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 Is there a table that compares/contrasts the various USP dissolution instruments?
A See Table 1.

Q Is there any harmonization on dissolution testing equipment for use in the drug-elution device field?
A Harmonization of the dissolution chapters in the European Pharmacopoeia,Japanese Pharmacopoeia,and US Pharmacopeia has produced agreement on the descriptions for Apparatuses 1�4 (basket,paddle, reciprocating cylinder, and flow-through cell,respectively). If drug release from novel drug-eluting devices can be evaluated using any of these four apparatuses, then we would be able to answer,yes. The USP Biopharmaceutics Expert Committee has initiated work by several newly formed ad hoc Advisory Panels to evaluate performance testing of novel dosage forms. The Panels are charged with recommending new apparatuses if the testing cannot be performed using those already described in USP. If new apparatuses are included in USP,there is a possibility for harmonization.

Q How do you calibrate small volume vessels?
A By calibration you mean demonstrate suitability for use. Such a demonstration will require a full understanding of the critical operating and dimensional variables at work in testing with small-volume vessels.Once an understanding is attained of the effect that deviations in these variables produce on dissolution results,we can start to find ways to determine that the system is suitable.

Q How to decide if the medium should be deaerated or not?
A Dissolution profiles should be obtained for the same sample using deaerated and non-deaerated media.The profiles should be compared and the condition that gives better discrimination should be considered.

Q If a particular type of dissolution equipment is used with both manual and automatic sampling how do we perform its calibration?
A Automated sampling brings variables into play that, strictly, are not controlled by calibration. Calibration is intended to control the variables associated with the production of drug solution in the medium by the apparatus. In the dissolution procedure, automated sampling is downstream of that process. In our opinion, control of the timing of sampling, carryover in any sampling lines, pump flow rate to the spectrophotometer, volume removed, and other variables in the automated sampling system can be better performed by other means.We recommend that calibration be done with manual sampling.

Q Should the placement of baskets and paddles be fixed in a given equipment?
A As far as we know there are no guidances or guidelines stating that the paddle or basket or shaft should have dedicated positions in any dissolution equipment.We know that there are several companies using this approach to facilitate the evaluation of out of specifications results or any other deviation.

Q We are evaluating a dissolution test for orally disintegrating tablets and we are getting very variable results because the tablets float.We cannot use sinkers because the tablets are very fragile.Do you have any suggestions to solve or minimize this problem?
A There are some options you can try:1 - the use of USP apparatus 1 (basket);2 � the use alternative sinker given in the harmonized Dissolution General Chapter (see page 205 of the Pharmacopeial Forum 31(1) [Jan-Feb 2005]) or see USP monograph for Nifedipine Extended-release Tablets on page 1377 of USP 28),this sinker is not tightly wrapped around the dosage form;3 � you can try a basket similar to the one described in USP monograph for Felodipine Extendedrelease Tablets (pages 808 � 810 of USP 28). In any case,you will need to verify the suitability of any of these devices in practice.

Q What should be the next steps when we have f1 and f2 not passing the acceptance criteria for two products that are being compared?
A Dissolution profile comparison is very helpful when evaluating post-approval changes and biowaivers. It helps to assure similarity in product performance and signals bioinequivalence.To assure similarity in product performance, it is important to know how similar the two curves are. Thus,the f2 comparison is very useful (See Dissolution profile comparison using similarity factor,f2. Dissol.Techn. 6(3):15, 1999). If the comparison shows that the dissolution profiles are not similar,two approaches are possible:1 � make small changes in the formulation and or manufacturing process and compare the profiles of the product after the changes or, 2 - carry out a bioequivalence study with a small population so see if the in vivo performance shows that the products are really different.

Q If I have one vessel out of requirement using the USP Calibrator Tablets,can I continue the testing through S2 and S3?
A The Acceptance Table in the USP general chapter <711> Dissolution is not applicable to the calibration of dissolution equipment.The procedure and acceptance criteria for the calibration are available at http://www.usp.org/standards/calibrators.html. When you have one vessel giving results out of the ranges for calibrator tablets,an investigation should be carried out to find the possible causes of this deviation.These causes must be corrected and a new calibration,including all vessels,should be run.

Q We are developing a dissolution test for a product with very low strength.The amounts released into the medium are very small and the quantitation step is by HPLC.Can we introduce two dosage forms in each dissolution vessel to increase the amount of drug released into the medium?
A Introducing more than one dosage form in each dissolution vessel is not a good approach.To solve this problem related to very low amounts of drug dissolved in the medium you have some options:1 - decrease the volume of dissolution medium.Although 200 mL vessels are not compendial they can be used together with mini paddles.They should be properly calibrated (see question 3 above);2 � you can change the chromatographic system to increase the sensitivity of the method;3 � you can use another analytical technique with better sensitivity;4 � you can increase the amount of sample injected into the HPLC column,making the appropriate modifications in your chromatographic system.

Q Can we modify the quantitation step of an USP dissolution test but keeping all dissolution conditions (apparatus,speed,medium,etc) the same?
A Yes,you can.The USP General Notices (page 7 of USP 28) states that �Compliance may be determined also by the use of alternative methods,chosen for advantages in accuracy, sensitivity,precision,selectivity,or adaptability to automation or computerized data reduction or in other special circumstances. Such alternative or automated procedures or methods shall be validated.�

Q We are developing a dissolution test for a powder material and we are having problems with the sampling.Powder is being adsorbed to the filter of the sampling probe.Do you have any suggestions?
A Automatic sampling is not suitable for all dissolution tests. In some cases,results are more precise and reproducible using manual sampling because you can use pre-filtration using a coarser material,and subsequently filter through a material with a smaller porosity.You should also evaluate different filter materials to find one where your powder might not be adsorbed.Another possible option is to use the USP Apparatus 4 (flow-through cell).

Editors Note: The following Question deals specifically with USP Apparatus 3.We consulted with a technical adviser of a manufacturer of this equipment,Bryan Crist,who supplied the response.His email address is bryan.crist@Varianinc.com

Q My question is specific to the type 3 dissolution apparatus.The rim of the outer medium tube (250�300mL dissolution vessel) is extremely susceptible to wear and tear.All our vessels are chipped or cracked at the rims.Is there any product on the market such as a rubber covering for the rim that could prolong the life of these vessels? This would also solve the problem of the sampler tube getting caught in the chips and cracks of the rim during a row change.
A Rims may become chipped when struck by the evaporation covers and cannulas if the vessels are allowed to float in the media.Vessels should only be in the apparatus when they contain dissolution medium,which is necessary to keep them at the proper level. Laboratories that are consistent with this practice have very few cracked vessel rims. Also,if a low volume of dissolution medium is used in the vessel,the circulator water must be at a level low enough to prevent the vessels from becoming buoyant and struck by the cannulas as they transverse from row to row.Thank you for your suggestion regarding a covered rim to prolong the life of the vessels.