Question and Answer Section — August 2015

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:

Q The dissolution test is a two-step process; the first step involves placing the dosage form in the dissolution apparatus and letting the dissolution occur, and the second step is the analysis of the aliquot taken from the dissolution medium. According to the USPGeneral Chapter <1225> Validation of Compendial Procedures, dissolution testing is a Category 3 test, and the only parameter recommended for its validation is precision. I would like to know if this precision is evaluated only in the first step or in the first and second steps of the dissolution test.
A The USP General Chapter <1225> Validation of Compendial Procedures does not give details for validating dissolution procedures. For more information, refer to <1092> The Dissolution Procedure—Development and validation. See the revised version of this chapter in the First Supplement to USP 38. The parameters that need to be validated for dissolution procedures are specificity, linearity range, accuracy, and precision. The limit of quantification is useful when you have a dosage form with very low drug content.

Q How much sampling volume can be withdrawn at each sampling time without medium replacement?
A This needs to be evaluated in a case-by-case approach. Although maintaining constant and reproducible hydrodynamics is an issue, the drug substance solubility may also be a consideration. The solubility of the drug load should not violate sink conditions with the reduced volume.

Q When should the pH of a dissolution medium containing surfactant be measured, after or before the addition of the surfactant to the buffer?
A You need to consider the type (anionic, cationic, and amphoteric) and the concentration of the surfactant in the medium. These two parameters may affect the performance of the electrode. It may be necessary to regenerate the electrode after the measurement. It will be advisable to check the recommendations from the electrode manufacturer.

Q What should be the water level in the dissolution water bath?
A You should always check the recommendations of the manufacturer of the dissolution equipment. The level of water in the water bath should always be above the level of dissolution medium in the vessel.

Q The USP has a monograph where the dissolution test is done with ordinary vessels. Can we use peak vessels in the dissolution test of this product?
A The vessel is part of the test conditions. Furthermore, the conditions of the test cannot be changed without proper justification. Peak vessels are not compendial apparatus, and their use also requires proper justification. In most cases, the problem can be solved just by increasing the speed of the paddle.

Q What type of adhesives can be used to fix the transdermal system (TDS) on the USP Apparatus 6?
A Several options on how to fix the TDS in the USP Apparatus 6 are described in the USP General Chapter <724> Drug Release. They need to be selected in a caseby- case approach and verified for possible interference with the quantitative procedure.

Q We are developing a dissolution test for soft gelatin capsules and are finding a relative standard deviation (RSD) greater than 20% after 2 h. After 3 h, the dissolution is completed and the RSD is around 0.5%. Does the RSD have significance in dissolution testing?
A Yes, RSD does have significance in dissolution testing. The variability in dissolution has two components: the variability from the manufacturing process and the variability of the dissolution procedure. It is difficult to determine the contribution of each one of these components. Variability should be evaluated along the dissolution profile to understand the product and evaluate the test method. In most cases, as with your results at 3 h, the variability from the dissolution procedure tends to decrease after a certain time because the dissolution rate is decreasing as complete drug release is approached. For your soft gelatin capsule, the high variability after the relatively long time of 2 h may indicate that the capsule contents are dissolving variably due to capsule shell opening or to the properties of the capsule contents.

Q What is the logic behind using 6 units in the dissolution test and 12 units for dissolution profile?
A We recommend that you read the article “An Early Look at Dissolution Testing, Including Equipment, Calibration, and Acceptance Criteria” by Dr. Tim Grady published in Dissolution Technologies (August 2014).

Q After a mechanical calibration is performed on a dissolution equipment setup for baskets, we are keeping each vessel-basket-shaft combination constant for the calibration to remain valid. In other words, post-calibration, the baskets are not to be used interchangeably among all the vessels. Is this interpretation correct? If a basket was damaged during the cleaning procedure, does the replacement basket need to be calibrated before use? Or, can the new basket be considered “like-for-like” and be used right away? When switching a calibrated system from 40-mesh baskets to 100-mesh baskets, is calibration required on the new 100-mesh baskets?
A There are two schools of thought on this subject. Strictly, the apparatus is the shaft, stirring element, vessel, and position of the test assembly. From that point of view, any change will have to be qualified. We recommend this more conservative approach where the suitable performance of the system is confirmed. Our recommendation is to demonstrate that the new system acts as a whole system and provides acceptable performance. Once qualified, the stirring elements and vessels should be kept in the positions where they were qualified. We do not have any data for baskets with finer mesh baskets.

Q How should peak vessels be calibrated?
A There is no official procedure to calibrate peak vessels. Because this type of vessel is not compendial, it is not standardized and the dimensions may vary among different vessel manufacturers. A full description of the vessel should be included in the dissolution procedure.

Q If we have one drug product in two different strengths, can we select one of these two strengths to validate the dissolution method?
A Especially when differences in formulation exist, the method needs to be validated for all strengths.

