Question and Answer Section — November 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

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Q USP General Chapter <724> Drug Release states that the qualification of USP Apparatus 5 (paddle over disk) should be done in the same way as directed for USP Apparatus 2 (paddle) in <711> Dissolution. Should we carry out this qualification with the disk assembly?
A The qualification of USP Apparatus 5 should be done using the procedure stated for USP Apparatus 2 in the General Chapter <711> Dissolution without the disk assembly. The paddle in USP Apparatus 5 is the same as that in USP Apparatus 2.

Q The monograph for Thyroxin Sodium Tablets in the British Pharmacopoeia mentions the use of two tablets per vessel. Can we use multiple tablets per vessel in the case of very low product label claim?
A We do not know the rationale for using two tablets in the monograph for Thyroxin Sodium Tablets in the British Pharmacopoeia. According to USP, only one unit should be introduced in each vessel or cell. If the product has a very low strength, a quantitative analytical procedure with high sensitivity should be used. If more than one unit is used in each vessel, the interaction between the product and the dissolution medium will be compromised and a higher variability in the results may be found.

Q In the USP General Chapter <711> Dissolution, Apparatus, Apparatus 2 (Paddle Apparatus) is written, “The dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started.” Does this mean that the sample must be introduced before mixing or may the sample be introduced after mixing starts?
A The dosage form should be at the bottom of the dissolution vessel before the paddle starts its motion. If the dosage form is introduced with the paddle in motion, it may hit the paddle and be damaged, invalidating the test.

Q Are there any USP monographs, official or proposed, that call for USP Apparatus 4 (flow-through cell)?
A At this time, the only USP monograph that calls for the use of USP Apparatus 4 is Rufinamide Tablets. It can be seen in the FDA dissolution methods database ( ) that the agency has already approved other products that use the flow-through cell in the dissolution test.

Q Until some years ago there was a recommendation in USP to run pooled sample with six tablets or capsules in one of the six vessels. I was not able to find this information in the current edition of USP. We need to run the dissolution test for a particular product according to the USP monograph, but the text does not indicate how many tablets should be placed in each vessel. Has the number of dosage units per vessel any relationship with the sensitivity of the quantitative procedure?
A USP has never recommended the use of more than one unit per dissolution vessel. This is written in the USP General Chapter <711> Dissolution, under Procedure, Apparatus 1 and Apparatus 2, Immediate-Release Dosage Forms. The pooled sample procedure described in the same chapter should not be confused with testing multiple units in a vessel. If the USP monograph calls for the pooled sample, one unit is placed in each vessel, the aliquots of the six vessels are combined in just one solution, and this solution is used to quantify the amount of drug substance dissolved. The limitation of the analytical method is not a justification for testing multiple units in a single vessel. In all cases, only one unit is introduced in each vessel or cell. If the product has a very low label claim, a quantitative procedure with high sensitivity should be used.

Q USP General Chapter <701> Disintegration does not state to use disks, but rather to use them only if mentioned in the specific USP monograph. Does this mean that disks are not recommended for tablets and capsules? At the time of disintegration testing of hard gelatin capsules, should we evaluate the disintegration of only the capsule or the disintegration of the capsule filling? Sometimes a powder filled in a capsule becomes a “lump” and remains on the screen. Shall we wait for complete disintegration of powder lumps?
A The chapter says, “if prescribed, add a disk.” That means that the use of a disk is not common and needs to be part of the procedure in the monograph. If the use of a disk is not part of the explicit procedure in the monograph, it is not used. Only a few monographs have disks as part of the explicit procedure. An example of a monograph with the disk used for disintegration testing is Phenelzine Sulfate Tablets. The chapter states, “For the purposes of this test, disintegration does not imply complete solution of the unit or even of its active constituent. Complete disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.” This allows some residue to remain at the end of testing but restricts the allowable residue to a soft mass having no palpably firm core. If the powder is not firm to the touch, it will pass this criterion.

Q The USP General Chapter <1092> The Dissolution Procedure: Development and Validation, under Validation, Accuracy, states that in the cases of poor drug solubility, it may be appropriate to prepare a stock solution by dissolving the drug substance in a small amount of organic solvent (typically not exceeding 5%) and diluting to the final concentration with dissolution medium. Is this common practice during validation of dissolution procedures where the quantitative determination is by spectrophotometric techniques (UV-vis range)
A If the drug substance has low solubility in the dissolution medium, you can either prepare a stock solution using organic solvent then make the further dilutions with dissolution medium or you can dissolve the drug substance in a small amount of organic solvent (typically NMT 5% of the volume of the first dilution) and then dilute to volume with dissolution medium. You can use this strategy during method development, method validation, and in routine analysis regardless of the technique used in the quantitative step in the dissolution procedure.

Q Regarding the amount of pepsin to be used in the dissolution testing of gelatin capsules that present cross-linking, we carried out the assay test on the pepsin, and we obtained an activity value of 1205 for 2.5 mg of pepsin. Would this be a typical activity value for this amount? Also, how would you calculate the quantity required to give 750,000 U/L?
A There is no typical value for the pepsin activity; it depends on the activity of the pepsin you bought. The activity varies from supplier to supplier and even within the same supplier from batch to batch. This is the reason for the recommendation of determining the activity in your lab. Also, keep in mind that enzymatic activity may change with time. To calculate the amount of pepsin to be used, you need to know the activity per mg of enzyme. If the pepsin has an activity of 2000 units per mg, you could use up to 375 mg in a liter of dissolution medium.

Q I would like to know what could be a suitable dissolution medium for cilnidipine.
A Based on information available in the literature, cilnidipine is a BCS Class 2 compound; it has poor solubility in aqueous solvents in the physiological pH range. To select the most appropriate dissolution medium for this compound, you need to determine the solubility of the drug substance you will use in your formulations in different media within the physiological pH range at 37 °C. As different formulation strategies may be used to increase the solubility of BCS Class 2 compounds, the dissolution test will be formulation dependent. Therefore, you need to discuss with your formulation/development group how the drug product will be formulated. Depending on the formulation, you may need to use surfactants in the dissolution medium. You can find a recommendation on how to select the appropriate surfactant in the February 2000 issue of Dissolution Technologies.

Q Based on the results obtained during the validation of a dissolution procedure, I needed to go to S2 stage. Do I need to justify the reasons for going to S2?
A During the validation of dissolution procedures, no parameter is validated against the acceptance criteria. Therefore, there is no reason for going to S2 or S3 stages. In the validation of dissolution procedures, the entire dissolution profile should be considered.

Q If a failing dissolution test result is obtained at L2 and an additional 12 tablets need to be run, can two different apparatus be used so that the 12 tablets are run at the same time or should the tablets be run on the same apparatus, which means that only six tablets will be run on that apparatus at a time and the data from a total of 12 tablets will be obtained?
A There are no official rules or guidelines to be used in a situation like the one you described. Based on the method validation and the performance qualification of the assemblies, you can run 12 units in two separate dissolution apparatus or you can do two runs of six units in the same apparatus.

Q According to the USP Dissolution Toolkit version from 22 March 2010 ( ), when degassing the dissolution medium by vacuum, “the measured vacuum should be less than 100 mbar,” while in the current USP General Chapter <711> Dissolution, only “vacuum” is required. It this parameter critical, and if so, what would be the appropriate range for 100 mbar?
A The tool kit is not official USP text. It is only a recommendation and is intended to help you perform the PVT. The official text is the one in USP-NF. In <711>, there is only one procedure to deaerate dissolution medium. Other procedures can be used if validated. See the paper Comparison of Effectiveness of Various Deaeration Techniques ( ).