Chemistry Reference
In-Depth Information
formulation, when increased sensitivity is required, or when there is a desire to auto-
mate the dissolution test procedure. HPLC instruments can be used in a flow injec-
tion mode when separations are not necessary, and HPLC also has the advantage of
different modes of detection (conductivity, fluorescence, and MS, for example) for
both sensitivity (molecules lacking chromophores) and selectivity purposes. When
developing a dissolution procedure that includes an HPLC assay, the compatibility of
the dissolution media with the mobile phase must be considered, especially if large
injector volumes (over 100 µL) are needed. Single injections of each vessel time
point with standards throughout the run constitute a typical run design. Regardless
of the mode of assay utilized, however, the procedure must be validated.
7.4.3 d
ISSolutIon
P
rocedure
v
AlIdAtIon
Dissolution testing is an example of a USP Category III test (Section 7.1.3 and
Table 7.1). Because dissolution is a quantitative test, all the analytical performance
characteristics apply, with the exception of the limit of detection. In addition, for
HPLC-based assays, system suitability is always required [(32); and Chapter 5].
However, in a dissolution test, in addition to the procedure used to perform and assay
the test results, some individual “subprocedures” (e.g., filtration, solution stability)
must also be validated. And while the various validation performance characteris-
tics listed in the USP are well defined in a general sense, the specifics of how the
analytical performance characteristics apply to dissolution testing deserve a little
more focus.
7.4.3.1 specificity/placebo Interference
To evaluate specificity in dissolution procedures, it is necessary to demonstrate that
the results are not affected by placebo constituents, other active drugs, or degradants
in the drug product. A proper placebo should consist of everything in the formulation
except the active ingredient; all the excipients and coatings (inks, sinker, and cap-
sule shell are also included when appropriate), other actives, etc. In some instances,
placebo interference may be evaluated by weighing samples of a placebo blend
and dissolving or dispersing it into the dissolution medium at concentrations that
would normally be encountered during testing. The interference generally should
not exceed 2%.
For extended-release products, a placebo version of the actual drug product may
be more appropriate to use than blends, because this placebo formulation will release
the various excipients over time in a manner more closely reflecting the product than
will a simple blend of the excipients. In this case, it may be appropriate to evaluate
potential interference at multiple sampling points in the release profile.
If the placebo interference exceeds 2%, then method modification, such as (1)
choosing another wavelength, (2) baseline subtraction using a longer wavelength, or
(3) using HPLC, may be necessary in order to avoid the interference.
Absence of interfering peaks in the placebo chromatogram or lack of absorbance
by the placebo at the analytical wavelength demonstrates specificity. Additional gen-
eral information on determining specificity can be found in Chapter 4, Section 4.3.3.
