A Critical Overview of FDA and EMA Statistical Methods to Compare In Vitro Drug Dissolution Profiles of Pharmaceutical Products

Abstract

A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.

Chitosan and Sodium Alginate Implementation as Pharmaceutical Excipients in Multiple-Unit Particulate Systems

“…The f 2 value was equal to 100 when the test and reference profiles were identical, and exponentially decreased as the two profiles became less similar. The f 1 values up to 15 (0–15) and f 2 values greater than 50 (50–100) suggest the “similarity” of the two dissolution profiles [ 34 ]. Given the data in Table 7 , it can be stated that the similarity was not only between the dissolution profiles of drug from the pellets compared to the HPMC pellets used as the reference, but also between the dissolution profiles of the drug released from pellets versus MUPS tablets (e.g., alginate pellets versus alginate MUPS tablet, etc.).…”

“…The similarity factor f 2 is a logarithmic reciprocal square root transformation of the sum of squared differences between the profiles of the tested and the reference product. It represents the measurement of similarity in the percentage (%) of dissolution between the “average” dissolution profiles, where n is the number of time points and R t and T t are the mean percentages of the released drug from the ( R ) and ( T ) products [ 34 ]: …”

Rational Design of Self-Emulsifying Pellet Formulation of Thymol: Technology Development Guided by Molecular-Level Structure Characterization and Ex Vivo Testing

“…In the 120th min, on average, all M1 samples released 87.5% of thymol; in the 360th min, they all released ≥ 100%. Although the differences between W-series and AA-series were found, according to f 2 analysis, all dissolution profiles were considered similar ( Figure 2 a, Table 3 ) [ 44 ]. The similarity of dissolution profiles has also remained in the M1-W90 stability study.…”

The Influence of the Polymer Type on the Quality of Newly Developed Oral Immediate-Release Tablets Containing Amiodarone Solid Dispersions Obtained by Hot-Melt Extrusion

“…Dissolution profile comparison was performed based on the f2 similarity factor [ 45 ]. Since f2 value is sensitive to the number of dissolution points taken into account for calculation [ 46 ], the similarity factor was calculated up to 45 min, the first time point where the dissolution exceeded 85% amiodarone released for all evaluated formulations.…”