Question and Answer Section — May 2015

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

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Q The ICH guidance Q6A, Section 2.1 Periodic or Skip Testing, indicates that for some tests (e.g., residual solvents and microbiological testing) for solid oral dosage forms, skip-testing can be applicable. Is it possible to justify skip-testing for dissolution?
A No. If the dissolution test was well-developed, it is discriminative for the critical quality attributes of the products. As these attributes may change over time and affect the release behavior of the dosage form, the dissolution test needs to be done at batch release and at each time point in the accelerated and normal stability studies.

Q Regarding the USP General Chapter <1087> Apparent Intrinsic Dissolution—Dissolution Testing Procedures for Rotating Disk and Stationary Disk, how long should the deaeration procedure be applied? We are working with a drug substance that is still under development, and we do not have large quantities available to prepare the 150-mg compact for the evaluation of intrinsic dissolution. Can we dilute the drug substance with an excipient? Also, we would like to know what the critical variables in this test are.
A The dearation procedure described in footnote 1 in this USP chapter can be used (filtration and subsequent stirring above the test temperature with the application of vacuum). A 5-min stirring time is described, but only following filtration. The medium should be deaerated immediately before use in the test. The chapter does not yet specify an amount of material needed to prepare the compact; the design of the apparatus may require 150 mg. One way of dealing with limited sample is to dilute the active ingredient with an excipient. Caution should be exercised with this approach because the combination of the drug substance with an excipient may produce a dissolution rate that is affected by an interaction between the two compounds and not strictly an attribute of the pure material. As the most valuable use of the procedures in <1087> is in the comparison of the apparent dissolution rates between two different materials representing different sources of drug substances or its preparation, both samples should be prepared with the same excipient in the same percentage. In this way, a comparison can be made, but it would be incorrect to state that the observed rate is a property of the pure drug substance. The critical variables in intrinsic dissolution are the stirring rate, the exposed surface area (apparatus diameter), the medium, temperature, and compression pressure.

Q Which apparatus can be used for the evaluation of drug release from transdermal systems?
A The apparatus that can be used in the drug release testing of transdermal systems are described in the USP General Chapter <724> Drug Release and in the European Pharmacopoeia monograph 2.9.4 Dissolution Test for Transdermal Patches.

Q What is the temperature for the drug release testing of transdermal systems?
A For any dosage form applied to the skin, the temperature should be 32 ± 0.5 °C. This is the temperature of the site of application/introduction/administration of the dosage form.

Q How is the validation parameter, accuracy, evaluated for a drug release test for transdermal systems (TDS)?
A Two possible approaches could be (1) spike the placebo of the transdermal system with known amounts of the reference standard of the active ingredient or (2) add the placebo of the transdermal system to the dissolution medium, let them interact for a certain period of time, remove the TDS from the medium, and spike the medium with known amounts of the reference standard of the active ingredient. The evaluation of accuracy should be done for all the TDS strengths.

Q When working with a UV-coupled online sampling system in a dissolution test for an extended-release dosage form, a bubble appeared in one of the flow cells, and an aberrant reading was obtained at one sampling time. How should this be addressed? If samples are collected and archived, can the analyst run that one sample again to obtain an accurate reading?
A Collecting a backup sample is a good strategy. Where the automated system has been proved equivalent to offline analysis, the backup is representative of the missed sample so there is no missing data if the analysis is done on the backup. Without that luxury, that data point is missing. If the missing data point invalidates only the results from the affected vessel, could the test be repeated for that vessel alone on the grounds that no probable cause can be assigned? If the answer is yes, the test would be repeated only for that vessel but effectively consumes, if not the total resources, then the time needed to repeat the whole test. In that case and if there is no limitation on samples, it is recommended to repeat the entire run for all vessels just to make sure that a complete data set is obtained. It may be easier to justify running the entire test again than inserting data.

Q Is it necessary to run a dissolution test for oral suspensions at the time of reconstitution and also after a certain period of days after the initial reconstitution?
A The dissolution profiles of all the pilot samples and the samples in accelerated and normal stability studies are evaluated during product development. In the case of suspensions, the samples need to be prepared following the instructions to the patient/practitioner. The stability of the formulation on reconstitution is part of the product development information. Routine stability studies for a marketed product will typically look at the attributes of the product as reconstituted. One parameter that you need to check is the uniformity of dose for this type of product in multiple-unit containers. See the proposal for the new General Chapter <909> Uniformity of Dose from Oral Suspensions in Multiple-Unit Containers published in Pharmacopeial Forum 40 (4), available free of charge at

Q How can we deaerate dissolution medium that contains surfactants?
A If deaeration is necessary, the medium can be deaerated before the addition of the surfactant.

Q We are evaluating the dissolution of a tablet that has a very low content of a particular drug. Is it possible to use 10 tablets per vessel to facilitate the quantitation of the drug released?
A The USP General Chapter <711> Dissolution, under Procedure, states to place one dosage unit in the apparatus. If the product has a very low content of the active ingredient, a more sensitive quantitative procedure will be needed. Another approach is to work with a smaller volume of medium. This may require a non-compendial apparatus such as the mini-paddle.

