Question and Answer Section — November 2014

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 We have a soft-gel capsule that fails dissolution testing because of the presence of cross-linking. We repeated the testing with the addition of enzymes to the dissolution medium, and the products met the acceptance criteria at S1 level. Is there any requirement to perform S2 and S3 without the enzyme before we repeat the test with the addition of enzymes?

The current text in the USP General Chapter <711> Dissolution is not clear regarding this issue, and it is open for interpretation. The revision that will be published in Pharmacopeial Forum 40(6) (available free of charge at www.usppf.com) will address this issue. In the proposal, if the failure was observed at S1 level and it was due to the presence of cross-linking, the test can be repeated with the addition of enzymes at S1 level. There is no need to show failure at S2 or S3 before adding the enzyme to the medium.

Q We are developing a dissolution test for an oral suspension, and we are seeing a cone of particles at the bottom of the dissolution vessel. What should be done?

When developing a dissolution test for oral suspensions, several steps should be considered: (1) The product needs to be reconstituted according to the instructions to the patient. The procedure should be standardized and well described in the method to reduce variability in the results. (2) The amount of product to be introduced into the dissolution vessel should be equivalent to the biggest dose that can be administered at each dosing. (3) The introduction of the sample in the dissolution vessel needs to be evaluated in a case-by-case approach. It needs to be done in such a way that the dispersion of the sample is as fast as possible. In most cases, this introduction is done with the paddle slowly rotating to allow dispersion of the product. The location of sample introduction and the time to introduce the entire sample can be modulated to disperse the sample as fast as possible. One example of different ways of sample introduction can be found in the USP monograph for Megestrol Acetate Oral Suspension.

Q In the USP General Chapter <711> Dissolution, the Acceptance Table 2 for Extended-release Dosage Forms, L2 level states, “none is more than 10% of labeled content outside each of the stated ranges.” If the stated dissolution range is 20-50%, must all the individual results lie between 10% and 60% or between 18% and 55%?

The text in the introduction of any of the Acceptance Tables in <711> Dissolution says that the limits on the amounts of active ingredient dissolved are expressed in terms of the percentage of the product label claim. If the range is 20-50%, the range for individual results in L2 will be (20% of the product label claim - 10% of the product label claim) - (50% of the product label claim + 10% of the product label claim).

Q When tablets or capsules are weighed to perform dissolution, does the average weight used in the calculations correspond to 6, 12, or 24 units tested or is the average weight determined with 20 units?

The weight of capsules or tablets is not used in the calculations of the amount dissolved during the dissolution test. All the calculations for dissolution of tablets and capsules are done on the basis of the product label claim. The only exception is osmotic-pump tablets where, because of the product overage, the calculations are based on the labeled dose delivered. Some companies determine the individual weight of capsules and tablets before the dissolution test to use this information for other purposes such as in an investigation of out of specification results, but this is a company’s decision.

Q Is there a conversion factor to convert pepsin units/mg to units/mg of protein?

There is no conversion factor. The activity/mass relationship is variable, and enzyme activity determination depends heavily on the method used. The majority of enzyme activity determination procedures are not interchangeable or equivalent. In the case of pepsin for dissolution applications, the activity must be determined by the hemoglobin procedure under Pepsin in the Reagent Specifications section of USP. This procedure is under revision, and a more detailed procedure will be published in a future issue of Pharmacopeial Forum (available free of charge at www.usppf.com).

Q For dissolution testing, should the temperature of each individual vessel be measured or is it enough to measure just the temperature of the bath to ensure that the test is carried out at 37.0 ± 0.5 °C?

You need to measure the temperature in each individual vessel. The bath temperature will often be slightly higher than the temperature of the vessel contents.

Q Specifications for different sinkers are available in USP and other guidelines, but it is not clear when to use sinkers. In one document, I found that whenever capsules float for more than 30 sec, sinkers need to be used.

Sinkers can be used if the tablet or capsule floats (with no time specified) or if the capsule or tablet sticks to the vessel wall. Sometimes the dosage form floats only after the agitation is started. The design and size of the sinker should be evaluated in a case-by-case approach because it may affect the disintegration or opening of the dosage form.

Q We would like to know if it is mandatory to evaluate intrinsic dissolution of the drug substance during the development of a dissolution test.

