Questions and Answers August 2021
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.
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Q In the USP monograph for Ibuprofen Oral Suspension, there is a note stating that the tubing of the syringe is placed into a zone that is between the surface of the medium and the top of the rotating blade. We indeed found a considerable difference in dissolution results and sample behavior in the bottom of the vessel when comparing dissolution runs in which the sample is added while the blade is static compared to the runs where the blade is rotating upon addition of the sample. Based on the note in the monograph we understand that the ibuprofen suspension sample should be delivered into dissolution medium while the paddle blade is rotating. Would you kindly comment and confirm.
A “Rotating” means that the paddle is in motion. The introduction of the suspension sample into the dissolution equipment is formulation dependent because the dissolution results will depend on the viscosity and density of the sample. When developing a dissolution test for suspensions, the method of introducing the sample into the dissolution vessel must be considered and described clearly in the final method. Another good example is the USP monograph for Megestrol Acetate for Oral Suspension.
Q Is disintegration a mandatory test for solid dosage forms such as coated and uncoated tablets and for soft and hard capsules? If there is no USP monograph for a particular product, should a disintegration test be developed?
A No, the disintegration test is not mandatory for the dosage forms mentioned. First, a dissolution test should be developed. Then, depending on the physical-chemical characteristics of the drug substance and the dissolution profile, the dissolution test may be replaced by a disintegration test with appropriate justification. The only dosage forms that require both a dissolution test and disintegration test are chewable tablets and orally disintegrating tablets. See USP general chapter <1711> Oral Dosage Forms—Performance Tests.
Q In the Dissolution Toolkit procedure for Mechanical calibration and Performance Verification Test of Apparatus 1 and Apparatus 2 Version 2.0 (https://www.usp.org/sites/default/files/usp/document/our-work/chemical-medicines/dissolution-toolkit-version2.pdf), under study design and interpretation, it states: “For each position in assembly determine the percent dissolved at the sampling time point specified.” In our laboratory we have two types of dissolution testers, i.e., 8 and 14 positions. According to above statement we are conducting a performance verification test (PVT) on 8 and 14 vessels and using 6 and 12 vessels, respectively, for routine release testing. Can we do performance verification on 6 and 12 vessels on an 8 and 14-position dissolution tester, respectively, with proper assurance that the vessels used for PVT will only be used for release testing?
A The intention of the PVT is to serve as the performance qualification for the instrument as a whole, thus, the PVT test should be performed for all available positions in the dissolution assembly. Even if only a fraction of vessels are used for routine testing, all of the positions in the instrument should be evaluated as part of the whole instrument qualification. The main reason for this is that the collaborative study from which the specification limits are determined is based on all available positions of the dissolution test assembly being used. The geometric mean ranges and the %CV limits are determined based on all vessel positions being utilized. There is also a practical advantage of using this approach. We have several 8-position dissolution testers in our lab. All eight positions are qualified during the PVT process even though we routinely run n = 6 positions for product testing. When there is a mishap in the lab and a vessel is broken, there are two additional positions to serve as a backup until the calibration period ends and the PVT can be completed for that instrument.
Q What time points are recommended for dissolution profiling of a sample with a 60-minute dissolution time stated in the procedure?
A It is up to your laboratory to decide. It depends on the purpose of the study and on the conditions/equipment available in your installation. It also depends on the way in which the data from the dissolution profile will be used. If the intention is simply to understand the characteristics of the dissolution profile, then the frequency and number of time points can be decided by the laboratory. If the purpose of the profile is to compare dissolution profiles to a reference product, then the statistical method used to compare the profiles may require certain time points to be collected. Note: If an automated system is being used, the sampling can be done more often than in a manual system; however, it is important to keep in mind that the sample should be withdrawn within a tolerance of ± 2% as per USP general chapter <711>. This may be a challenge for early time points depending on the volume withdrawn and the pull time of the auto sampling system.
Q What is the meaning of “stated times” in this portion of the text from the USP general chapter <711> Dissolution: “Time: Where a single time specification is given, the test may be concluded in a shorter period if the requirement for the minimum amount dissolved is met. Specimens are to be withdrawn only at the stated times, within a tolerance of ± 2%?
A These are the times specified in the dissolution procedure, when the samples need to be withdrawn for quantitative determination of the amount of drug released/dissolved.
Q Is it acceptable to sample each dissolution vessel using a single cannula?
A The recommendation is to use one canula, one syringe, and one filter for each sample withdrawn from the dissolution vessel. Otherwise, the individual samples will be contaminated from the contents of other vessels.
