dx.doi.org/10.14227/DT140207P42

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 There are several types of sinkers available on the market. How can one decide which sinker design is the best one?
A The type of sinker used should be carefully evaluated because it can have a big impact on the release of the drug from a dosage form. (See Soltero et al.,J.Pharm.Sci. 1989, 78 (1),35�39.) The sinker can affect the dissolution rate by either restricting the dissolution by forming a barrier or by providing additional agitation in the environment of the dosage form.The sinker can cover the capsule shell, retarding its dissolution. This can also be the case with the dissolution of the capsule contents,where the sinker does not allow proper contact between the dosage form and the medium.When comparing the dissolution rates obtained with different sinkers, the variability of the results should be evaluated;the lower the variability,the better,provided the low variability is not caused by very slow and thwarted dissolution. Another item to be evaluated is which design gives more uniform liquid flow and better mixing. Observations of the behavior of the system during the test will be of use when a sinker is evaluated. If one sinker gives faster dissolution than another,you will have to determine which one is acceptable. Faster dissolution may be a result of sinker interference with the hydrodynamics. Slower dissolution may result from an inhibiting effect of the sinker. As the goal of the dissolution test is control of the performance of the dosage form,the ideal sinker should not interfere. Once a sinker design is selected for a particular application,the dimensions and drawings should be recorded to ensure uniformity in the procedure.

Q Is a dissolution test necessary for fixed combination products? If so,how is such a test developed?
A
Yes,the dissolution test is necessary for fixed combination products,and it is developed in the same way as for products containing only one active pharmaceutical ingredient. See the USP General Chapter <1092> The Dissolution Procedure: Development and Validation. Sometimes the same dissolution conditions (medium,apparatus,rotation,etc.) and tolerances are suitable for all the drugs in the formulation.There are some cases where,depending on the physical-chemical characteristics of the drugs,different dissolution conditions or tolerances will be necessary. In some regions,if provided with adequate justification,the regulatory agencies may accept a dissolution test developed only for the drug with the lowest solubility in the formulation.This should be confirmed with the appropriate regulatory agency. For multivitamin products with or without minerals,see the USP General Chapter <2040> Disintegration and Dissolution of Dietary Supplements.

Q What is the difference between releasing media and discriminating media?
A A releasing medium is the one that promotes solubilization of the drug substance from a pharmaceutical dosage form without further qualification. A discriminating medium is the one where the more subtle aspects of the pharmaceutical dosage form can be differentiated by observing their individual rates of dissolution. Particle size,crystal form,salt form,presence of water of hydration,differences in the manufacturing processes,and so forth,may all affect the dissolution performance.The dissolution test should be sensitive to any attribute that may affect the in vivo performance of the product.

Q What is the right procedure to use pepsin in dissolution testing of gelatin-containing formulations?
A Gelatin can develop cross-linking in the presence of certain compounds or due to environmental conditions and with aging becoming relatively insoluble in aqueous solvents, which slows down the in vitro release rate. (A good review of this issue is Singh,S.,Rao,K.V. R.,Venugopal,K.,Manikandan,R. Alteration in dissolution characteristics of gelatin-containing formulations.A review of the problem,test methods,and solutions. Pharm.Technol.,April 2002,36�58.) To overcome this problem,enzymes can be added to the dissolution medium. Details on the types and amounts of enzymes to be used can be found in the USP General Chapter <711> Dissolution. Where water or a medium with a pH of less than 6.8 is used,purified pepsin can be added to the medium in an amount that results in an activity of 750,000 Units or less per 1000 mL. Keep in mind that purified pepsin,with high activity per mg,should be used.The specifications for this purified pepsin can be found in the section of USP Reagents,Indicators, and Solutions,under Reagent Specifications.The activity of the enzyme should be determined just before use. For media with a pH of 6.8 or greater,pancreatin can be added to produce not more than 1750 USP Units of protease activity per 1000 mL.The pancreatin to be used should meet the requirements in the USP monograph for Pancreatin.

Q Regarding the use of pooled sampling, is the procedure of pooled sampling applicable for releasing the drug product? Is this procedure applicable during the stability study? How can one decide when pooled sampling could be used?
A The concept of pooled sampling in dissolution was developed several years ago to reduce the number of quantitative analyses performed during dissolution testing.To select the product for which this concept could be used,some requirements were established:it must be an immediate-release dosage form;the active ingredient should not have bioavailability problems;the drug should not have a narrow therapeutic index;and it should have a long history of dissolution results. Based on these requirements,there are only 79 USP monographs where the use of pooled sampling is allowed. Pooled sampling cannot be used unless the USP monograph calls for it. A few years ago,USP received several comments regarding the applicability of pooled sampling. Several companies commented that with the use of pooled sampling, information regarding the variability of the product is lost, and this information is very important to monitor the performance of the product.These companies proposed not to expand the pooled sampling approach to other products.The USP Biopharmaceutical Expert Committee,responsible for the general chapters <701> Disintegration, <711> Dissolution, and <724> Drug Release,among others,agreed with this proposal.At this time,pooled sampling is limited to the 79 products already in USP.

Please note that USP General Notices distinguish between compendial standards and release tests in that compendial standards define what is an acceptable article at any time from production to consumption and provide test procedures to demonstrate compliance.

Variability in dissolution performance is expected as a product ages. Pooled sampling tends to mask some of that variability.

Q What might cause floating tablets during the dissolution test using baskets?
A One possible cause is the presence of an air bubble being trapped in the center of the disk.The vent hole in the disk of the rotating basket apparatus is located on only one side,and trapped air does not readily escape.Another cause is the surface interaction at the flat surface of the tablet.Occasionally, the tablet will ride up to the top of the basket when the apparatus is lowered and remain there for several minutes before the tablet top surface becomes wetted,allowing it to fall to the bottom of the basket. Floating tablets are often associated with anomalous dissolution results.The value of recording observations of the behavior of samples during the test can not be stressed enough.

Q What apparatus is used to evaluate drug release from ointments?
A There are several apparatus suitable for the evaluation of drug release from topical preparations;among them are (1) USP Apparatus 4,flow-through cell with a special cell developed specially for this type of dosage form;(2) vertical diffusion cell,also known as Franz cell;and (3) modified semisolid holding cell systems (e.g.,�enhancer�cell). See Ueda,C. et al. Performance test for topical and transdermal dosage forms. Pharm.Forum 2006,32 (5),1586�1589.More papers on this subject can be found at www.NCBI.NLM.NIH.GOV (access free of charge).

Q What can cause dissolution results to be higher than the assay results for the same batch of a particular product?
A Considering that the appropriate filter was selected and validated and that the interference from any excipients was evaluated and discarded,dissolution results higher than the assay results can be found because of the variability associated with the uniformity of dose. In general,the acceptance criterion for uniformity of dose is 85�115% of the label claim. This means that a small percentage of dosage form units with content higher than 100% can be found if the manufacturing process is under control giving higher results than those obtained in the assay test.The assay test is performed on a composite sample,usually of 20 units,to minimize the variability due to the uniformity of dose.Thus,an acceptable sample might have a lower assay value but also some higher dissolution values. If dissolution values are consistently higher than the assay,it may be an indication of problems with elements of the dissolution method validation.