Q Is it necessary to do a dissolution test for dry syrups?
A Dry syrup is not a name accepted by USP for a dosage form. It is an expression used for marketing purposes. The correct name of the pharmaceutical dosage form is Powder for Oral Solution or Powder for Oral Suspension. Any dosage form that, when reconstituted according to the instructions to the patient, results in a suspension needs a dissolution test. If it results in a solution, a dissolution test typically would not be required.

Q What validation parameters should be applied to a dissolution test for gelatin capsules when enzymes are used because of potential cross-linking?
A A complete validation of the dissolution procedure with and without the enzyme is required. Also, if you have any components in the dissolution medium that may inactivate the enzyme, you need to develop a pretreatment step where the enzyme is added to the medium without this component, and the component is added to the medium later, after the enzyme is able to digest the cross-linked gelatin. This pretreatment needs to be completely validated. See more information in the USP General Chapter <1094> Capsules—Dissolution Testing and Related Quality Attributes, the Stimuli article Use of enzymes in the dissolution testing of gelatin capsules and gelatin-coated tablets—Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements, published in Pharmacopeial Forum 40 (6) (available free of charge at, and in the paper Enzymes in the Dissolution Testing of Gelatin Capsules AAPS PharmSciTech 2014, 15 (6), 1410-1416.

Q What are the reasons that a USP dosage form monograph would have multiple dissolution tests?
A The dissolution, drug release, or disintegration tests in any USP monograph are the tests approved by FDA for products marketed in the United States. Because the dissolution performance may be formulation-dependent for immediate-release products with a poorly soluble drug substance or for products with a modified-release mechanism, a single dissolution test may not be suitable for all products covered by the USP monograph.

Q We measure the pH of the dissolution medium before and after the dissolution test. Is there an acceptable range for pH variation during the dissolution test?
A There is no general acceptable range for pH variation during the dissolution test. If a pH change is observed due to the dissolution of the sample, its effect on the drug substance solubility must be evaluated. Where the drug substance has low solubility, the dissolution process will be slowed or completely interrupted. This problem of pH change in the bulk medium can be eliminated or minimized by increasing the buffer capacity of the dissolution medium. Insight into the buffer used for dissolution of weak acid or weak base substances can be found in Dissolution Technologies 21 (4), Formulating Buffered Dissolution Media for Sparingly Soluble Weak Acid and Weak Base Drug Compounds Based on Microenvironmental pH0 Considerations.

Q Is a USP capsule monograph applicable for soft and hard gelatin capsules?
A The monograph will be applicable to any type of capsule approved by FDA to be marketed in the United States. It is recommended to do a search in the FDA website for human drugs ( to find more details about what type of capsules are approved by the agency. If a particular test is specific for a particular type of capsule, a mention will be made in the monograph text stating in which cases the test is applicable.

Q How can the transdermal system (TDS) be fixed in USP Apparatus 6 (rotating cylinder)? Can we cut the TDS to accommodate it on the cylinder?
A The USP General Chapter <724> Drug Release lists some options on how to attach the TDS to the cylinder: glue, double- faced adhesive tape, membrane, net, inert metal ring, or polymer ring. Any possible interference with the quantitative step should be evaluated. The recommendation is to not cut the TDS. The cylinder for Apparatus 6 is available on the market with an extension that can be used for larger TDS. Keep in mind that the TDS needs to be covered with dissolution medium during the entire test.

Q We are working with a formulation that has an active ingredient with a very high affinity for plastics. Is there a suitable filter to be used in the dissolution testing of such a formulation?
A The best option will be to centrifuge the samples using glass tubes. Even if the filter membrane is not a plastic, it will be encased in a plastic support. You need to determine the time and the speed for this centrifugation experimentally.

Q Should the paddle be running before the sample is introduced in USP Apparatus 2?
A The paddle should not be in motion, otherwise there is a risk that the dosage form will hit the paddle and be damaged. Running the paddle ahead of the start of the test will reintroduce dissolved gas into deaerated medium.

Q Should the sampling in USP Apparatus 1 and 2 be done with the equipment running?
A The sampling should be done with the equipment in motion. This is especially important when multiple time points are sampled.

Q Is it mandatory to deaerate all dissolution media?
A No. The need for deaerated dissolution medium is verified case by case.

Q Is there a general rule for the relation between dissolution parameters of tablets and capsules containing the same active ingredient. If we use USP Apparatus 2 at 50 rpm, 30 min, for tablets, can we use the same conditions for capsules?
A No, there are no general rules. Tablets and capsules are considered different dosage forms even if the formulations are very similar and they contain the same drug substance. Most obviously, capsules may float where tablets will probably sink. The critical quality attributes will be different, in part due to different manufacturing processes. Also, if you are working with gelatin capsules, you need to take into account the potential for cross-linking in the gelatin. See the USP General Chapter <1094> Capsules—Dissolution Testing and Related Quality Attributes, <1092> The Dissolution Procedure— Development and Validation, and <711> Dissolution.