Questions and Answers November 2020
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 We are using a degassing method where the dissolution medium should be heated up to 41 °C. The vessels are then filled with the indicated volume (± 1%) of dissolution medium, then the temperature in the vessels is equilibrated to 37 °C. Is it acceptable that the volume is measured when the medium temperature is 41 °C (higher than room temperature)?
A As the medium will be at a higher temperature, the recommendation is to determine the appropriate amount of media gravimetrically. See https://www.usp.org/sites/default/files/usp/document/our-work/chemicalmedicines/dissolution-toolkit-version2.pdf “Volume is measured to be within ± 1% of the specified value. The volume of medium stated (e.g. 500 mL) is for measurement at room temperature. As the test temperature is higher than room temperature, allowance for expansion of heating should be made. A more accurate and temperature independent measure of the medium volume is through weight.”
Q In the USP monograph for Valsartan Tablets, the dissolution medium for Test 1 is “pH 6.8 phosphate buffer prepared as follows. Dissolve 6.805 g of monobasic potassium phosphate and 0.896 g of sodium hydroxide and dilute with water to 1000 mL. Adjust with 0.2 M sodium hydroxide or 1 M phosphoric acid as required to a pH of 6.8; 1000 mL degassed.” The dissolution medium for Test 2 is “0.067 M phosphate buffer prepared as follows. Dissolve 91.2 g of monobasic potassium phosphate and 12 g of sodium hydroxide in 10 L of water. Adjust with 1 N sodium hydroxide or 1 N orthophosphoric acid to a pH of 6.8; 1000 mL.” What are the reasons for using degassed and non-degassed media for the same product?
A The use of degassed or non-degassed dissolution medium depends on the formulation. Specific formulations may have a different behavior if the medium is degassed or not. Sensitivity of the dissolution behavior to degassed versus non-degassed media should be determined as part of the dissolution method validation procedure (see USP general chapter <1092> The Dissolution Procedure: Development and Validation). It is up to you to verify if degassing is needed for the specific formulation under consideration.
Q Is it necessary to have a disintegration test for filmcoated tablets like Tadalafil 20-mg Film-Coated Tablets? We have developed a dissolution test for this product, but is it necessary to also carry out the disintegration test?
A The only dosage forms that require both dissolution and disintegration are orally disintegrating tablets and chewable tablets. For all other dosage forms, only one test, dissolution or disintegration, is required. Please refer to the new USP general chapter <1711> Oral Dosage Forms - Performance Tests.
Q Can a centrifuged sample be considered unfiltered? How should the filter compatibility study be done?
A Centrifugation is a separation technique that can be used when filtration is not the most appropriate procedure, such as in the case of interaction/adsorption of the sample components to the filter and filter support. Centrifugation may also be used when leachables and/or extractables from the filter and filter support interfere with the quantitative procedure. For general instructions to perform a filter compatibility study as part of the dissolution method validation procedure see USP general chapter <1092>.
Q Our product is pellets for delayed-release oral suspension packed in single dose sachets. We are thinking about introducing the entire content of the sachet into the dissolution vessel. What is the appropriate method for introducing the sample?
A Look at the new USP general chapter <1711> Oral Dosage Forms - Performance Tests. The product needs to be reconstituted according to the patient instructions stated on the leaflet or package insert. Although the conditions should be standardized to minimize the variability of the dissolution results, the conditions should also represent those that will be used by the patient.
Q We are working with tablets for oral suspension. The leaflet instructs to disperse the tablet in water, but it does not stipulate the volume to be used. How should the sample be introduced into the dissolution vessel? Should a suspension in water be prepared or should the whole tablet be transferred to the vessel?
A The sample should be prepared in conditions as close as possible to those used by the patient. If the water volume is not specified in the leaflet, an arbitrary volume like 250 mL, roughly equivalent to glass of water, may be used. Once the volume is selected, it should be stated in the final version of the dissolution method to minimize the variability of the dissolution test results.
Q Where in USP can we find the instructions to prepare biorelevant dissolution media?
A They can be found at the end of the USP general chapter <1236> Solubility Determination.
Q I am trying to ascertain the revision date and which USP version contains the change of “Pancreatin USP units of protease activity per 1000 mL” from 1750 to 2000 in General Chapter <711> Dissolution.
A The proposal for the revision to the amount of pancreatin to be used in the presence of crosslinking in gelatin capsules (USP general chapter <711> Dissolution) was published in Pharmacopeial Forum 40(6) [Nov - Dec 2014] (available free of charge at www.usppf.com). The proposal became official in USP 39 on May 1, 2016.
Q In the USP monograph for Mesalamine Delayed-Release Tablets, the dissolution test is performed using three different dissolution media: 0.1 M hydrochloric acid (HCl), pH 6.0 buffer, and pH 7.2 buffer, indicating that is for colon-targeted delivery. For normal delayedrelease tablets, the dissolution method uses two dissolution media, typically 0.1 N HCl and pH 6.8 buffer. Are there any specific recommendations for the disintegration test for colon-targeted delayed-release tablets? They are not covered in the USP general chapter <701> Disintegration.
A A dissolution test should be developed first with the three dissolution media mentioned in your question. Then, depending on the dissolution behavior of the product, the dissolution test may be replaced by a disintegration test. It requires a scientific justification and both methods need to be discriminative for the critical quality attributes of formulation being evaluated. See the new USP general chapter <1711> Oral Dosage Forms - Performance Tests.
Q Regarding orally disintegrating tablets, is there an alternative to the disintegration procedure described in <701> Disintegration that can be used?
A Both dissolution and disintegration tests are required for orally disintegrating tablets. See the new USP general chapter <1711> Oral Dosage Forms - Performance Tests.
Q We are following the dissolution test in the USP monograph for Perphenazine Tablets and we are obtaining very low absorbance values. Is it allowed to change the volume of the dissolution medium from 900 to 500 mL, or use a 5-cm cell path? The cuvette size is not mentioned in the monograph.
A The volume of the dissolution medium cannot be modified. If the size of the cuvette is not mentioned in the monograph, a 1-cm cell path should be used. In this situation, the best option is to increase the size of the cell path.