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?
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.
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.
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?
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.
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.