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Questions and Answers August 2018

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 When running a dissolution test for an immediate release dosage form using USP apparatus 2, do we have to analyze the six tablets at the same time with the same equipment? In case of a technical issue, could we analyze tablets independently at different times with different equipment?
A USP general chapter <711> Dissolution does not address this situation. The chapter describes how to run the procedure for one vessel and this procedure should be repeated with as many vessels as you have in your equipment. The situation that you are describing is going to introduce unnecessary variability in the results, and it is going to be difficult to identify its possible origins if the results fail the appropriate acceptance table.

Q Can sinkers be used when the USP monograph does not specify one? Should sinkers be used for all strengths of the same product or only with one? Can sinkers be used with split tablets? How can we choose the right sinker for a particular tablet weight/diameter? How many samples must be tested before fixing the use of sinker? Should we validate the dissolution method after adding the sinker?
A Yes, sinkers can be used even if the USP monograph does not mention it. The use of sinkers is product dependent and it may be the case that the USP monograph was developed based on a method for a particular product that does not need sinkers during the dissolution testing. You can submit a proposal for the revision of the USP monograph to include a text allowing the use of sinkers, if necessary. Sinkers are used only if the dosage form floats and/or sticks to the vessel walls. The decision on the use of sinkers and on their design and size requires a case-by-case approach. Different designs and sizes should be evaluated, keeping in mind that the dosage form may swell when in contact with fluids. It is up to your lab to define the protocol for the evaluation of sinkers, and this item needs to be considered in the method validation protocol.

Q Are sinkers mandatory in the dissolution testing of the following: polymer matrix based or hypromellose based tablets; and extended release tablets?
A The use of sinkers is not mandatory. See answer to the previous question.

Q Should the agitation be stopped when sampling dissolution samples? For example, should the agitation be stopped before sampling the last point in the dissolution profile; or in a routine dissolution test where the sampling is done at just one time?
A Any sampling, done for any reason (single point or dissolution profiling), must be done with the agitation in motion because the content of the vessel needs to be as homogeneous as possible.

Q USP general chapter states that the temperature of the dissolution medium should be 37 °C ± 0.5 °C. If we consider 37 °C without any decimal places, should the temperature of the dissolution medium be between 37 °C and 38 °C or 36.5 °C-37.5 °C?
A The temperature of the dissolution medium should be between 36.5 °C and 37.5 °C.

Q Why does the EMA Guideline on Bioequivalence Investigation not allow the use of surfactants in the dissolution medium (IV. Drug Product, IV.1 In Vitro Dissolution, IV.1.1 General Aspects, pp 26-27. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf)?
A Appendix III of the EMA Guideline on the Investigation of Bioequivalence discusses the procedure for the BCSbased biowaiver approach that is applicable only for drug substances classified as BCS1 (high solubility and high permeability) and BCS3 (high solubility and low permeability) and are formulated in an immediate release dosage form. In this case, there is no need to use surfactants in the dissolution medium because the drug substance has high solubility in aqueous solvents.

Q We are developing a new product where the dosage form is soft gelatin capsules containing an oily filling intended to produce local action. Is it necessary to develop a dissolution test for this type of product? Or is a disintegration test more appropriate?
A Regardless of the site of action, the first step is to develop a dissolution test. We assume that the product is orally administered, so the drug must be released from the capsule and dissolved in the fluids in the gastrointestinal tract. The physical-chemical characteristics of the drug substance and the behavior of the dosage form in the dissolution profile may provide justification for the dissolution test to be replaced by the disintegration test.

