Chemistry Reference
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if the method results in better discrimination between bulk batch properties without
adversely affecting method reproducibility.
Apparatus site selection is also important; vibrations from doors closing or pumps
(e.g., mass spectrometry instrument vacuum pumps) can cause significant variability.
7.4.2.3 dissolution study design
Dissolution is evaluated by measuring rate release profiles, or the amount dissolved
over time. Single or multiple points in time can be measured, depending on the dosage
type or data desired. For immediate-release dosage forms, the procedure duration is
usually 30 to 60 min; and in most cases, a single time-point specification is adequate.
However, for formulation development comparison purposes, profile comparisons are
required, and it is common to collect data from numerous time points, for example,
every 2 min or less over the course of the test. For profile comparisons, a sufficient
number of time points should be selected to adequately characterize the dissolution
curve's rise and plateau.
For an extended-release dosage form, at least three test time points are typically
chosen to characterize the in vitro drug release profile. An early time point, usually
1 to 2 h, is chosen to show that there is little probability of dose dumping (too much
drug product dissolving too soon). An intermediate time point is chosen to define the
in vitro release profile of the dosage form, and a final time point is chosen to show
the essentially complete release of the drug. Test times and specifications are usually
established on the basis of an evaluation of drug release profile data. For products
containing more than a single active ingredient, drug release is to be determined for
each active ingredient.
Sampling is another important experimental design consideration. For many tests,
particularly immediate-release formulation tests using one time point over a short
(less than 1 h) period, sampling can be done manually. For extended tests, tests with
multiple sampling times, or to increase throughput, automated sampling is a useful
alternative. When automated sampling is employed, it is important to determine that
no bias versus the manual method has been introduced. Regardless of the method
of sampling, the sampling site must conform to specifications in the USP [26]. Any
hydrodynamic disturbance of the vessels by the sampling probes should also be con-
sidered, and adequate validation performed to ensure that the probes are not intro-
ducing a significant change in the dissolution rate.
Filtration should also be considered during the method development or experi-
mental design. Dissolution sample filtration is usually necessary to prevent undis-
solved drug particles from entering the analytical sample and further dissolving,
skewing the test results. Also, filtration removes insoluble excipients that may other-
wise cause high background or turbidity in the assay technique.
Acceptance criteria must also be considered during test development. The accep-
tance criteria should be representative of multiple batches from the same nominal
composition and manufacturing process, include key batches used in pivotal stud-
ies, and batches that are representative of the drug product performance in stabil-
ity studies. Acceptance criteria in the form of “Q-factors,” or the percentage of the
labeled content, are derived, that specify a certain amount dissolved at a given time.
Dissolution tests can have a single Q-factor or may have multiple Q-factors in, for
