Questions and Answers November 2022

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 Is it possible to obtain dissolution results that are higher than the assay results for a particular product batch?
A Yes, it is. First, the filter and cleaning methods used should be properly evaluated to ensure that there is no placebo interference or carryover issues and that the sampling and sample filtration were carried out in the proper way. If all these parameters were found to be appropriate, one possible reason for dissolution results being higher than the assay results is that the dissolution values reflect variability better captured by uniformity of dosage units for the batch. Although the assay value for a given batch reflects the average content of several individual dosage units, as only one dosage unit is introduced in each dissolution vessel, there is a chance that a particular unit could be close to the upper limit of the range of uniformity of dosage unit values observed.

Q To define the sink condition in a dissolution test, which parameter should be evaluated: “Apparent solubility - Physical Assessment of Solubility” or “Methods for Determination of Equilibrium Solubility (saturation shake-flask method)”?
A Sink condition is defined as at least three times the volume of dissolution medium needed to obtain a saturated solution considering the highest product dose. The shake flask method, which is used to determine the equilibruim solubility in a specified solubility medium, is the easiest procedure for the determination of the equilibrium solubility. The solubility medium should be considered when defining sink conditions for the proposed dissolution meduim. Apparent solubility is typically used to characterize the pure drug substance. See USP general chapters <1236> Solubility Measurements and <1087> Intrinsic Dissolution - Dissolution Testing Procedures for Rotating Disk and Stationary Disk.

Q Can the immersion cell apparatus be used to carry out the in vitro permeation test (IVPT) of semisolid dosage forms using membranes of natural origin (e.g., pig skin)?
A The immersion cell is most commonly used with synthetic membranes due to the robustness of the synthetic membranes. The recommendation is to use the vertical diffusion cell or the horizontal flow-through cell when using biological membranes. Human skin obtained from cosmetic surgeries is preferred for this type of test. A major revision to the USP general chapter <1724> Semisolid Drug Products - Performance Tests was developed to include the IVPT procedures and equipment. See Pharmacopeial Forum 48(3) May - June 2022, available free of charge at www.uspnf.com. This revision discusses various proposed test conditions for in vitro permeation tests.

Q The USP general chapter <711> Dissolution contains instructions on how to run the Performance Verification Test (PVT) only for 1-L vessels. Can this procedure be used with 2-L vessels or is only mechanical verification necessary for these larger vessels?
A The PVT was developed for vessels having a nominal capacity of 1 L. The collaborative study used to set the PVT limits is conducted on instruments with 1 L vessels, so the PVT limits do not apply to dissolution systems with alternative vessel dimensions and volumes. A typical approach is to setup the instrument and perform the PVT with 1 L. Then, set up the equipment with your 2-L vessels provided that the mechanical calibration parameters (i.e., vessel alignments, paddle height, etc.) with the 2 L vessels installed meet the requirements stated in <711>, then it is assumed that the instrument will perform as expected.

Q The deaeration procedure described in the USP <711> Dissolution states that "the measured vacuum should be less than 100 mbar." Does it mean the vacuum pressure range is 0-100 mbar or the opposite?
A Yes, the pressure of the container under vacuum should be in the range from 0-100 mbar. The applied vacuum should below 100 mbar for the entire 5 minutes.

Q What is the role of sodium lauryl sulfate (SLS) in the dissolution test in the USP monograph for simvastatin? What will be the impact if there is an excess of 50 g in preparation of the dissolution medium?
A Simvastatin is a poorly soluble drug. SLS, a surfactant, is used to increase the solubility of simvastatin. The dissolution test for any formulation containing simvastatin is likely to be formulation-dependent. The validated dissolution test should be discriminative for the critical quality attributes of the formulation. A higher amount of SLS may lose the discriminatory power of the dissolution test. Whatever the concentration of SLS used, the discriminatory power of the dissolution method will have to be verified as part of the dissolution method validation.

Q We are developing a dissolution test for tacrolimus capsules. In the USP monograph for this product, the dissolution medium uses hydroxypropyl cellulose. Is there any information about what specific type (viscosity grade/ molecular weight) of hydroxypropyl cellulose that we can use?
A The dissolution test for tacrolimus capsules is formulationdependent. Each formulation is going to have its own specific and discriminative dissolution test. This is the reason for multiple dissolution tests in the USP monograph for tacrolimus capsules. Each dissolution test in this monograph is specific for a particular product approved by FDA for the US market. A dissolution test that is discriminative for the critical quality attributes of your formulation should be developed and validated. You can find the specification of any reagent mentioned in USP-NF in the Reagent Specifications section where all reagents are listed in alphabetical order. Hydroxypropyl cellulose is used to minimize the adsorption of tacrolimus into the glass walls of the dissolution vessels.

Q As per USP <711> Dissolution, "The assembly consists of the following: a vessel, which may be covered, made of glass or other inert, transparent material." Usually, we are using glass and polycarbonate vessels for drug product dissolution analysis. Which one is recommended by USP or is a glass vessel mandatory?
A As there are drug substances that adsorb in glass and others in plastic, this effect will need to be evaluated on a case-by-case approach to determine which type of vessel is the most appropriate for each formulation being evaluated.

Q What should be the temperature of dissolution medium during the test?
A The temperature of the dissolution test is 37°C for products with internal use (see USP general chapters <711> and <1092>) and 32°C for products applied to the skin (see USP <724> and <1724>). For veterinary products, the temperature depends on the animal species (see USP <1236>). Other temperaturesmay be used with appropriated justification. Examples ofdissolution tests approved with other temperatures canbe found at https://www.accessdata.fda.gov/scripts/cder/dissolution/ and https://www.usp.org/resources/dissolutionmethods-database.

Q In the USP <711> Dissolution it is stated that if the Stage 1 (S1) dissolution test does not meet the criteria, then the test continues to Stage 2 (S2), and if it still does not meet the test criteria, then continue to Stage 3 (S3). If there is a QC laboratory conducting a dissolution test up to S3 and the results do not meet the criteria, is it necessary to investigate the Out of Specification (OOS) results for the sample or is the dissolution test up to S3 already part of the investigation? If results after S2 already fail S3, is it necessary to perform S3? That is, I already have more than 2 units < Q - 15%. Is it acceptable to state the samples fail S3 without performing S3?
A The three levels in the acceptance table are part of the results evaluation and are not an OOS investigation. If the sample does not meet the specification at the three levels, the product is considered not meeting the acceptance criteria, and an OOS investigation should be conducted. In this case the purpose of the OOS investigation would be to determine the root cause of the dissolution failure. If you have results at S2 already failing S3, then the results should be discussed within the context of the quality management system at your organization to determine next steps. In some cases, it may be necessary to have additional data obtained from S3, for example, to make the appropriate decision.