The primary constraint for comparison of two products or formulations or dosage forms is the in vitro dissolution profile. For comparison of in vitro dissolution profiles, similarity and difference factors are emphasized by US FDA.
Similarity Factor (f2)1, 2, 3:
As the name specifies, it stresses on the comparison of closeness of two comparative formulations.Generally similarity factor in the range of 50-100 is acceptable according to US FDA. It can be computated using the formula
f2= 50×log {[1+ (1/n) Σ t=1n (Rt-Tt) 2] -0.5 ×100}........(1)
where, n is the number of dissolution sample times,
Rt and Tt are the individual or mean percent dissolved at each time point, t, for the reference and test dissolution profiles, respectively.
The similarity factor should be between 0 and 100. It is 100 when two comparative groups of reference and test are identical and approaches 0 as the dissimilarity increases.
4.1. Significance and applications of similarity factorThe wide application of similarity factor signifies it as an efficient tool for comparison of dissolution profiles.Similarity factor finds its main application as
Difference Factor (f1)1, 2:
Difference factor focuses on the difference in percent dissolved between reference and test at various time intervals. It can be mathematically computed by using
f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100................(2)
Therefore the factors directly compare the difference between percent drug dissolved per unit time for a test and a reference product.
US FDA included the f1, f2 factors in various guidance documents and stated different criterias for dissolution profile comparison as 4, 5
1. The dissolution profiles can be compared only when number of dissolution units used are equal to or greater than 12. The similarity factor should be computed from the average mean dissolution data of 12 units. The mean data for comparison can be used only if the coefficient of variation at the first time point is NMT 20%, and NLT 10% at the rest of time intervals.
2. For accurate calculation of similarity factor, statistical approach of establishment of confidence intervals, to determine whether the reference and test are statistically significant or not may be used.
3. The dissolution conditions should be identical for both reference and test products (example the strength of dosage form, test time intervals, temperature, rpm, total test time etc).
4. The literature also states to consider only one time after 85% dissolution of product, since f2 values are sensitive to number of dissolution time points.
5. For rapid dissolving products, that may dissolve 85% in 15 minutes, comparison of dissolution profiles is not mandatory.
6. Similarity factor of 50-100 ensures sameness of two products
7. Difference factor of 0-15 ensures minor difference between two products.
Prior to in vivo study, comparison of in vitro dissolution profiles using similarity and difference factors may be the promising surrogate.
As the name specifies, it stresses on the comparison of closeness of two comparative formulations.Generally similarity factor in the range of 50-100 is acceptable according to US FDA. It can be computated using the formula
f2= 50×log {[1+ (1/n) Σ t=1n (Rt-Tt) 2] -0.5 ×100}........(1)
where, n is the number of dissolution sample times,
Rt and Tt are the individual or mean percent dissolved at each time point, t, for the reference and test dissolution profiles, respectively.
The similarity factor should be between 0 and 100. It is 100 when two comparative groups of reference and test are identical and approaches 0 as the dissimilarity increases.
4.1. Significance and applications of similarity factorThe wide application of similarity factor signifies it as an efficient tool for comparison of dissolution profiles.Similarity factor finds its main application as
- Response or dependent variable usually for optimization purposes, e.g. to compare manufacturing processes for establishing experimental conditions maximizing similarity between formulations.
- Part of a decision criterion to establish similarity of two formulations. The regulatory suggestion “decide similarity if (the sample) f2 exceeds 50” is applied in a literal sense.
- Challenges for considering similarity factor as a tool for comparison of dissolution profiles2, 4, 5
- This method is more appropriate when more than three or four dissolution time points are available.
- The dissolution treatment is effective in the presence of at least 12 individual dosage units
- This method is applied only when the average difference between reference and test is less than 100.Normalization of the data may be required if the average difference between reference and test is higher than 100.
- The f2 may become invariant with respect to the location change and the consequence of failure to take into account the shape of the curve and the unequal spacing between sampling time points lead to errors.
- It is difficult to formulate a statistical hypothesis for the assessment of dissolution similarity since f2 is only a sample statistic that further complicates to evaluate false positive and false negative rates of decisions for approval of drug products based on f2 .
- It may be too liberal in concluding similarity between dissolution profiles.
- In addition, the range of f2 is from minus infinity to 100 and is not symmetric about zero. From these evidences it may be stated that f2 is convenience criterion and not a criterion based on scientific facts.
Difference Factor (f1)1, 2:
Difference factor focuses on the difference in percent dissolved between reference and test at various time intervals. It can be mathematically computed by using
f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100................(2)
Therefore the factors directly compare the difference between percent drug dissolved per unit time for a test and a reference product.
US FDA included the f1, f2 factors in various guidance documents and stated different criterias for dissolution profile comparison as 4, 5
1. The dissolution profiles can be compared only when number of dissolution units used are equal to or greater than 12. The similarity factor should be computed from the average mean dissolution data of 12 units. The mean data for comparison can be used only if the coefficient of variation at the first time point is NMT 20%, and NLT 10% at the rest of time intervals.
2. For accurate calculation of similarity factor, statistical approach of establishment of confidence intervals, to determine whether the reference and test are statistically significant or not may be used.
3. The dissolution conditions should be identical for both reference and test products (example the strength of dosage form, test time intervals, temperature, rpm, total test time etc).
4. The literature also states to consider only one time after 85% dissolution of product, since f2 values are sensitive to number of dissolution time points.
5. For rapid dissolving products, that may dissolve 85% in 15 minutes, comparison of dissolution profiles is not mandatory.
6. Similarity factor of 50-100 ensures sameness of two products
7. Difference factor of 0-15 ensures minor difference between two products.
Prior to in vivo study, comparison of in vitro dissolution profiles using similarity and difference factors may be the promising surrogate.
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