Q USP has a monograph for Mefenamic Acid Capsules with a dissolution test. If we want to use this dissolution procedure for a tablet formulation, will we only need to perform a method verification following the USP General Chapter <1226> Compendial Method Verification?
A No. First, you need to verify that the dissolution procedure is suitable for your formulation by evaluating dissolution profiles obtaining with your samples. If you find it suitable for your product, you would need to do a complete validation of the method.

Q What are the mesh sizes of baskets that can be used in dissolution?
A See USP General Chapter <701> Dissolution. The sizes are 40 (default), 20, and 10 mesh. Any other mesh size can be used with appropriate justification.

Q How should the concentration range for the validation of linearity of a dissolution test be selected? One document we found states that the range should be ±20% of the Q value, and another document says that it should be ±20% of the dissolution profile.
A You need to select a quantitative procedure that is linear and has the appropriate levels of accuracy and precision for all the points in the dissolution profile. Therefore, you need to consider the entire dissolution profile to define the concentration range for the evaluation of linearity. Some companies also include the upper limit of uniformity of dose in this range.

Q The instructions for the Performance Verification Test (PVT) for USP Apparatus 1 and 2 call for water as dissolution medium. Where in USP is the description of the quality of this water?
A The specification for water for analytical purposes can be found in the Reagents, Indicators and Solutions section of the USP under 4. Definitions, 4.7 Water.

Q The deaeration procedure in USP General Chapter <701> Dissolution instructs to heat the medium to 41 °C and immediately filter under vacuum. The Performance Verification Test (PVT) for USP Apparatus 1 and 2 states that the temperature should not drop below 37 °C to avoid raising the dissolved gas level in the medium. Also, <701> states that the medium volume is specified between 20 and 25 °C. At what temperature should I transfer the medium to the vessels?
A The USP deaeration procedure results in medium that is above the test temperature, so you need to measure the volume by weight using the density of water at room temperature. You will transfer the weighed deaerated medium to the vessel as soon as possible and let it equilibrate by cooling to the appropriate temperature in the water bath.

Q In the proposed new monograph for Hard Gelatin Capsule Shell published in Pharmacopeial Forum 41(1) (, under Disintegration test, the instructions are to fill up the capsule with an inert excipient such as lactose and use the disks. Meanwhile, USP General Chapter <701> Disintegration states to run the test for hard gelatin capsules with a removable wire cloth. Why are the instructions in these two documents different? Should the instructions in the monograph be the same as those in the general chapter?
A USP general chapters contain the instructions that are applicable in most cases. Any deviation from the general chapter or additional instructions will be described in the appropriate particular monograph. The information in a USP monograph supersedes the information in any USP general chapter.

Q We are running the dissolution test for a delayedrelease formulation by performing the acid stage with 750 mL of dissolution medium and, after the appropriate time and sampling, adding 250 mL of the buffer dissolution medium. Should the buffer be at 37 °C?
A Yes. Any time you add dissolution medium to the vessel, whether in the case of delayed-release dosage forms or when replacing the volume of any aliquot withdrawn, the medium needs to be prewarmed to the temperature of the test.

Q In the USP General Chapter <701> Dissolution there are two ways of running the dissolution test for delayedrelease dosage forms: one option is to begin with 750 mL of the acid stage medium and later add 250 mL of a buffer; the second option is to use 1000 mL of both acid and buffer stage medium. How can the appropriate option be selected when developing a dissolution test for this kind of product? When using the second option, how can the dosage form be transferred to another vessel if the dosage form sticks to the bottom of the vessel?
A The selection of the procedure should be done during method development and in a case-by-case approach. The way the sample will be transferred to the other vessel depends on the type of dosage form (tablet, granules, capsule) and how the dosage form behaves during the dissolution test. Depending on the formulation, the dosage form may remain intact or can partially disintegrate during the acid stage. If the dosage form remains intact, you can use any instrument (spatula, tweezer, scoop, etc.) to transfer it to the other vessel. For granules, it may be necessary to filter the contents of the vessel to collect all the granules. In some cases, you will remove the dissolution medium by vacuum or any other procedure, and the dosage form will remain in the vessel. If the dosage form sticks to the vessel wall, it may necessary to use an appropriate sinker.

Q In the Question & Answer section of the February 2014 issue of Dissolution Technologies, you stated, “instead of measuring the amount of drug substance released into the acid stage medium of the dissolution test for a dosage form containing this type of compound, you can measure the amount of drug substance that still remains in the dosage form” when the drug substance degrades in the acid stage medium. Could you give more details on how to run this procedure?
A It depends on the type of dosage form. If it is a tablet and it remains intact during the acid stage, you can use any appropriate tool (spatula, tweezer, scoop, etc.) to remove it from the vessel, and then you run the quantitative procedure used in the evaluation of uniformity of dose. If the dosage form is granules, you may need to filter the entire contents of the vessel. You can use a cannula with a filter attached and remove the medium by vacuum.

Q We are developing a drug release method that uses USP Apparatus 6 (cylinder), and we would like to know the requirements to control the speed of the cylinder.
A The rotation speed of the USP Apparatus 6 (cylinder) should be controlled using the same range as for USP Apparatus 1 (basket)—within ±4% of the rate stated in the monograph or method.