Questions and Answers November 2025

Margareth R. Marques, Ph.D. and Mark Liddell, Ph.D.
The following questions have been submitted by readers of Dissolution Technologies. Margareth R. Marques, Ph.D., and Mark Liddell, Ph.D., United States Pharmacopeia (USP), 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: mrm@usp.org

Q If the dissolution medium is water, which theoretically has a pH of 7 but can range between pH 5-8, should we use the theoretical pH of 7 and use pancreatin for dissolution using water as the medium or should we measure the pH for each dissolution and adjust the enzyme accordingly?
A Yes, you should confirm the actual pH of the water used as the dissolution medium, as it may change during storage. Then use the appropriate enzyme for the measured pH.

Q Is it mandatory to withdraw samples from dissolution vessels while the paddles are rotating, or is this considered just good practice, knowing that we only have one sampling timepoint?
A The text from <711> Dissolution, under Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms states: “Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, not less than 1 cm from the vessel wall.” Notice, the chapter specifies “rotating” basket or blade; meaning that the basket or paddle is in motion. It is also important to note that when sampling a suspension, the medium needs to be as homogeneous as possible.

Q If the dissolution apparatus we are using is designed to stop by default (with no paddles rotating) when withdrawing samples, would this have any impact on the dissolution test results?
A Yes. It is likely to increase the variability of the results. According to the instructions given in <711> (see previous question), the agitation should not be stopped during the sampling because you are essentially withdrawinga sample from a suspension of both dissolved and undissolved drug. The dissolution sample solution should be well-mixed. Without the mixing that results from rotation of the stirring element, the sample solution may not represent the contents of the entire vessel. We recommend that you discuss this issue with the vendor/manufacturer of the equipment.

Q In USP general chapter <1092> The Dissolution Procedure: Development and Validation, under 5.1 Specificity/Placebo Interference, what is the composition of placebo solution? One sentence says all components except the drug substance, but the following sentence specifies that the placebo is spiked with a known amount of the drug. Furthermore, the concentration of the drug used to spike the placebo is not given in the formula. Considering a spike at 100% with drug that has the same absorbance as the standard, the result will be 100%. This is in contrast with the acceptance criteria, which states: “The interference should not exceed 2%.” Can you explain the procedure for evaluation of specificity using a placebo?
A The placebo solution should contain all components present in the formulation in the same proportion as in the final product, except for the drug substance. By spiking the placebo solution with a known amount of drug substance (100% of the label claim) and comparing the ratio of the spiked placebo solution absorbance/response to that of the standard solution containing the same concentration of drug substance, one can determine the degree of interference from the components in the placebo solution. Because the placebo solution does not contain any drug substance, you are correct that under ideal circumstances the ratio of the two absorbance/ response values will be equal to 1, giving a result of 100% based on the formula provided. In circumstances where the placebo solution interferes with detection of the drug substance (in an additive or subtractive manner),the deviation from 100% should be less than 2% (i.e., 98-102%). Using this method accounts for both the interference and specificity of the analytical method.

Q Does the sampling time requirement of ± 2% include filtration as well as withdrawing the dissolution sample?
A The requirement of sampling within ± 2% of the time is to start the sampling procedure. It is not the duration of the sampling; however, it is important to separate the sample solution from dissolving particles as soon as possible to stop the dissolution process. Generally, the best practice is to filter the solution immediately after withdrawing the dissolution sample. Inconsistent filtering techniques and timing can lead to inconsistent dissolution results.

Q When sampling cannulas are introduced at the start of the dissolution test, does this have potential to impact hydrodynamics of the vessel and hence the dissolution results?
A Yes, the presence of any probe in the vessel during the dissolution test could have an impact on the hydrodynamics depending on the size and shape of the sampling probe. Changes in the hydrodynamics inside the dissolution vessel may or may not have an impact on the dissolution profile depending on the release mechanism of the dosage form in question. This impact needs to be evaluated during method development. For additional information and references, see Gao Z, Smith A. The effect of sampling cannula on in vitro dissolution testing with USP paddle method. AAPS J. 2023, 25:46. https://doi.org/10.1208/s12248-023-00813-6.

Q What is the upper and lower range of the accuracy parameter for dissolution of an extended-release tablet?
A The validation of any dissolution test method and the associated analytical procedure is done considering the entire dissolution profile and not the acceptance criteria or classification of the dosage form type. You donot need to know the acceptance criteria to validate any dissolution method. For any type of finished dosage form, the accuracy should be validated at each of the expected concentration levels. Based on the validation of the method linearity, select at least three concentrations to validate accuracy. The key parameter used to determine accuracy is percentage of recovery. The placebo solution should be spiked with standard solution at a minimum of three different concentrations. For an extended-release product, it may be necessary to determine the accuracy at additional solution concentrations. Keep in mind that it is important to include the upper limit of uniformity for the product in the linearity range.

Q If we do not use USP apparatus 1, can we skip testing of apparatus 1 during the PVT procedure for qualification of the dissolution equipment?
A Yes. If a particular dissolution test assembly is dedicated for either apparatus 1 or apparatus 2 testing, the instrument qualification need only be performed for the specific apparatus in question. Keep in mind that for dissolution assemblies that can be configured for both apparatus 1 and 2, the instrument should be labelled to indicate that the instrument is qualified for “Apparatus 1 Testing Only” or “Apparatus 2 Testing Only.”