Q The USP general chapter <711> Dissolution states “The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A small, loose piece of nonreactive material, such as NMT (not more than) a few turns of wire helix, may be attached to dosage units that would otherwise float”. Is it acceptable to develop/validate a dissolution test method in which the dissolution test will be started with the dosage units floating? The dissolution test is with apparatus 2. The units will float for several minutes before disintegration of the units and the contents disperse.
A If the dosage form is a tablet or a capsule and it is floating, there is a risk that the dosage form will be hit by the rotating paddle resulting in damage that may invalidate the test results. This is the primary justification for the use of sinkers in the case of floating capsules and tablets. The type, design and size of the sinker is formulation dependent. An appropriate sinker should be selected using a case-by-case approach.
Q What is the tolerance limit for weighing surfactants to prepare dissolution media? I need to prepare a dissolution medium with a surfactant concentration of 1.5%. How much of deviation from the target weight of the surfactant is allowed?
A The tolerance around the concentration of different media components should be determined during the evaluation of the dissolution method robustness as component of the dissolution method validation scheme.
Q Can you suggest physiologically relevant dissolution methodologies for ophthalmic suspensions, nano-emulsions, nanoparticles, etc., that are discriminatory?
A The discriminatory power of any dissolution test comes from a set of conditions: equipment type, rotation/flow rate, medium volume, medium composition, including pH, and not from the medium only. The discriminatory power of any dissolution test is likely to be formulation dependent. The dissolution test conditions must be evaluated and selected on a case-by-case basis. Some biorelevant dissolution media are provided in the USP general chapter <1236> Solubility Measurements. Additionally, there are several papers in the literature which address this topic. For instance, a review paper is available at the following location:
For ophthalmic products see the USP general chapters <771> Ophthalmic Products - Quality Tests and <1771> Ophthalmic Products - Performance Tests. Dissolution tests are typically developed only for extended-release ophthalmic products. These products may be administered by injection or by surgery. If the ophthalmic product is applied to the surface of the eye, no dissolution test is required.
Q Can I use a mesh size other than 40 for my apparatus 1 method?
A Yes, you can use any mesh size with appropriate justification. See USP general chapter <1092> The Dissolution Procedure: Development and Validation.
Q In the tolerances/acceptance criteria for dissolution testing, what is meant by Q + 10% if Q is 60%? Is it 60% + 10% or 10% of 60% (i.e., 54-66%)? Kindly elaborate how to describe Q + 10%, or Q + 5%, etc.
A See Interpretation, Immediate-Release Dosage Forms and the Acceptance Table 1 in the USP general chapter <711> Dissolution. The Q value and all the percentages stated in the table are calculated based on the product label claim. As an example, if the product label claim is 100 mg and using the Q value of 60% as in your question, the calculations are 60% of 100 mg, 5% of 100 mg, 15% of 100 mg, and 25% of 100 mg. Thus, the +10% is just that, the Q value of 60% + 10%, so, 70% of the label claim.
Q Was there a previous version of the USP general chapter Dissolution <711> that had a drawing of a cannula that is described in the manual sampling?
A The USP general chapter <711> has never described the canula. The primary reason for this is that the cannula can be anything that has been demonstrated to be appropriate. The photo below is an example of a cannula that has been used at the USP laboratories. It can be found in suppliers of accessories for dissolution testing. The material, length and shape of the cannula may change depending on the media and equipment set up used for the dissolution test.
Q Is the dissolution procedure described in the USP general chapter <711> Dissolution appropriate for liquidfilled capsules?
A Yes, the procedures described in <711> are applicable for any type of capsules containing any type of filling. More information is available in the USP general chapters <1092> The Dissolution Procedure: Development and Validation, <1094> Capsules - Dissolution Testing and Related Quality Attributes and <1711> Oral Dosage Forms - Performance Tests.
Q We are developing a dissolution test for a delayedrelease injectable suspension using a flow through dissolution apparatus. The specification indicates the average of 12 units and calls out individual units limits as well. Is there any potential option or practicality to mechanically averaging the individual units by mixing an aliquot from each into a single solution and performing analysis on said solution?
A In this case the aliquots should not be combined. The aliquots must be evaluated individually, and the individual results can then be averaged. The suggested approach is referred to as a pooled sample and is typically only applied only to immediate-release dosage forms. Critical information about the individual sample variability would be missed by applying a pooled sample approach to a delayed-release injection.