dx.doi.org/10.14227/DT200313P56

Question and Answer Section — August 2013

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 What procedure should be used for the performance verification testing (PVT) and mechanical calibration of 250-mL dissolution vessels?
A At this time, USPprovides neither mechanical calibration nor a PVT for 250-mL vessels. Mechanical calibration requires first an understanding of the critical dimensions and parameters for the apparatus. Control of these dimensions and parameters is necessary for the minimization of variability of dissolution results as an artifact of the apparatus. A PVT requires a probe that will confirm that the apparatus functions acceptably as a system in its intended purpose, specifically the production of dissolution samples that represent the in vitro performance of the dosage form itself. The development of a PVT is not a trivial exercise. The maintenance of the USP Prednisone Tablets RS and the PVT for USP Apparatus 1 and 2 consume a significant portion of available staff, laboratory, and volunteer resources at USP. For the present, the user of alternative dissolution apparatus is responsible for the demonstration of acceptable equipment performance.

Q How is a dissolution test for an oral gel developed?
A The development of a dissolution test for an oral gel should follow the same steps as in the development of a dissolution test for any dosage form. See the USPGeneral Chapter <1092> The Dissolution Procedure: Development and Validation. A new USPgeneral chapter was developed for the dissolution test of semisolid dosage forms such as gel, lotions, creams, and ointments. General Chapter <1724> Performance Tests for Topical Drug Products, published in Pharmacopeial Forum38(3) (www.usppf.com), will be official in the First Supplement of USP 36. Depending on how and where a gel is applied, it may be necessary to use unusual testing conditions (see USPmonograph for Minocycline Periodontal System that uses the rotating flask apparatus).

Q We would like to do a comparison of dissolution profiles for a particular product that has no compendial monograph. Can surfactants be added to the dissolution medium? If yes, what are the limits for the amount to be added and what is the apparatus speed to be used?
A The use of surfactant in the dissolution medium should be the last resort because surfactants can mask problems in the formulation or in the test. Before adding the surfactant, you should explore other options such as (1) increasing the volume of medium (with USP Apparatus 1 or 2 you can easily use up to 2 L, or try USP Apparatus 4 that can go up to 3 L/h); (2) increasing the agitation speed or flow rate; (3) increasing the time to run the dissolution profile; (4) changing the composition of the medium (ionic strength, different counterion, different salts, etc.); or (5) using USP Apparatus 3; which has a more turbulent mixing mode than Apparatus 1 or 2. If none of these options is appropriate, then you can explore the use of surfactants. You need to justify the amount and type of surfactant used. The amount to be used should be the smallest possible. Recommendations on how to select a surfactant and the amount to be used are given in the paper "Steps for Development of a Dissolution Test for Sparingly Water-Soluble Drug Products" available at http://www.dissolutiontech.com/DTresour/200articles/200art3.html. The list of surfactants that have already been used in dissolution testing is available at http://www.dissolution-tech.com/DTresour/200511Articles/DT200511_QA.html.

Q Is it necessary to establish the discriminatory power of the dissolution method if the test conditions (medium, apparatus, speed, etc.) are the same in a compendial monograph for the product under evaluation?
A The first step is to verify that the compendial test is suitable for your product by running a dissolution profile. If the drug substance present in your formulation is BCS Class 1 or 3 and if your formulation is immediate-release, there is a good chance that the compendial test may be appropriate for your product. If the drug substance is BCS Class 2 or 4 in an immediate-release formulation or if your product is modified-release (delayed- or extended-release), there is a good chance that the compendial test will not be appropriate for your formulation because with these products, the dissolution test is formulation/release mechanism dependent. In this case, you need to develop an appropriate and discriminative dissolution test for your formulation.

Q The USPGeneral Chapter <1087> Apparent Intrinsic Dissolution—Dissolution Testing Procedures for Rotating Disk and Stationary Disk recommends the use of 15 MPa in the compact preparation. Our equipment measures pressure as tons. How are the units converted to MPa?
A The Pascal is an SI unit of pressure equal to 1 N/m 2 . A mega Pascal is 10 6 Pascal. A Pascal is equivalent to 1.450377 × 10 4 psi. Therefore, a MPa is 1.450377 × 10 2 psi. From there, one would have to know if the ton is short or long. A short ton is 2000 pounds (U.S.); a long ton is 2240 pounds (U.K.). You need to know what is meant by the ton on your equipment.

Q The USPGeneral Chapter <711> Dissolution seems to suggest that only 1-L, 2-L, or 4-L vessels are allowed for dissolution, and yet there are monographs that use volumes less than the typical 900 mL. I have a validated method for a 50-mg tablet using 900 mL of medium, and I want to scale the dissolution volume down to 450 mL so that the current validated method can be used for the lower dose tablets. Can we scale down to a 500-mL dissolution vessel, or should we use the 900-mL vessel with the 450-mL volume and use extensions on the dissolution autosampler?
A The text in the USPGeneral Chapter <711> Dissolution specifies the nominal capacity of the vessels and not the volume of medium to be used. The volume of medium is defined by the sink condition. Vessels with volumes other than the ones mentioned in <711> can only be used with appropriated justification. The 500-mL vessel is not described in USP. Consequently, its dimensions are not standardized, and they can vary from one supplier to another. If you decide to use the 500-mL vessels, you need to check the dimensions of the vessels used during method development and the ones that will be used in routine analysis. If you decide to use 450 mL of medium in a 1000-mL vessel, you need to be careful when performing a dissolution profile. The volume of medium withdrawn has to be replaced with the same volume of a prewarmed medium. If the volume of medium inside the vessel is less than 300 mL, it will be difficult to sample in the proper place, and the mixing inside the vessel will be compromised.

Q Are there any recommended procedures regarding the investigation of extraneous peaks observed in dissolution testing? Is there a guideline that describes at what point an extraneous peak should be investigated?
A Any extraneous peak observed in dissolution testing must be investigated at least to confirm that the active ingredient is not degrading in the test conditions. Possible causes for the presence of extraneous peaks are: degradation of the active ingredient; impurities or degradation products present in any of the components of the formulation or in any reagents used in the test; interference from components of the formulation; and leachables or extractables from the filter or any other accessory including the chromatographic column. See the USPGeneral Chapter <1092> The Dissolution Procedure—Development and Validation. An updated version of this chapter will be published in Pharmacopeial Forum40(1) [Jan–Feb 2014], available free of charge at www.usppf.com.

Q How can the acceptance criteria at different time intervals be established for extended-release tablets?
A The acceptance criteria are defined from the dissolution profiles obtained from the biobatch (batches used in any in vivo testing), the production batches, the batches with deviations in key quality attributes, and the batches from accelerated stability studies. The acceptance criteria for extended-release tablets need to have at least three time points: one at the beginning of the profile to demonstrate that there is no dose-dumping, one in the middle, and the last one when about 80% of the label claim has been released or when the profile reaches a plateau. If there is an in vivo–in vitro correlation, it can be used to better define the acceptance criteria with even broader ranges.