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Questions and Answers May 2017

William Brown and Margareth Marques
The following questions have been submitted by readers of Dissolution Technologies. Margareth Marques, Ph. D. and Will Brown, United States Phamacopeia, authored responses to each of the questions.
*Note: These are opinions and interpretations of the authors, and are not necessarily the official viewpoints of the USP
Email for correspondence: web@usp.org

Q Typically, the rotation speed for USP Apparatus 2 is between 25 and 75 rpm. Can we increase this rotation speed to improve the accuracy of the dissolution method? We are working with a fixed combination product, and one of the drug substances has very low solubility in aqueous solvents.
A The dissolution test evaluates the rate of drug dissolved over time. It is destructive of the sample. Accuracy may not be the most appropriate term in the context of the rotation speed of a dissolution method. In contrast to sample preparation in an assay, dissolution test conditions are selected based on their discriminatory power and not on their ability to extract as much of the active ingredient as possible. The dissolution test should be discriminatory for the critical quality attributes of the product. If the product contains more than one active ingredient, depending on the solubility of each one of them, separate dissolution tests with different test conditions may be needed.

Q The time point in our dissolution procedure is 30 min. Can we program the automated sampler to collect the sample with the paddles still rotating or should we program the equipment to stop paddle rotation at 30 min and then collect the sample?
A The sampling should be done with the paddles rotating. The rotating paddles mix the vessel contents and are a condition of the test procedure. Sampling in dissolution testing should be done at the time specified in the method with a tolerance of ±2%. This information is in the USP General Chapter <711> Dissolution.

Q We have a dissolution method for a capsule that does not mention the use of sinkers. A new analyst ran the method without the sinkers and justified that the method did not require them. Is this correct? Is it mandatory to use sinkers in the dissolution testing of capsules?
A Sinkers can be used if the dosage form (tablet or capsule) floats or if it sticks to the vessel walls. The need to use sinkers should be evaluated during method development. As the size and shape of the sinker may have a big impact in the dissolution profile, it has to be selected in a case-by-case approach. Once a suitable sinker is selected, it has to be described in the analytical procedure with as much detail as possible (photo, drawing, catalog number, etc.).

Q My question relates to the use of surfactants in the dissolution medium for poorly water-soluble drugs. For example, the recommended dissolution method in the FDA database for posaconazole delayed-release tablets indicates the use of 0.37% polysorbate 80 in pH 6.8 buffer. If this concentration of polysorbate 80 is not sufficient to provide sink conditions or improved drug solubility to reach 100% release, is a slight increase of the polysorbate 80 content in the medium acceptable? What would be the allowable range of the surfactant content in the dissolution medium?
A The main objective of the dissolution test is to be discriminative for the critical quality attributes of the product, not to release 100% of the product label claim. The dissolution test conditions are selected in such a way that if there are any deviations in the critical quality attributes of the product, there will be differences in the product dissolution profiles. With poorly soluble drugs, individual products may have different testing conditions based on the physical characteristics of the drug substance and on the release mechanism of the dosage form. If surfactants need to be added to the dissolution medium, it is necessary to justify the type and the concentration of the surfactant used. See the paper Steps for Development of a Dissolution Test for Sparingly Water-Soluble Drug Products published in the February 2000 issue of Dissolution Technologies (dx.doi.org/10.14227/DT070100P16). A list of surfactants and solubilizing agents that have already been used in dissolution media was published in the Q&A section of the August 2005 issue of Dissolution Technologies (dx.doi.org/10.14227/DT120405P30).

Q Is it possible to have a correlation/relationship between rotations per minute with USP Apparatus 1 or 2 and dips per minute with USP Apparatus 3?
A Not as far as we know. USP Apparatus 1 (basket), 2 (paddle), and 3 (reciprocating cylinder) have different hydrodynamics. To establish any kind of correlation, it is necessary to do computer modeling of the hydrodynamics of each apparatus and confirm by dissolution testing an array of different products. Even then, any correlation may be product/release mechanism dependent.

