Questions and Answers November 2018

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 are validating a dissolution procedure for a delayed-release dosage. form. The acceptance criteria for the acid stage is not more than (NMT) 10%. The validation protocol was written with a precision acceptance criteria for the acid stage of NMT 5% but we are obtaining a variability between 20% and 50% with our samples. As the acid stage is a type of limit test, can we validate only the precision of the buffer stage?
A You need to validate the acid stage as well. The variability of the dissolution results has two components, the variability of manufacturing process and the variability of the dissolution test. The analytical method should not be producing variability at the level you are reporting. The variability of the samples is likely to come from a problem with the analyte (drug or degradant) or a problem with the manufacturing process.

Q Is the Performance Verification Test (PVT) required in addition to the mechanical qualification test to qualify 2-L vessels after using 1-L vessels?
A Although the dimensions of a 2-L vessel differ from 1-L vessels in height only, the PVT procedure is established only for 1-L vessels. There is no specific PVT procedure for 2-L vessels. You should qualify the equipment for 1-L vessels and check that the 2-L vessels that you intend to use meet the description given in the USP dissolution chapter. If you choose, you may test the 2-L vessels in place of using the PVT.

Q In dissolution testing of delayed-release dosage forms, is it necessary to verify the stability of the sample solutions?
A Delayed release dosage forms are tested in acidic and buffered media. As with any dissolution test, the stability of the dissolved drug substance in the medium is an important consideration. You need to see for how long the sample solutions are stable. This information is going to be used to decide if the amount of drug released to both the acid and to the buffer stages can be quantified by the analytical method.

Q In the USP monograph for doxycycline hyclate tablets, the dissolution test is to be performed using USP apparatus 2 with a distance between the paddle and the bottom of the dissolution vessel of 4.5 ± 0.5 cm. According to the PVT protocol, the test is carried out with a distance of 25 ± 2 mm. If we are going to run the test according to the instructions in the doxycycline monograph, do we need to do the PVT with the distance of 4.5 ± 0.5 cm?
A No. Perform the PVT as specified in the USP certificate. Paddle height has been shown to be an important effect in the results of the PVT (Eaton, J.; Deng, G.; Hauck, W.W.; et al., Perturbation study of dissolution apparatus variables—a design of experiment approach, Dissolution Technol. 2007, 14, 20-26. doi: 10.14227/DT140107P20.). In this particular monograph, the distance of 4.5 ± 0.5 cm is specifically for doxycycline hyclate tablet to allow enough space for the dosage form to sit below the paddle.

Q The USP general chapter <711> Dissolution states to use NMT 2000 units of pancreatin/L in the dissolution medium, this amount is based on pancreatin potency. Whereas, in the composition of simulated intestinal fluid the amount of pancreatin is stated in grams. Which one should be followed?
A These are two completely different situations that are neither equivalent nor interchangeable. Pancreatin at 2000 units/L can only be used if there is evidence of cross-linking in gelatin capsules or dosage forms coated with gelatin during the dissolution testing (see more details in the USP general chapter <711> Dissolution). The composition of simulated intestinal fluid uses a weight of pancreatin with enzymatic activity within a certain range.

Q Is it necessary to do manual sampling with the dissolution equipment in motion? Does the rotation influence the results? We need to perform a dissolution test with manual sampling with only one sampling point at 30 min. The test ends after 30 min. Is it possible to stop the rotation of the equipment at 30 min and then withdraw the sample? If not, could you explain why the sampling should be performed with the paddles rotating?
A No, you cannot stop the agitation when sampling. The sample needs to be representative of the entire content of the dissolution vessel. Therefore, the sampling needs to be done with the agitation in motion to maintain homogeneity. Remember that the dissolution process is continuing as long as there is undissolved drug substance. Therefore, sampling should be done from the medium that is being mixed.

Q For a dissolution test that has a single time point of 15 minutes, the ± 2% time range as recommended by the USP general chapter <711> Dissolution makes manual sampling for all the vessels really difficult to perform. . How can manual sampling be performed in these situations?
A A 2% tolerance for 15 minutes is no more than 18 seconds. Check with the technical support of the vendors of your dissolution equipment to see if the equipment supports staggered introduction of the sample. If so, the sampling can be done conforming to the 18-s time tolerance but still will need to be done at a fast pace.

Q Can we use soap to clean the dissolution vessels?
A Be aware that soaps can leave residue on the vessel walls. This can cause interference with the dissolution samples. If soaps are used, a cleaning procedure needs to be developed. The vessels can also be cleaned with organic solvents or a mixture of organic solvents and water or buffers. Any cleaning procedure should not leave residue that interferes with the dissolution test.

Q We submitted a study of solubility determination to a regulatory agency and it was not accepted. The regulatory agency stated that our solubility results were not appropriate because they were determined after 24 hours only with no demonstration of equilibrium. What is the appropriate solubility determination procedure?
A The shake-flask method or solubility at equilibrium is typically used. To demonstrate equilibrium, you need to have similar results for determinations at two consecutive time points. Until that is observed, the procedure is continued for a longer period with quantification at appropriate intervals. See the proposal for a new USP general chapter <1236> Solubility Measurements in Pharmacopeial Forum, available free of charge at www.usppf.com and the WHO Protocol to conduct equilibrium solubility experiments available at http://www.who.int/medicines/areas/quality_safety/quality_assurance/03_07_18_qas_17_699_rev_2_protocol_equilibrium_solubility_experiments.pdf

Q Is there any need to observe the dosage form behavior during the disintegration test or is it sufficient to check the sample only at the end of the test?
A It Idepends on the purpose of the test. Using a validated quality control method, it may be enough to check if the dosage form is completely disintegrated by the specified time. For development/investigational purposes, you may need to observe the entire disintegration process or at least track the time that the individual units are disintegrated. By the nature of the test, the disintegrating samples make observation difficult while the test is ongoing. An apparatus with automated endpoint detection is available on the market.