Questions and Answers May 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.
Email for correspondence: mrm@usp.org

Q The USP general chapter <701> Disintegration is harmonized with the corresponding texts of the European Pharmacopeia (EP). The Apparatus and Procedure and Criteria section refers to the 6-tube basket-rack assembly. There is no mention of a 3-tube basket-rack assembly for larger tablets or capsules (i.e., > 18 mm long). It seems to be specific to EP method 2.9.1, which is not harmonized. How do we perform the disintegration test of tablets or capsules greater than 18 mm long?
A The disintegration apparatus for dosage forms greater than 18 mm is described in the USP general chapter <2040> Disintegration and Dissolution of Dietary Supplements. The European Pharmacopoeia is coordinating a revision to the disintegration chapter in EP, USP, and the Japanese Pharmacopoeia to add this equipment to the disintegration chapter in the three pharmacopeias. The proposal is going to be published in a future issue of the forum for each of the three pharmacopeias.

Q What quality grade of sodium lauryl sulfate should be used to prepare dissolution media, as this reagent is available with different content/purity?
A The highest quality grade of commercially available sodium lauryl sulfate should be used. Typically, the purity is 99% or higher to avoid the interference of surfactant impurities and degradation products in the associated analytical quantitation step of the dissolution procedure.

Q Is the disintegration test a requirement in the quality control and stability studies for oral tablets that are being evaluated using a dissolution test?
A The only oral dosage forms that require both disintegration and dissolution tests are chewable tablets and orally disintegrating tablets. See the USP general chapter <1711> Oral Dosage Forms - Performance Tests.

Q Regarding orally disintegrating films and orally disintegrating tablets, could a disintegration test replace the dissolution test?
A For orally disintegrating tablets, it is mandatory to develop a dissolution test and a disintegration test. See the USP general chapter <1711> Oral Dosage Forms - Performance Tests. For orally disintegrating films, first, a dissolution test is developed, then, depending on the physical-chemical characteristics of the drug substance and on the dissolution profile, the dissolution test may be replaced with a disintegration test with appropriate justification.

Q During a dissolution method validation, for the evaluation of accuracy we determined the absorbance at concentrations of 25%, 100%, and 200% of the drug substance. Should the absorbance be within the range of 0.200 to 0.800?
A You need to work within the linearity range of your spectrophotometer. There is equipment available on the market that has a linearity range up to 1.5 units of absorbance or even higher. This will depend on the equipment and the absorptivity of the molecule of interest. In general, when determining the linearity, a minimum of 5 concentrations is recommended. For dissolution procedures the linearity should be established for ± 20% over the specified range. See USP general chapters <1092> The Dissolution Procedure: Development and Validation and <1225> Validation of Compendial Procedures.

Q We are validating a dissolution method for a tablet in which the USP monograph dissolution test is performed using a pooled sample. How should the validation be done in this case?
A Pooled sampling is typically used only for quality control purposes. For any other application, including method validation, unit sampling should be employed.

Q In the dissolution test, the sample is filtered using a particular type of filter, e.g., nylon, PTFE, PVDF, etc. Should the standard solution be filtered using the same filter?
A The dissolution test has two components, the dissolution step, which some refer to as the sample preparation step, and a quantitative step. In the dissolution step, the filtration is used to stop the dissolution process and to remove undissolved particles from the sample. Typically, in this step the standard solution is not filtered. Depending on the quantitative method, the standard solution needs to be filtered to remove possible particulates and air bubbles. In both situations, the filters to be used should be selected in the appropriate way. A separate filter validation study should be conducted on both the sample solution and the standard solution to ensure that the filter compatibility and saturation effects are accounted for in the dissolution procedure.

Q The USP general chapter <711> Dissolution states to “withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating basket or blade, NLT 1 cm from the vessel wall.” Is this procedure also applicable for 500-mL vessels?
A Yes. Although sample withdrawal from the recommended sampling zone when using 500-mL volume can be challenging, especially in the case of apparatus 1, the recommended sampling zone should still be used.

Q When we are carrying out dissolution profiles, we always replace the volume of dissolution medium withdrawn with the same volume of medium preheated at 37 °C. Are there any recommendations or guidance on the volume of sample to be withdrawn/replaced depending on the total volume of the dissolution vessel?
A The volume of the solution to be withdrawn depends on the quantitative method being used. The amount of sample should be appropriated to be within the linearity range of the quantitative analytical procedure and to provide the appropriate levels of accuracy and precision. The recommendation is to always replace the volume withdrawn with the same volume of preheated dissolution medium to maintain sink conditions and to facilitate the sampling in the recommended region.

Q The USP general chapter <1092> The Dissolution Procedure - Development and Validation, under the section Specificity/Placebo Interference, states that it is necessary to demonstrate that results are not unduly affected by the dissolution medium blank, placebo constituents, other active substances, or potential degradation products from the dissolved drug substance in the dissolution medium. Does this mean that the impurities should be resolved from the main peak?
A The text in <1092> refers to degradation products from the dissolved drug product and not to impurities of the pure drug substance. The analyst should be aware of whether the drug substance is degrading under the conditions of the dissolution test and if this degradation is reproducible. The percentage of the degradation product may be added to the amount of drug substance not degraded to account for the total amount of drug released. One example of such a procedure is the USP monograph for Tacrolimus Capsules, where the total amount of drug released includes the percentage tacrolimus, tacrolimus 19-epimer, and tacrolimus open ring from the sample solution.

Q Should simulated gastric fluid always be degassed for use in dissolution tests? If yes, how should degassing be performed?
A Dissolution medium deaeration is not mandatory. During the method development, the need of deaeration is evaluated in a case-by-case approach. See USP general chapter <1092> The Dissolution Procedure - Development and Validation. You can find a deaeration procedure in the USP general chapter <711> Dissolution. Other deaeration procedures may be used with appropriate validation. See the paper by Degenhardt et al, “Comparison of the effectiveness of various deaeration techniques” at https://dissolutiontech.com/DTresour/200402Articles/DT200402_A01.pdf (Dissolut. Technol. 2004, 11, 6-11).