Q We are performing the dissolution test using a sample size of 5 mL of an oral suspension and are not sure how this volume will affect the final volume of dissolution medium. The test calls for 900 mL of medium. Do we need to take into account the 5 mL of sample? If so, should we use 895 mL of dissolution medium? Or should we use 900 mL of medium and consider the actual volume of 905 mL in the calculations?
A The decision to include the volume of the sample in the final volume of dissolution medium in the vessel has to be based on experimental data obtained with the samples under evaluation. There are several cases where the product was approved without taking sample volume into consideration (e.g., USP monograph for Megestrol Acetate for Oral Suspension), and there other cases where the final volume of medium takes into account the volume of the sample (e.g., FDA Dissolution Methods Database, Carbinoxamine Maleate Suspension, 895 mL of dissolution medium plus 5 mL of the sample resulting in a final volume of 900 mL).

Q Is it mandatory to withdraw samples at ±2% of the time point when performing dissolution profiles?
A The text of the USP chapters related to dissolution (<711>) and drug release (<724>) only states that the sampling is done at the times specified in the procedure with a tolerance of ±2%. The text does not address dissolution profiles. The variability in the dissolution results has to be controlled and minimized as much as possible. Therefore, it is recommended that sampling during any type of dissolution test evaluation be done within the requirements stated in the USP general chapters. This will be very important when doing any type of dissolution profiles comparison and in developing an in vivo-in vitro correlation.

Q When dissolution testing is performed in my lab, the temperature of the water bath is measured prior to the introduction of the samples and again before the final sample is pulled. Are there any recommendations that specify taking the temperature at the end of the dissolution test?
A The USP general chapters related to dissolution and drug release do not specify when to do the temperature check. It is up to your lab to decide, but keep in mind that every time you introduce a probe in the dissolution vessel, the hydrodynamics inside the vessel is perturbed, and this perturbation may or may not interfere in the dissolution results. Therefore, the recommendation is to check the temperature of the medium in the vessel after the last sample is taken.

Q We received an inspection by the local regulatory agency, and the inspectors recommended that we do mechanical qualification before each dissolution test. Is this qualification mandatory? Which controls should be done before running each dissolution test?
A The dissolution equipment has to conform with the requirements in USP General Chapters <711> Dissolution and <724> Drug Release as part of the dissolution procedure. Beyond the requirements in <711>, USP provides additional details in the Dissolution Toolkit, http://www.usp.org/sites/default/files/usp_pdf/EN/referenceStandards/dissolution-toolkit-2.pdf. The USP Dissolution Toolkit recommends a frequency of six months for routine operational qualification and also recommends that it is done on installing, relocating, or repairing the apparatus. The local agency requires operational (mechanical) qualification more frequently. Discussions with the local regulator will help inform you of his/her expectations.

Q When performing the dissolution test as per the USP monograph for Oxycodone and Acetaminophen Tablets, is it expected that the analyst will prepare and analyze only the pooled sample? If a monograph has a Procedure for a Pooled Sample <711>, is it expected that data should be generated for individual vessels as well? Would it ever be considered appropriate to analyze only individual vessels in lieu of a pooled sample as specified in a monograph?
A The monograph dissolution procedure is the official means to determine conformance. You should be aware that the pooled dissolution procedure should produce the same result that would be obtained by mathematically averaging the results from individual vessels. Some USP monographs were revised to provide both options, single and pooled sampling. However, if the testing is performed for other purposes, sampling will depend on the purpose of the test. Note that following the pooled sampling procedure as written will lose any information about the individual units tested. Individual dosage unit results are more useful for any other purpose (dissolution profiles, investigations, etc.).

Q Dissolution testers have a number of configurations with 6-12 vessel positions in most cases. Vessels and baskets or paddles are provided for each position. My understanding is that for the performance verification test (PVT), each vessel should have unique and fixed shaft/paddle/basket assignments. During product testing, should the vessels have the same shaft/paddle/basket combination with which the PVT was carried out?
A Keeping all the parts paired (vessel, shaft, basket, or paddle) is not required by the USP General Chapter <711> Dissolution, but it is a good practice because it will facilitate any investigations.