them. First of all, there is a large quality gap between different manufacturers and different grades of surfactants, so it is necessary to screen and compare the manufacturers and grades before the method is determined. The foaming nature of surfactants also makes it difficult to effectively degas the media. When placing the basket in surfactant media, surface air bubbles may adhere to the bottom of the basket and significantly reduce the rate of dissolution. Surfactants can pose serious cleaning problems, especially when the concentration is high, such as more than 0.5%. In the sampling line during automatic sampling, surfactants such as sodium lauryl sulfate may require multiple flushes to ensure complete cleaning. remove.

The problems caused by different surfactants are not the same. The commonly used sodium lauryl sulfate is easy to control the quality, and it is easy to precipitate when it is combined with potassium salt, and it is also easy to precipitate at low temperature. The quality of Tween 80 varies greatly between batches, and the operation is not as convenient as sodium lauryl sulfate. Select the appropriate surfactant by profiling the reference formulation.

The ion concentration of the medium also needs attention. Different countries have different medium configuration methods and different ion concentrations, such as the pH6.8 buffer salt in the Japanese Pharmacopoeia and the Chinese Pharmacopoeia. “Assessing the influence of media composition and ionic strength on drug release from commercial immediate-release and enteric-coated aspirin tablets” The effect of different ionic strengths on drug release is described in detail in the article. In practical work, it may be necessary to investigate the influence of different ionic strengths.

Part 5 Observation

Accurate dissolution occurs as the product dissolves without interference from dissolution barriers or container hydrodynamics from any source. Therefore, close visual observation of the test is very important. The particle disintegration pattern must show freely dispersed particles. Abnormal dissolution usually involves one or more of the following observations: floating masses of tablets, spinning, coning, packing, sticking, swelling, capping, “clamshell” erosion, eccentric positioning, sticking, sticking of particles to On the device or cup wall, bladder, swelling/rubber mass or transparent film, slower dissolution due to aging of the gelatin capsule, etc., may also be “position dependent” during tableting. For example, if the tablet is off-center, the dissolution rate may be higher due to shear forces. It has also been reported in the literature that different casting positions cause differences in dissolution rates. Film-coated tablets can be sticky and cause problems related to tablet placement. Mr. Sun Yazhou Sun mentioned the importance of observing phenomena many times in various public occasions, even the hand feeling of the dissolved particles after the dissolution is completed. Some observed phenomena are described in detail in Mr. Sun’s “API, preparation characteristics and dissolution rate, BE correlation and case analysis”, which can be linked in actual work.

With the improvement of the industry’s awareness of dissolution, some phenomena of abnormal dissolution have been widely recognized, such as accumulation, floating, and the influence of the position of the tablet, and there are also some methods to prevent or solve them. However, the observation of dissolution phenomenon runs through the entire process of drug development and even drug life cycle management. In the early stage of the drug development process, it is necessary to observe the dissolution phenomenon of the reference preparation, understand the dissolution behavior, and even adjust the dissolution method according to the dissolution phenomenon to prevent abnormal data and inter-batch errors. In the subsequent development of generic drugs, it is necessary to carefully observe the dissolution phenomenon of the generic drug and compare it with the reference preparation, which is consistent with the dissolution phenomenon of the reference preparation. In the late stage stability test, such as capsule dosage form, the aging of gelatin capsules causes the dissolution rate to slow down, which needs to be observed emphatically. The post-marketing stability test of the drug or each change application test needs to be observed.

Part 6 Sampling And Filtration

1 Sample

There are currently two types of sampling: automatic sampling and manual sampling. Automated sampling saves effort, but can sometimes cause more problems than manual sampling. Sampling lines are often a source of errors for a variety of reasons: unequal lengths, crimps, wear beyond limits, partial or complete blockage of sampling lines, disconnections, residues, mix-ups or cross-connections, and inadequate cleaning. The pump tubing may become worn from frequent use or flushing and may need to be replaced. The automatic sampling methods of dissolution apparatus of different dissolution manufacturers are different, and there are two forms of syringe pump and piston pump. In theory, the syringe pump is better, and the pipeline is emptied after each sampling point, that is, the pipeline residue is 0, and the sampling time is shorter. The piston pump cannot completely empty the pipeline, and a large amount of medium is required to rinse the pipeline, and the sampling time is early. There are also differences in online filtration methods, including membrane filtration and filter head filtration. It is recommended to determine the appropriate method before using the automatic sampling system.

Manual sampling techniques introduce error due to differences in the strength and size of hands between analysts. The speed of pull through the filter can vary widely.

