Questions and Answers February 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 When the bath is connected to a pump, filtration station, spectrophotometer, or fraction collector, and can be used as a semi-automatic system, do we have to perform the performance verification test (PVT) on the dissolution apparatus only or on the entire system (this means automatic sampling)? In case we must perform the PVT on the automated system, should we perform ultra-violet (UV) online measurement or collect samples and do the UV measurement manually?
A For the results to be comparable to those obtained from the collaborative study that is used to set the acceptance ranges, it is best to perform the PVT with manual sampling. The purpose of the PVT is to assess the performance of the dissolution bath only. Accessories that are added such as automated sampling, filtration, and online UV measurements should be validated against the manual sampling method.

Q Is the use of surfactant acceptable or allowed in the comparison of dissolution profiles for a biopharmaceutical classification (BCS)-based waiver? The World Health Organization and European Medicines Agency guidelines mention in the conditions for comparative dissolution studies for a BCS-based biowaiver that no surfactant should be used in the dissolution media.
A The biowaiver based on the BCS is applicable only for class 1 and 3 drugs in immediate-release dosage forms. If the formulation contains a class 1 or 3 drug, then the drug is highly soluble and there is no need to add surfactant to the dissolution medium. See the USP general chapter <1711> Oral Dosage Forms - Performance Tests (will be official May 2021) and the FDA Guidance for Industry (August 2018): “Dissolution testing and acceptance criteria for immediate-release solid oral dosage form drug products containing high solubility drug substances,” available at https://www.fda.gov/media/92988/download.

Q We are developing a dissolution method for oral suspensions and we plan to collect the samples by withdrawing six samples form three different reconstituted bottles. Is this procedure acceptable?
A Oral suspensions should be prepared according to the instructions given to the patient, and the preparation method should be standardized. The amount of sample transferred to the instrument should be equal to 1-unit dose. If labeled for single use, then the suspension should be prepared according to the patient instructions, and the entire suspension should be transferred to the dissolution instrument. See the USP general chapter <1711> Oral Dosage Forms- Performance Tests (will be official May 2021) and FDA guidance for specific products at https://www.fda.gov/drugs.

Q There is no monograph in USP for ibuprofen soft gelatin capsules. Should we develop a normal dissolution (as for tablets) or it is enough to carry out rupture test?
A In USP there is no distinction between soft, liquidfilled, hard, powder-filled, or granule-filled capsules. All are considered under monographs for capsules. The recommendation is to develop a dissolution test. See the new USP general chapter <1711> Oral Dosage Forms - Performance Tests (will be official 1 May 2021). Then, depending on the physical-chemical characteristics of the drug substance and the dissolution profile, the dissolution test may be replaced with a disintegration test with appropriate justification.

Q Can HPLC-grade water be used in the preparation of dissolution medium? Are there any quality specifications for water to be used in the dissolution medium preparation?
A The water to be used in the preparation of dissolution medium should meet the compendial requirements for purified water. HPLC water is a type of purified water.

Q We are working on development of a dissolution test using apparatus 4 by UV spectroscopy, and I have concerns regarding the method variations that should be covered in robustness testing during method validation. For example, do we need to check the variability of cell bath temperature and flow rate on the apparatus 4, or is there no need as these parameters have already been verified as part of the instrument qualification?
A The dissolution method is composed of two parts: the dissolution procedure and the quantitative procedure (analytical finish). When using apparatus 4 for the dissolution procedure, the parameters mentioned above, i.e., the flow-through cell temperature and flow rate, can only change within the ranges stated in the USP general chapters <701> Dissolution.
The flow must be within the range of ± 5% of the nominal flow rate, with pulsation rate of ± 10 pulses/min and temperature of 37 ± 0.5 °C. It may be worth evaluating changes in the target flow rate and cell temperature that are within the allowable tolerances as part of the robustness check of the final dissolution method.

Q We are studying different formulations with different excipients to evaluate the discriminatory power of a dissolution method for a product containing two drug substances. Is it necessary to achieve discrimination for both drug substances?
A In the case of combination products, you need to take into consideration the biopharmaceutical (BCS) classification of the two drug substances. If one or both drug substances is a class 1 or 3 and the dosage form is intended for immediate release, then the dissolution test need not be discriminative (see the USP general chapter <1711> Oral Dosage Forms - Performance Tests). If one or both drug substances are class 2 or 4, then the dissolution test needs to be discriminative for these drug substances. Depending on the solubility and physical-chemical characteristics of both drugs present in the formulation, you may need to develop two different dissolution tests. For instance, if there is a large difference between the solubility of the two drug substances, you may need to develop two separate dissolution tests, one for each active pharmaceutical ingredient (API). In the case that a single dissolution method can be developed to assess the dissolution of both drug substances, the discriminatory power of the dissolution method should be evaluated considering the critical quality attributes of the entire formulation and manufacturing process, from the raw materials up to and including how the product behaves during accelerated and long-term stability studies. Other parameters that may have an impact in the dissolution performance of the formulation include, as examples, the particle size range of poorly soluble drugs, the presence of polymorphs, moisture content of excipients and drug substances, coatings, the presence of solvents, etc.