Chemistry Reference
In-Depth Information
used for this purpose. Calibrator tablets and reference standards are available from the
USP with lot-specific specifications to aid in qualifying dissolution baths and associated
equipment. Recent FDA guidelines suggest that alternative mechanical calibrations can
also be used, and when properly executed, satisfy cGMP requirements [29,30].
7.4.2 d
ISSolutIon
P
rocedure
d
eveloPment
The dissolution procedure has several distinct components. These components
include a dissolution medium, an apparatus, the study design (including acceptance
criteria), and the mode of assay. All these components must be properly chosen and
developed to provide a method that is reproducible for within-laboratory day-to-day
operation, and robust enough to enable transfer to another laboratory.
7.4.2.1 dissolution medium
Selection of the most appropriate media conditions is based on discriminatory capa-
bility, robustness, stability of the analyte in the test medium, and relevance to in
vivo performance, where possible. When selecting the dissolution medium, physical
and chemical data for the drug substance and drug product must be considered, for
example, the solubility and solution state stability of the drug as a function of the pH
value. Other critical drug product properties include the release mechanism (imme-
diate, delayed, or modified) and disintegration rate as affected by formulation hard-
ness, friability, presence of solubility enhancers, and presence of other excipients.
When selecting the composition of the medium, the influence of buffers, molarity,
pH, and surfactants on the solubility and stability of the drug need also must be
evaluated.
The most common dissolution medium is dilute hydrochloric acid; however, other
media used includes buffers in the physiologic pH range of 1.2 to 7.5, simulated
gastric or intestinal fluid (with or without enzymes), water, and surfactants (with or
without acids or buffers) such as polysorbate 80, sodium lauryl sulfate, and bile salts.
The use of aqueous-organic solvent mixtures, while generally discouraged, can also
be used if justified. Enzymes are also sometimes used in the media when testing
gelatin capsule products.
Media volumes are typically in the range of 500 to 1000 mL, with 900 mL being
the most common volume. Volumes as high as 2 to 4 L have been used, and as
low as 100 mL for high-potency (low dosage strength) drug formulations. Media
deaeration is usually required, and can be accomplished by heating the medium or
(more commonly) filtering the medium or placing it under vacuum for a short period
of time. USP Chapter <711> contains additional information on deaeration [26].
During method development, results from dissolution samples run in a nondeaer-
ated medium versus a deaerated medium should be compared to determine whether
deaeration is necessary.
When developing a dissolution procedure, one general goal is to have “sink”
conditions. Sink conditions are defined as the volume of medium that is at least
three times that required in order to form a saturated solution of drug substance.
Dissolution results will more accurately reflect the properties of the dosage form
when sink conditions are present.
