Question and Answer Section

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 When the dissolution medium is being transferred to the vessels, should the medium be at room temperature, or should it be at 37 °C?
A Regardless of the temperature of the medium, after transferring it to the dissolution vessels, you will need to wait for its temperature to equilibrate with the temperature of the water bath. Room temperature medium will require a longer equilibration time. If the medium is delivered at 37 °C, some method will be needed to ensure that it is equivalent to the specified volume if measured at 25 °C. You can only start the dissolution test after the dissolution medium in all vessels has been equilibrated to 37 � 0.5 °C. See the USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and 2, Immediate-Release Dosage forms, page 282 of USP 30. Remember that temperature and timing are important variables that impact the deaerated status of dissolution media if that is a particular concern.

Q Could you suggest formulations of dissolution media that simulate fed and fasted states?
A You can find some suggestions of formulation and how to prepare dissolution medium simulating fast and fed states in the paper “Dissolution media simulating fasted and fed states,” Dissolution Technol. 2004, 11 (2), 16, available at www.dissolutiontech.com. You can find more information on this topic in the web site www.NCBI.NLM. NIH.GOV (access free of charge).

Q Can the dosage form unit be introduced in the dissolution vessel with the paddle in movement?
A If the dosage form is introduced with the paddle in movement, there is a chance that the dosage form is going to hit the paddle and possibly change the disintegration time or damage the coating. If that happens, you need to start the test all over again. The recommended procedure is to introduce the dosage form with the paddle not in movement, and as soon as the dosage form hits the bottom of the dissolution vessel, immediately operate the apparatus at the specified rate given in the individual method or monograph. See the USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and 2, Immediate-Release Dosage forms, page 282 of USP 30. For deaerated media, the rate of re-equilibration is increased in a moving medium. Thus, for the Performance Verification Test, USP recommends that the medium not be stirred before the start of the test to achieve temperature equilibration. An additional consideration is that the motion of the medium is a critical factor contributing to the observed dissolution rate. Different observed dissolution rates may be observed for the same sample in media that is initially still and media in motion.

Q When running dissolution tests in multiple stages, such as acid and buffer stage, how can the dosage form be transferred from one stage to the other?
A We suggest you have a look at the USP General Chapter <711> Dissolution, under Procedure, Delayed- Release Dosage Forms, method A and B, page 282 of USP 30. There are basically two ways you can do the transfer of the dosage form from one stage to the other: 1) you can use 750 mL of acid medium and, after the appropriate time and with the acid-stage sample withdrawn, add 250 mL of an appropriate buffer to increase the pH to 6.8 and 2) you can drain the acid medium and replace it with the buffer medium. There are other alternatives you can use, depending on your dosage form. You can remove the dosage form from the vessel containing the acid medium using an appropriate device and transfer it to the vessel containing the medium for the next stage. There are some automated dissolution systems that change the medium with the dosage form inside the vessel.

Q The ICH guidance Q2(R1) is not very clear on how to validate dissolution tests. Is there any other guidance or document with more details?
A The U.S. Pharmacopeia developed a new general chapter that gives more details on how to validate a dissolution method. It is the general chapter <1092> The Dissolution Procedure: Development and Validation, pages 579�584 of USP 30. This general chapter was preceded by a paper published in Pharmacopeial Forum: Gray, V. A.; Brown, C. K.; Dressman, J. B.; Leeson, L. J. A New General Information Chapter On Dissolution. Pharm. Forum 2001, 27 (6), 3432�3439.

Q Are there any industry practices that address tablet calibrations on USP Apparatus 1 when two different mesh baskets are used? For example, USP states that a 40-mesh basket should be used unless otherwise stated in the individual monograph. I have a procedure that will be using a 10-mesh basket. Should separate tablet calibrations be performed on a single system with both 40- and 10-mesh baskets?
A The procedure for verification of the suitability of the dissolution apparatus has been recently reviewed, and the new version can be found in Pharmacopeial Forum 33 (4), page 626. USP does not specify the operational qualification for basket screen sizes other than the nominal 40 mesh. The performance verification of USP Apparatus 1 uses the 40-mesh basket. If the equipment meets the acceptance criteria for the particular reference standard tablet (found at www.usp.org/referenceStandards/useAndStorage/calibrators.html), the equipment is considered to be acceptable.

Q Do sample acquisition and analysis for the dissolution apparatus performance verification test (calibration) have to be done manually or can they be done using an automated system?
A The recommended procedure (that can be found at www.usp.org/referenceStandards/useAndStorage/calibrators.html ) uses a manual procedure for sample acquisition and UV spectrophotometry for quantification. You can use validated automated procedures. Remember that the automated system, while providing decreased opportunity for variability due to operator and more efficient use of human resources, may introduce other sources of uncertainty not encountered with manual methods.