dx.doi.org/10.14227/DT100403P41

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 ­ In the document that comes with the USP Prednisone calibrator tablets there is a note stating that an amount of alcohol not to exceed 5% of the total volume of the standard solution may be used to bring the prednisone standard into solution prior to dilution with dissolution medium.What procedure is used to prepare the prednisone standard solution?
A ­ Prednisone is soluble at the concentration that results from performing the dissolution apparatus calibration. However, it is not rapidly dissolved. To facilitate rapid preparation of the standard solution, USP recommends using alcohol (ethanol) as a co-solvent.

Two basic procedures are used; direct final solution and indirect dilution. In the direct final solution procedure,a mass of USP Prednisone RS is transferred directly to an appropriate volumetric flask. An amount of alcohol not to exceed 5% of the nominal capacity of the flask is carefully added so that all of the prednisone crystals are wetted. The flask is sonicated and the resulting solution is diluted with dissolution medium (water) to volume. The indirect dilution procedure uses a mass of USP Prednisone RS delivered to a volumetric flask; the prednisone is then dissolved (with sonication) in alcohol and diluted with alcohol to the mark. An aliquot from this solution is transferred to a second flask and diluted with water to produce the desired prednisone concentration. In this procedure, the concentration of prednisone in the purely alcoholic solution must be high enough that the final dilution is at the range of interest while maintaining the alcohol concentration below 5% in the final dilution.

Both procedures have advantages as well as disadvantages. The advantages of the direct final solution procedure are that fewer manipulations are needed thus reducing sources of error, and that the RS material is conserved. Its disadvantage lies in the reduced ability of the analyst to verify that all material was dissolved by the alcohol. The indirect dilution enables the analyst to completely dissolve the RS material but can require a larger amount of RS and also involves additional dilution with associated error.

Q ­ I have seen some USP monographs that use 2000-mL vessels in the Dissolution test.Are these vessels custom-made? What is the specification for these vessels?
A ­ The specifications for the 2000-mL and 4000-mL dissolution vessels are described in the USP - NF General Chapter <711> Dissolution. The vessel is cylindrical,with a hemispherical bottom:for a nominal capacity of 2 liters, the height is 280 mm to 300 mm and the inside diameter is 98 mm to 106 mm and for a nominal capacity of 4 liters,the height is 280 mm to 300 mm and the inside diameter is 145 mm to 155 mm.You can purchase these vessels from most of the vendors of dissolution supplies.

Q ­ During our calibration of a dissolution unit using the paddle apparatus,we have obtained results using the Prednisone Tablets that were out of range on the high side for two of the vessels. When we repeated the run our results were all within the range. Is there some problem with the reference standard?
A ­ The 10-mg USP Prednisone Tablets RS are based on the NCDA-2 formulation that was found by the FDA National Center for Drug Analysis in St. Louis to be sensitive to a number of dissolution test parameters, including the dissolved air content of the medium. When USP reproduced this material, if anything, the sensitivity to deaeration may have been enhanced. Typically,when using less than optimally deaerated water,USP Prednisone Tablet RS results will tend to be higher and can also be distributed over a larger range than is observed with testing using well-deaerated water. This effect can appear randomly among the vessel positions in a dissolution assembly,thus the failing result in a particular vessel may not be repeatable. Since the calibration process in poorly deaerated water does not necessarily produce failing results, it is also possible to pass the next run. However,any time the results for either basket or paddle testing show a high scatter and the average of the values is on the high side of the acceptable range, the deaeration of the medium should be a concern even if all of the values are otherwise acceptable. Please remember that the dissolved gas content of the medium has been demonstrated to increase over time so once degassed, it should be promptly used (see Diebold SM,and Dressman JB, Dissolution Technologies, 5(3), 1998.).

Q ­ How can I determine the solubility and sink conditions of a particular compound?
A ­ There are several procedures in the literature that could be used to determine the solubility of particular compounds:Abdou,H.M., Dissolution,Bioavailability & Bioequivalence,Mack, 1989, page 32; Scholz, A. et al.,Can the USP paddle method be used to represent in vivo hydrodynamics? J.Pharm.Pharmacol. 55: 443-453, 2003; Kostwicz,E. et al. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media,Pharm.Research, 19(3): 345-349, 2002.

The FDA/CDER Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (www.fda.gov/cder/guidance/ 3618fnl.htm) also has some procedures for determining the solubility of drug substances. There are some aspects to the solubility determination that should be considered: 1 � determine the solubility profile at 37 � 1�C (for dissolution purposes),2 � use adequate agitation, 3 � make a minimum of three replicate determinations at each time point, 4 - verify solution pH after addition of the drug substance to a buffer, and 5 � determine the concentration of the drug substance using a validated stability-indicating assay.

There are many definitions for sink condition, in general; the concept is that the concentration of the compound already in solution should not interfere with the dissolution process. A range varying from 10% up to 33% relative to the concentration in a saturated solution is mentioned in the literature as satisfying this dissolution testing prerequisite.