Questions and Answers February 2024

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 In the USP monograph for Esomeprazole Magnesium Delayed Release Capsules, Dissolution Test 1, there is not quantitation step in the acid stage. Are there any cases where this quantitation step can be skipped?
A The development of any dissolution test should always start by using the standard conditions. In the case of delayed release dosage forms, the development should use initially the conditions stated in the USP general chapter <711> Dissolution. The procedure for delayed-release dosage forms has two methods, Method A and Method B. It is up to the developers to decide which is most appropriate using a case-by-case approach for each new dosage form. Deviations from the standard procedure are allowed with scientific justification when supported by data obtained from the samples being evaluated.

Q Can gelatin cross-linking occur either in hard or soft gelatin capsules?
A Yes, gelatin cross-linking can occur in any type of gelatin capsules as well as other dosage forms coated with gelatin. Gelatin, in the presence of certain compounds such as formaldehyde, or in high temperature/high humidity conditions, can form covalent bonding between gelatin chains that are irreversible. Proteolytic enzymes can break this bond. For more information, see USP general chapter <1094> Capsules - Dissolution Testing and Related Quality Attributes.

Q What is the reason for several USP monographs for dosage forms to have multiple dissolution tests? Which one of these tests should be used? Is it possible for an immediate-release dosage form monograph to have more than one dissolution test?
A The USP monograph may have multiple dissolution tests when a) a poorly soluble drug (BCS class 2 or 4; see USP general chapter <1090>) is formulated in an immediate release dosage form, or b) any drug substance is formulated in a modified-release dosage form (extended or delayed). Because different manufacturers use different formulation strategies to increase the drug solubility and/or to achieve the desired drug release profile, in both cases the dissolution test is likely to be formulation dependent. In addition, the dissolution test must also be discriminative for the critical quality attributes of the formulation. These critical quality attributes may also be dependent on the formulation manufacturing processes. The dissolution, disintegration, and/or drug release tests in USP monographs are the studies that have been approved by the US FDA for products marketed in the USA.

Q Should samples from the dissolution vessel be collected with the paddle or basket in motion or should it be stopped before sampling?
A During the dissolution test, the contents of the vessel are essentially a suspension, containing undissolved and dissolved drug particles and excipients. To obtain as homogeneous a sample as possible, the paddle or the basket must be in motion during the sampling process.

Q How should dissolution results be expressed? If the tolerances are NLT 80% (Q), how should the results be rounded?
A In general, analytical results should always be rounded based on the acceptance criterion under consideration. If the results are going to be used for quality control, the values should be reported with the same number of significant figures as the acceptance criteria (see USP General Notices and Requirements). In contrast, when the dissolution results are used during product/method development, it may be more useful to consistently round the values to one or two decimal places to allow more precision when evaluating product performance.

Q When should one use a basket versus a paddle apparatus?
A Typically, baskets are used when the dosage form floats and/or sticks to the vessel wall. In general, when operated at the same rotation speed, the fluid velocities observed inside the vessel are, on average, lower with baskets when compared with the paddle apparatus. This leads to differences in the shear force distribution throughout the vessel. Consequently, the use of baskets may not be appropriate for some formulations even if the dosage form does float. Baskets are useful with certain dosage forms, such as osmotic pump tablets or films. Ultimately, the selection of the dissolution apparatus should be decided on a case-by-case basis and must be justified with results obtained from the samples being evaluated.

Q In the USP general chapter <1092> The Dissolution Procedure - Development and Validation, under section 5.3 Accuracy/Recovery, there is a reference to a case in which the sample has very low strength, which states that “it may be more appropriate to prepare a stock solution than to attempt to weigh very small amounts.” Does this mean that one can prepare a drug substance stock solution for the entire accuracy study, and add appropriate aliquots to each vessel instead of weighing powder?
A The USP chapter <1092> contains recommendations that may be adapted for the individual dissolution procedure under development. It is up to the analytical scientist to select conditions that are the most suitable for each project. In practice, a standard stock solution could be used in any project. Depending on the solubility of the compound when diluted in the media and the effect of additional organic solvent on the analytical method, the stock solution may be prepared in organic solvent whenever appropriate. See <1092> for more details and examples.

Q The USP general chapter <711> Dissolution has a note stating that “Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37 °C, or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in the calculation. Keep the vessel covered for the duration of the test and verify the temperature of the mixture under test at suitable times.” In the case of single point sampling, does the temperature need to be verified at suitable times?
A The temperature of the medium inside the vessel is checked before starting the test. The test can only be initiated if all the vessels equilibrate to the appropriate temperature, i.e., 37 ± 0.5 °C. Typically, the temperature is also measured at the end of the test to verify if the test was performed under the appropriated temperature conditions. The temperature of the dissolution medium inside the vessel is not measured during the dissolution test because the introduction of a thermometer or probe may modify the hydrodynamics within the vessel and could impact the dissolution results. Some dissolution test equipment includes temperature sensors within the paddle or basket shaft, and it is possible to monitor the temperature while the dissolution test is being performed without introducing and external temperature probe. In either case, when the dissolution instrument is qualified, the ability of the dissolution equipment to maintain temperature control is a key operational parameter that must be verified (see USP Guideline on Procedures for Mechanical Calibration and Performance Verification Test Apparatus 1 and Apparatus 2).