2 Filters

Filtration is a non-negligible step in the dissolution sampling process. The filtration step must be evaluated to determine whether an appropriate amount of solution has passed through the filter so that the final filtered solution is not biased by loss of drug adsorbed through the filter. Filtration is usually performed to prevent undissolved particles from entering the analytical sample and further dissolving. Care should be taken that the filter pore size is not larger than the drug particle size, which is especially important for micronized or nanoparticles. Filtration can also remove insoluble excipients that can cause high background. Validation of filters usually involves preparation of appropriate standard solutions (minimum and maximum recommended concentrations) and fully dissolved sample solutions. For standard solutions, compare the results for the filtered solution (the appropriate discard volume should be determined in advance) with the results for the unfiltered standard solution. For filtered sample solutions, the results should be compared with fully dissolved and centrifuged sample solutions. Acceptable ranges for standard and sample filtration efficiencies are typically between 98% and 102% of unfiltered standard solutions and unfiltered but centrifuged sample solutions. If there is interference in the filtering steps, it is necessary to screen different types of filters from different manufacturers and different processing methods.

In the process of generic drug research, in addition to the standard solution and sample solution that need to be investigated, the influence of the filter membrane of the reference preparation also needs to be paid attention to.

The filter membrane adsorption of the automatic sampling dissolution apparatus may be more complicated than manual sampling due to its pipeline problems, and the pipeline may adsorb and interfere with the sample. There has been an article (Interference of automatic dissolution apparatus on the determination of the release rate of nifedipine sustained-release tablets (I)) reporting that the automatic sampler interfered with the results of the dissolution rate. Therefore, it is necessary to increase the interference of pipeline adsorption for automatic sampling dissolution apparatus, and compare it with manual sampling.

Part 7 Detection

Due to the large number of samples typically generated in dissolution testing, the analytical system should be relatively fast. The most common analytical instruments used for dissolution testing are UV-Vis spectrophotometry and HPLC with UV detection. Whichever method is used, the detection method needs to be validated. It is believed that each company has its own method for dissolution method verification, so in this article, only a few important points that are easily overlooked are briefly mentioned.

1 Linear

Usually the linear concentration needs to cover the concentration range from the minimum amount detected for dissolution to 120% of the highest expected concentration. Linearity testing of dosage forms should cover the entire specification range of the product. If necessary, all samples should be heated to 37°C (or the stated dissolution temperature) prior to analysis; this is especially important if samples are near sink conditions.

Although linear verification is relatively simple, some situations cannot be ignored. For larger specifications or special drugs, the concentration range from the minimum amount of the detected dissolution rate to 120% of the highest expected concentration is not necessarily linear, and piecewise linearity can be used to solve the problem. For some drugs, the external standard one-point method may not be applicable, and a standard curve is required for each dissolution calculation.

2 Accuracy

Generally, accuracy is determined by preparing multiple samples containing the drug and other ingredients present in the dosage form (eg, excipients, coating materials, etc.). Capsule shells, paint mixtures, inks and sinkers should also be added where appropriate. For larger strengths, the order in which the drug is added to the medium before or after the excipient may be important. For example, some drugs require proper wetting in a medium without excipients, and vice versa, where the excipients need to be mixed first before being introduced into the drug. If the size is small or the drug has high static electricity, making accurate weighing difficult, it can be in the form of a solution. If necessary, all samples should be heated to 37°C (or the specified dissolution temperature) prior to analysis.

For some poorly soluble drugs, the solubility in the medium is low, and the preparation of the reference solution requires an appropriate amount of organic solvent to aid the dissolution, but the proportion of the organic solvent should not exceed 5.0%.

3 Solution Stability

Due to the large number of samples typically produced in dissolution testing, solution stability is a required experiment. Generally, both the reference substance solution and the test solution need to be investigated. The inspection time should be as long as possible to prevent special circumstances in the follow-up work. If the drug product is unstable in the medium, it can be solved in different ways. For example, the temperature control of the sample, the addition of stabilizers, or the detection of degradation products at the same time can be considered. Some medicines have different stability in different media, and it may be considered to add a pH regulator to an unstable medium to adjust to a stable pH value. It is crucial to choose a method that saves effort and time by analyzing the drug instability mode.

Part 8 Cleaning

In many laboratories where different products are tested on the same equipment, cleaning is a critical issue, and insufficient cleaning can lead to inspection failures and erroneous results. When using the Fucus FADT-1200RC dissolution apparatus, the dissolution apparatus cover is integral, and cleaning the dissolution apparatus cover is a problem that is easily overlooked. In the automatic sampling dissolution apparatus, the cleaning of the automatic sampling pipeline is also an important consideration.

Part 9 Conclusion

Dissolution profile testing plays a pivotal role in the current drug development process. The data of the dissolution curve needs to be accurate in order to give an accurate judgment on the prescription and process. Therefore, it is necessary to confirm the key parameters when performing the dissolution experiment, and conduct the experiment in an accurate “framework” to avoid giving wrong judgments.