Evaluation of intrinsic dissolution is not mandatory. It may be a useful tool to characterize drug substances obtained from different processes/manufacturers. You need to discuss possible applications of intrinsic dissolution with your formulation group. For more information on intrinsic dissolution, see USP General Chapter <1087> Apparent Intrinsic Dissolution—Dissolution Testing Procedures for Rotating Disk and Stationary Disk and papers on this subject published in Dissolution Technologies.

Q We are facing problems with the evaluation of the accuracy of a particular dissolution test due to the low solubility of the drug substance in the dissolution medium. What can be done to overcome this problem?

We assume that the solubility of the drug is adequate to perform the dissolution test. In that case, you want to make sure that you can control the concentration of the drug for accuracy/recovery purposes. Use a spiked placebo for this procedure. The drug substance can be dissolved in an appropriate solvent, and then an appropriate portion transferred to the medium with placebo. The recommendation is to use a volume of the appropriate solvent not more than 5% of the final volume. USP General Chapter <1092> The Dissolution Procedure—Development and Validation discusses validation of dissolution procedures. Chapter <1092> has been proposed for revision. The revision proposal was published in PF 40(1). PF is available free of charge at www.usppf.com.

Q What statistical tools should be used to compare deaerated and non-deaerated dissolution medium? Can the f2 calculation be used in this case?

The calculation of f2 is not usually applied in this case. You will make visual observations of how the dosage form behaves in deaerated and non-deaerated medium over time. In addition, you will evaluate the individual values, the average, and the standard deviation at each time point. Another important point is the influence of dissolved air on the discriminative power of the method.

Q Should the agitation in the dissolution vessel be stopped during sampling?

Sampling should always be done with the paddle or basket in motion whether the sampling is done manually, automatically, or semi-automatically. You are sampling a suspension that has to be homogeneous and representative of the contents of each vessel. Check with the manufacturer of the dissolution apparatus for how to stagger the rotation in each vessel in the case of manual sampling.

Q The USP monographs that have multiple dissolution tests always have the statement, “If the product complies with this test, the labeling indicates that it meets USP Dissolution X.” What does USP mean by labeling? Should this information be on the label of each box, in the leaflet, or the certificate of analysis?

This statement is applicable only for products marketed in the United States. For products marketed in other regions, the appropriate regulatory body should be consulted. In the United States, most companies put this information in the leaflet.

Q The USP monograph for Estradiol Transdermal system is silent on the method of attachment of the transdermal system (TDS) to the apparatus. How can the TDS be fixed in the apparatus? USP General Chapter <724> Drug Release mentions the use of a double-faced adhesive tape. Is there any additional information to specify this material?

The newest version of <724> Drug Release contains several options on how to attach the TDS to the apparatus. The selection is done in a case-by-case approach. It is important to evaluate the absence of interference with the release mechanism of the TDS and with the quantitative procedure used to quantify the amount of drug released. The doubleface adhesive tape can be found at any supplier of office materials.

Q What should be the acceptance criteria for dissolution during stability studies?

The dissolution test should be discriminative for the critical quality attributes of the product and changes on stability. Once the acceptance criteria have been selected, they will be applicable both for batch release as well as for the stability studies.

Q Should the accuracy of a dissolution test be evaluated at 37 °C?

The temperature of a dissolution test will usually be the same as the temperature of the site of application of the dosage form. If the dosage form has internal use/application, such as capsules, tablets, inserts, and suppositories, the temperature should be 37.0 ± 0.5 °C. If the dosage form is applied to the skin, the temperature of the test should be 32.0 ± 0.5 °C. Accuracy of a dissolution test should be evaluated in conditions as close as possible to the way the method is going to be run in routine analysis, which means that it should be evaluated at the same temperature at which the test is carried out.

Q Should an out-of-specification (OOS) investigation be carried out if the product meets the dissolution acceptance criteria at the S2 level?

S1, S2, and S3 levels are part of the Acceptance Table for immediate-release dosage forms. An OOS investigation should be done only after the product has failed S3 level.

Q Is it acceptable to have two different dissolution tests for the same product, one for quality control applications and the other for stability studies?

No. The dissolution test should be discriminative for the critical quality attributes of the product. Once the dissolution conditions and acceptance criteria have been selected and defined because of their discriminative power, they will be applicable for the entire life cycle of the product including stability studies.