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 To avoid filtration of dissolution samples, we have employed several methods that use UV detection at a specific wavelength with background subtraction at another wavelength where the analyte does not absorb. As part of validation, we have shown equivalence between results generated by this technique and results obtained by filtration of samples. Recently, there have been some concerns about the impact of secondary dissolution in our technique where undissolved material in a withdrawn sample might dissolve prior to analysis, thus biasing the results high. Do you have any comments?
A This answer was provided by Bryan Crist, member of USP Expert Committee on Biopharmaceutics and a Varian associate (bryan.crist@varianinc.com). A dissolution result is a moment captured in time. In a disintegrating sample, the sample integrity is compromised if particles are still present and in contact with sample medium for any time-point beyond a 2% window. In other words, the dissolution process continues until solid particles are removed by filtration. If the sample is pulled through sample tubes, pumps, and transmission lines for on-line UV analysis, there may also be a significant increase in dissolution results due to solid particles encountering extreme turbulence as they travel to the sample compartment of the UV detector. Occasionally, one may notice a very high result in an early time-point even with manual sampling, which is generally due to a single particle entering a syringe unfiltered. Such a particle will be exposed to extreme turbulence inside the sampling cannula and syringe and enter into the solution even before a syringe filter is used to clarify a sample for analysis. It is not uncommon for such a solution to yield a result well over 100% at the first time-point, only to return to normal with subsequent time-points. The reason is that a particle of active drug is much more noticeable in a nominal 10-mL sample size than it would be if it were missing from 900 mL. On-line fiber-optic UV may be an answer, but this technique may also enhance dissolution through the increased hydrodynamics associated with resident-dwelling probes. The only exceptions are when one does not have a disintegrating dosage form and particles are not present in the sample medium.

Q What does the Q value stand for in the dissolution acceptance criteria?
A
The Q value is a percentage of the product's label claim. It is found in a USP monograph dissolution test under the Tolerances section and has a time interval associated with it. The usual form of the monograph statement is “Not less than X% (Q) of compound is dissolved at Y minutes. ”Q is also a variable that is used in Acceptance Table 1 in the USP General Chapter <711> Dissolution, where it provides the specific criteria to evaluate a product's conformance to the USP dissolution standard. To evaluate conformance, the Q value found in the monograph is inserted in the acceptance table. Acceptance Table 1 is primarily used for immediate-release dosage forms, where only one testing time interval is required.

Q What is the most appropriate procedure for introducing the baskets into the dissolution apparatus, lowering all baskets simultaneously to all vessels or staggering them?
A Dissolution testing with baskets requires that the dosage unit is placed in a dry basket during the setup. This means that at the start of the test, the basket with dosage unit is lowered into the medium. The start of timing is when the basket is in position in the vessel and rotating. The sample is withdrawn to end the test. The requirement for timing the test allows a 2% error. That means that a nominal 30-minute test must be sampled within 36 seconds (before or after). Staggering the start of the run so that a specific time lag is introduced between the lowering of baskets into successive vessels is an option offered by some test assembly designs. The ability to disengage and engage the drive from each shaft position is important for such staggered starts.

Simultaneous lowering of all baskets is best used when an autosampler is provided that will pull samples from all vessels at the sampling time. This ensures that the test interval is the same from vessel to vessel. As you consider the two procedures, remember the discussion with question 1 of the effect of undissolved material in the withdrawn unfiltered test solution.

Q Where can the information about the Biopharmaceutical Classification System for a particular drug be found?
A The FDA Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (BCS), available at www.fda.gov/cder/guidance/3618fnl.htm, has a list of some drugs with their respective BCS classifications in Attachment A. In addition, the following papers have a provisional BCS classification for the WHO essential drugs:

Kasim, N. A.;et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Molec. Pharm. 2004 1 (1), 85�96.

Lindenberg, M. ;Kopp, S.;Dressman, J. B. Classification of orally administered drugs on the World Health Organization model list of essential medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm. 2004, 58, 265�278.

This information may also be available, but not as tabulated data, in papers related to biopharmaceutics aspects of drugs available at www.NCBI.NLM.NIH.GOV (access free of charge).

Q What is a biowaiver?
A It is when the applicant requests a waiver of in vivo bioavailability or bioequivalence studies for immediaterelease solid oral dosage forms from the regulatory agency. This waiver can be requested in special cases;one example is when the approach of Biopharmaceutics Classification System is used. For more information, see the FDA Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (BCS), available at www.fda.gov/cder/guidance/3618fnl.htm). Also, verify with the regulatory agency of the region where the product is going to be registered.

Q What does the term “discriminating media” mean?
A It is not only the medium that may be discriminating, it is the whole dissolution test. When developing a dissolution test, the dissolution conditions (medium composition, apparatus, speed, etc. ) should be selected in such a way that if there is a deviation in a critical attribute of the product, a difference in the dissolution profile will be observed. The critical attribute is going to vary from one product to another. It can be particle size, crystal form, percentage of a certain excipient, hydration state of the drug substance, etc. In most cases, this critical attribute should be the one that is going to interfere with the in vivo performance of the product. One example is particle size of the drug substance for poorly soluble drugs. If the particle size is out of the optimal range, the drug is not going to dissolve appropriately, and a difference in the in vivo performance may be observed.

Q What could be the reason for observing dissolution results higher than the assay results?
A Assuming that the determinative step involves spectrophotometry with the analysis conducted at a given wavelength, several factors may produce apparently higher dissolution percentages than what was found in the Assay. Degradation of the compound under the test conditions is a possibility as is additive interference due to excipients. These types of interferences should be identified in method development and validation. Of course, errors in the preparation of the standard solution(s) could also play a role. Again, careful attention to detail, such as the requirement to prepare check standards and familiarity with the absorptivity of the standard solution, can provide protection against these types of problems. It is important to consider the possibility that the higher values found in the dissolution sample may be true. The assay value is typically the result of the analysis of a composite of multiple dosage units and, as such, represents an average. If individual dissolution values that are higher than the assay are observed, content uniformity might be to blame. The amount available for dissolution in the higher-than-assay dosage unit may indeed be higher than the amount in the assay composite. If consistently higher values are found in dissolution than in the assay, it may indicate that the validating information for the dissolution test should be reevaluated.