In-Vitro Dissolution Profiles Comparison &
Bioequivalence Inference
Pearl PereiraNambiar , Oct 2023
Importance of Sampling Times
We need to have sufficient time For oral immediate release
points for dissolution similarity More frequent sampling during the formulations with intestinal
testing to help draw valid period of the most significant absorption, a sampling time for
conclusions and decide if can dissolution changes is comparison at 15 min is essential
adopt the biowaiver approach; recommended. to know if complete dissolution is
ideally at least every 15 minutes. reached before gastric emptying.
For rapidly dissolving products, At least three time points are This sampling schedule
where complete dissolution is required: the first time point should be extended as
within 30 minutes, generation of before 15 minutes, the second at
an adequate profile by sampling at 15 minutes and the third when the
necessary if the dissolution
5- or 10-minutes intervals may be release is close to 85% (e.g., 5, 10, rate is slower (e.g., 5, 10, 15,
necessary. 15, 20 and 30 min). 20, 30, 45, 60 min)
For modified release products, the
advice given in the relevant
guidance should be followed.
Pearl PereiraNambiar , Oct 2023
Similarity of Dissolution Profiles
• Similarity factor, f2, is the most widely used metric to compare dissolution
profiles
• For immediate release oral dosage forms where over 85% dissolves within 15
minutes, profiles can be accepted as similar without complex mathematical
analysis.
• For both the reference and test formulations, percent dissolution should be
determined.
• An f2 value between 50 and 100 suggests that the two dissolution profiles are
similar.
Similarity factor (f2) requirements
The evaluation of the similarity factor is based on the following conditions:
At least twelve individual Not more than one mean
Minimum of three time points Time points should be the
values for every time point for value of > 85% dissolved for
(zero excluded) same for the two formulations
each formulation any of the formulations
The RSD or CV of any product All sampling times that were pre-defined in
The similarity acceptance limit of 50
should be less than 20% at the dissolution study protocol until the
corresponds to a mean difference of
early time points (up to 10 sampling time where one of the products
10% in percentage dissolved over all
minutes) and less than 10% at reaches > 85% dissolved should be used in
sampling times used.
other time points. the f2 calculation.
Bootstrap Methodology
• When dissolution profiles are highly variable, using the two-sided 90% confidence
interval of f2 is recommended for dissolution comparison.
The bootstrap analysis should be The calculation of the 90% confidence interval
performed using at least 5,000 should be conducted using any of the
samples and the number of samples percentile methods described by Hyndman
should be reported. and Fan
All sampling times pre-defined in The dissolution
The estimation of the f2 value on
study protocol should be considered in the
each bootstrapped dissolution
calculation until the sampling time where one of
sample should be performed using
the products reaches >85% dissolved should be
the Expected-f2 formula
considered in the bootstrap dissolution samples
Reporting of Study results
• Provide individual results of the percentage dissolved at the different sampling times pre-
defined in the protocol
• Mean percentage dissolved with its variability (CV(%))
• Discuss the basis for the similarity conclusion: dissolution is > 85% in 15 min for oral
products with systemic action, f2 similarity factor calculation (e.g., acceptable variability,
no more than one sampling time above 85% dissolved, etc.) is needed, or if the 90%
confidence interval of f2 is required.
• In case of bootstrapping, similarity in dissolution profiles will be concluded when the
lower limit of the 90% confidence interval for the Expected f2 is ≥ 50.
• The results should be reported rounded to the next integer without decimal units.
Software Packages
• Specific software packages for the calculation of the 90% confidence interval of
f2,EXP or in-house platforms can be used for calculations
• In the case of specific software packages, the selected options (e.g., whole vectors,
one profile, number of bootstrap samples, seed number, if available) should be
described.
• In the case of in-house platforms, the code of the platform should be provided, and
it should be demonstrated that the employed software is able to calculate the 90%
confidence interval of f2,EXP correctly.
• Documentation and descriptions of selected options should be provided to ensure
transparency and reproducibility.
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Disclaimer: The contents of this post are for informational purposes only. Any opinions expressed are solely my own and do not express the views or opinions of my employer.