Q We are developing a transdermal system and have already tried different buffers with different pH values and different apparatuses (paddle over disk and rotating cylinder), but we were unable to obtain a dissolution profile according to the Eur. Pharm 5.17.1 Recommendations on Dissolution Testing. In fact, we are unable to obtain complete release of the drug even after 3-4 days of dissolution testing. The Eur. Pharm. and ICH guidelines recommend three release points (about 20%, 50%, and 80%); if we cannot reach the 80% dissolved point, is a dissolution test with 50% dissolved be acceptable?
A As it is written in the Eur. Pharm. 5.17.1 Recommendations on Dissolution Testing, this document is not mandatory, and it is for oral dosage forms. The recommendations in this document may not be appropriate for transdermal systems (TDS). The dissolution/drug release test for TDS is typically run until 85% of the dose is released or until a plateau is reached. In general, TDS contain an excess of drug to guarantee that the specific dose is going to be released until the end of the prescribed treatment. Therefore, the dissolution/drug release results for TDS are expressed according to the dose and not the drug load. The objective of the dissolution/ drug release test is not to release all the drug content but rather to be discriminative for the critical quality attributes of the formulation. The recommendation is to evaluate at least three points in the release profile. Most companies define the acceptance criteria for TDS with four or five points to better control the in-vitro performance of the product.

Q Can automated sampling be used in dissolution procedures validated with manual sampling? In the case of compendial monographs, can automated sampling be used?
A Automated and manual sampling can be used in any dissolution procedure. Automated sampling needs to be validated for each product to demonstrate that there is no adsorption of any components of the formulation in the entire automated system and that no leachables or extractables will interfere with the quantitative procedure. Also, it may be necessary to establish a specific washing and rinsing procedure for the automated sampling system to minimize cross-contamination between samples. For more information, see USP general chapter <1092> The Dissolution Procedure: Development and Validation.

Q We are developing a dissolution test for an oral suspension with a maximum dose of 2 g divided in three doses during the day. We thought that a volume of 0.5 mL of the sample should be appropriate for the dissolution testing in order to meet sink conditions using 900 mL of dissolution medium. Is this procedure appropriate?
A The amount of sample to be transferred to the dissolution vessel should be equivalent to the highest unit dose that can be administered at each dosing and not the total daily dose. The dissolution sample is the product constituted according to the instructions to the patient. The volume of the dissolution medium is defined based on the solubility of the drug substance. It is not mandatory to use 900 mL. It is not mandatory to meet sink conditions. You need to select the dissolution test conditions that are discriminative for the critical quality attributes of the product being evaluated. It may be the case that the dissolution test may be more discriminative if sink conditions are not met. The selection of the dissolution conditions is made based on experimental data obtained with your samples.

Q We are developing a dissolution test for a suspension with very low strength. We were unable to use 500 or 900 mL because the signal in the quantitative step was too low. Is it possible to use 100-mL vessels in such a case?
A Small vessels such as 100 mL vessels are not compendial apparatuses; they are not standardized and should only be used as last resource. Our suggestions are to look for quantitative procedures that have been used to quantify the drug substance in biological fluids, where the typical concentrations are very small. If you decide to use small-volume vessels, then you must qualify them and have them well described in the final version of the method. In any case, the dissolution procedure should be discriminative for the critical quality attributes of the product.

Q When running a dissolution test for a split tablet, should the same dissolution medium volume used for the whole tablet be used for the split tablet? Or can we reduce the dissolution medium volume proportionally? If 900 mL are used for the intact tablet, can 450 mL be used for the split tablet?
A USP general chapter <705> Quality Attributes of Tablets Labeled as Having a Functional Score states that 'with the exception of dose, each split portion from tablets labeled as having a functional score are expected to conform to the quality attributes of the whole tablets.' The dissolution test given in the chapter also says to use the appropriate dissolution test. If a specific dissolution test is available for the product having a corresponding fractional dose, then that is the dissolution test that should be used. If the available dissolution test is only for a tablet with the intact dose, there are problems that need to be recognized with the approach of changing the dissolution medium volume merely to suit the fractional dose from the split tablet. The dissolution test conditions represent a particular environment that is established around the dissolving material. The stirring element, speed, and medium volume all contribute to that particular environment. When the medium volume is changed, in essence, it constitutes a different test. The dissolution profile may change, and the dissolution tolerances and times may become inappropriate.