DISSOLUTION
METHOD
VALIDATION
MOKARAM HOSSAIN Nov 2, 2023 1
An ideal dissolution test should deliver information in three
key areas:
First, the dissolution test should be able to detect changes in
the physicochemical properties of the drug product from the
effect of these changes on the rate or amount of the drug
substance released. Such information is useful for the purpose
of establishing batch-to-batch production consistency for
quality control.
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Second, dissolution testing should be able to distinguish drug
products that have been manufactured using different
processes and/or formulations during the development phase.
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Finally, when in vitro–in vivo correlation is established,
dissolution should also reflect release and absorption rates in
humans.
However, not all drug molecules are able to fulfill all three
functions in a dissolution test.
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a definite volume (usually 500 to 1000 mL) of the dissolution
medium is introduced into a vessel and the temperature is
maintained at 37 ± 0.5◦C.
The testing assembly (i.e., basket or paddle) is fitted to the
shaft, and the apparatus is adjusted to rotate at a specified rate.
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The testing assembly is fixed to the shaft following the
compendial requirements for each relative position.
During operation of the dissolution apparatus, the vessels
should be covered appropriately to prevent evaporation of the
dissolution medium.
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When the basket apparatus is used, the sample is placed in the
dry basket; the basket fitted to the coupling disk and lowered
to the position specified, and rotation is started immediately.
When the paddle apparatus is used, the sample is allowed to
sink to the bottom of the vessel, and rotation of the paddle
started immediately at the speed specified.
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If use of the sinker is required, the sample is placed in the
sinker and allowed to sink to the bottom of the vessel.
The samples are collected at the appropriate time, filtered by a
suitable method, and
the filtrate used as the sample solution.
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The drug substance(s) in the sample solution
is assayed, and the quantity dissolved at the
specified time is expressed as a percentage
of the labeled amount.
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The time required for the capsule shell or tablet coating to
start breaking apart will provide an indication of possible
issues with the shell or coating that would retard the release of
the formulation (e.g., gelatin cross-linking).
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The time required for complete disintegration will provide an
indication of possible issues with the dosage unit that could
affect the release of active ingredient (e.g., overcompression
of capsule powders or tablet cores).
Behavior of the capsule within a specific sinker device (e.g.,
capsules being stuck to the basket mesh).
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The effectiveness of the mixing within the vessel. Coning (the
formation of a mound of insoluble excipient particles on the
bottom of the vessel) may indicate the need for a higher
rotation speed or the use of different apparatus (e.g., baskets
instead of paddles).
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The suitability of the media degassing method. The formation
of bubbles during the dissolution process can affect the rate of
release of the active ingredient.
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Apparatus
Dissolution Medium
Rotational Speed
Sample Collection
Effect of Non-USP Adaptation
Cleaning Validation
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The nature of the dosage form will determine the type of
dissolution apparatus that will be used for method
development and validation.
The following questions must be asked when selecting the
dissolution apparatus:
Is it a capsule?
Will a sinker be required?
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How stable is the drug substance after dissolution in the
medium?
Is the formulation an immediate release or an extended release
formulation?
Is this a transdermal patch?
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USP Dissolution Apparatus 1 (basket) and 2 (paddle) are
commonly used for immediate-release formulations.
USP Apparatus 3 (reciprocating cylinders) is the system of
choice for testing extended-release products or a dosage form
that requires release profiling at multiple pH levels and time
points.
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Low-dose products may require the use of flow-through
analysis or other low-volume test techniques (noncompendial
100- or 200-mL dissolution vessels).
Once the apparatus is selected and has been shown to be
suitable during method development, no further evaluation of
another apparatus is required during validation.
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The dissolution medium that is chosen for method
development and validation will depend on a variety of factors
that include:
The solubility of the drug molecule
The nature of the dosage form
The chemical structure of the drug molecule
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A speed of 100 rpm is commonly used with the basket
apparatus and a speed of 50 rpm is used with paddles.
The compendial limit for variations in rotational speed is
±4%, but a wider variation (e.g., ±10%) may be considered in
testing the robustness of the method.
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The two aspects of sample collection that need to be
considered during the development and validation of sample
preparation are
(1) the withdrawal of the sample aliquot from the dissolution
vessel and
(2) the clarification (filtration) of the sample aliquot.
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Filters are required for dissolution sample collection. It is
necessary to filter out the excipents that may cause
interference in sample analysis. Appropriate recovery studies
should be performed and documented. Any observed bias
should be addressed. Filtration must be performed when the
sample aliquots are withdrawn, not at a later time.
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The development and validation of the dissolution test for new
formulations will often probe into the use of
nonpharmacopoeia adaptations (e.g., peak vessel and unique
sinker configurations). The suitability of these adaptations
must be assessed during method development or validation.
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Once the vessels have been cleaned, a “blank” dissolution run
needs to be performed to ensure that the cleaning procedure
for the dissolution vessels is appropriate and will not give rise
to contamination.
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Linearity
Accuracy
Precision: Repeatability
Precision: Intermediate Precision
Range
Robustness for HPLC Analysis
Robustness for UV–Vis Analysis
Specificity
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Neat standard solutions are prepared to cover the nominal
concentration of the sample. ICH Q2B proposes an acceptable
range of ±20%.
A range of 25 to 125% of nominal concentration is commonly
used for the linearity determination.
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Visual inspection of a plot of response versus concentration
will show a straight line. The correlation coefficient (r),
residual sum of squares, and y-intercept should be reported.
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Sample solutions of known concentration (e.g., spiked
placebo) are used for the accuracy determination.
Experimental work may be organized so that the same stock
solutions are used to prepare both linearity and accuracy
solutions.
The accuracy solution must be exposed to normal test
conditions (e.g., mixing in a heated dissolution vessel).
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Determine any bias that is caused by the sampling and
analysis of the solutions.
If a dissolution profile of the drug product is required,
accuracy determinations at different concentrations of the
required profile will need to be performed (e.g., at 40, 75, and
110% of theoretical release).
The results are reported as percent theory.
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The repeatability experiment will be performed using six
dissolution samples that are prepared from the same
dissolution apparatus.
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Sets of six dissolution samples that are prepared using
different instruments and by different analysts are used to
determine intermediate precision
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Precision
Normalization of dissolution profile to remove tablet-to-
tablet variation
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The results of the linearity, accuracy, and precision will help
determine the range for the dissolution test (e.g., 25 to 125%
of nominal for a single-point dissolution and ±20% of the
stated range for a dissolution profile for a modified release
formulation).
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The investigation of the effect of column, mobile phase,
HPLC solution stability, and wavelength is performed in a
manner similar to the HPLC potency/related substance assay.
For solution stability, the solution can be analyzed on different
days or analyzed on the same day with both aged and fresh
solutions.
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Wavelength accuracy, wavelength repeatability, diluting
solvent (i.e., pH, concentration), solution stability, and bubble
formation by the sipper can be investigated during validation
of the analytical component.
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For HPLC analysis, resolution of the drug substance from any
potential excipient and system interference peaks should be
demonstrated.
For a UV–Vis analysis, the absorption of the placebo solution
should not be significant.
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There are various situations during the life cycle of a
dissolution test that will require revalidation of the method.
These are similar to those described for the potency assay
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THANK YOU
MOKARAM HOSSAIN Nov 2, 2023 38
Describe the different sample components of a dissolution
apparatus.
Describe how to validate sample preparation components of a
dissolution apparatus.
Explain the discriminating dissolution method.
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