William Brown
and Margareth Marques
Will Brown and Margareth
Marques share responsibilities as liaisons to the USP Expert Committee
on Biopharmaceutics. United States Pharmacopeia, Rockville, MD
Email for correspondence: web@usp.org
Q Can I have dissolution results
higher than 100.0% of the label claim?
A Yes, you can have results higher
than 100.0% for several reasons. First, in most cases the acceptance
criteria for the Assay of the drug is a range that has an upper
limit higher than 100.0%. For instance, the range for the Assay
test in the USP-NF monograph for Dextroamphetamine Sulfate Tablets
is "not less than 93.0 percent and not more than 107.0 percent
of the labeled amount of dextroamphetamine sulfate." Second,
the acceptance criteria for dosage uniformity (see USP-NF general
chapter <905> Uniformity of Dosage Units) is the range from
85.0% to 115.0% of the label claim for tablets. Dissolution results
higher than 100.0% should be less frequent because they depend
on the probability of testing a tablet with a dose higher than
100% of the label claim.
If you frequently have dissolution results higher than 100.0%,
this may be an indication of interference in your dissolution
system. You need to verify that substances are not leaching from
the filter and interfering with the measurements. Other sources
of interference could be carryover in automatic sampling systems
and inappropriate cleaning procedures.
Q Should I make a correction to
the dissolution results based on the results obtained with the
Assay?
A
No. The dissolution
results always refer to the label claim and not to the Assay values.
Q Can I carry out only the dissolution
test and not the assay and estimate the assay results from the
dissolution results?
A The dissolution test and the Assay
measure different attributes. In the Assay the amount of active
ingredient in the dosage form is measured. In general, the sample
is a composite of several units of the dosage form being tested,
and an extraction procedure generally is be used to extract the
active ingredient from the dosage form as completely as possible
and in a much shorter time than given for the dissolution test.
The dissolution test is a performance test that measures the rate
of active ingredient released from each unit of the dosage form.
Although the dissolution test procedure often can be used to
completely extract the contents of a dosage form, that is not
its primary function.
Q I am analyzing a tablet that
has a label claim of 250 mg. The tolerance in the dissolution
test for this particular tablet is not less than 80% (Q) of the
labeled amount dissolved in 30 minutes. What amount, 200 or 212.5
mg, represents the acceptance criterion given by the dissolution
test for this product?
A - The tolerances in the monograph define
the value of Q. In this case it will be 80% of the label claim
of 250 mg or 200 mg. However, the acceptance criterion is defined
by the acceptance table (see USP-NF general chapter <711>
Dissolution and <724> Drug Release), unless a different
acceptance table is presented in the specific monograph. The acceptance
table under <711>states that for the S1 stage the acceptance
criterion is "each unit is not less than Q + 5%." For
your product it means 200 mg (Q) + 5% of 250 mg, equal to 212.5
mg.
Q When opened, our bottle of Salicylic
Acid Tablets had a large amount of powder inside. Can I expect
the dissolution to be affected?
A Salicylic acid has a high vapor
pressure and will sublime completely at about 70 °C. Typically
some powder will be found inside the bottles due to recrystallization.
Brush off any powder from the tablets before use. Studies have
found that the dissolution performance of the salicylic acid tablets
is not affected. .
Q Why would the specification for
an oral extended-release product list multiple tests under <724>
Drug Release? Which test should I use?
A Extended release formulations use
various physical mechanisms to control the rate of drug delivery
in vivo; these formulations may or may not have different in vitro
drug release profiles. In most cases, when a new monograph for
an oral extended-release product is introduced in the USP-NF,
this monograph is written based on documentation from the innovator
and, therefore, there will be only one Drug Release test. In
order to market generic versions of extended release oral dosage
forms in the US, bioequivalence to the reference listed drug must
be demonstrated to the Food and Drug Administration. This is
in addition to the submission of the chemistry, manufacturing,
and controls information. An in vitro drug release test must
be included for quality control purposes. When the FDA receives
multiple product applications, the agency indicates their therapeutic
equivalence status in the Approved Drug Products with Therapeutic
Equivalence Evaluations ("Orange Book"). As a result
of differences in drug release properties, bioequivalent products
may not perform identically in vitro but can be approved by FDA
with different drug release tests. The USP monograph reflects
this by including multiple tests under <724> Drug Release.
FDA must have previously approved the use of each of these tests
The product label must indicate which of these tests was used
to demonstrate compliance with the monograph.