Docencia 507

COMPARISON OF DISSOLUTION PROFILES: CURRENT GUIDELINES

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Dpto. Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Univ. Complutense de Madrid, España.

Introduction across the gastrointestinal tract. Because of the

critical nature of the first two steps, in vitro
Comparison of therapeutic performances of two dissolution may be relevant to the prediction of
medicinal products cantaining the same active in vivo performance.
substance is a critical means of assessing the
possibility of alternative using between the The BCS can be used as a basis for setting in
innovator and any essentially similar medicinal vitro dissolution specifications and can also
product. Assuming that in the same subject an provide a basis for predicting the likelihood of
essentially similar plasma concentration time achieving a successful in vivo-in vitro
course will result in essentially similar correlation (IVIVC). Based on drug solubility
concentration at the site of action and thus in and permeability, the BCS is recommended:
an essentially similar effect, pharmacokinetic (2):
data instead of therapeutic results may be used - Case 1: High Solubility – High
to establish equivalence: bioequivalence. Permeability.
A bioequivalence study is basically a - Case 2: Low Solubility – High Permeability.
comparative study designed to establish - Case 3: High Solubility – Low Permeability.
equivalence between test and reference - Case 4: Low Solubility – Low Permeability.
products. In vivo bioequivalence studies are The BCS suggests that for high solubility, high
needed when there is a risk that possible permeability drugs and in some instances for
differences in bioavailability may result in high solubility, low permability drugs, 85 %
therapeutic inequivalence. But it’s also possible dissolution in 0.1 N HCl in 15 minutes can
to request a waiver of in vivo bioavailability ensure that the bioavailability of the drug is not
and/or bioequivalence studies for solid oral limited by dissolution. In the case of low
dosage forms based on an approach termed solubility / high permeability drugs, drug
the Biopharmaceutics Classification System dissolution may be the rate limiting step for
(BCS) (1). drug absorption and an IVIVC may be
Comparison of dissolution profiles expected. A dissolution profile in multiple media
is recommended for drugs products in this
→ FDA guidelines: category. In the case of high solubility / low
permeability drugs, permeability is the rate
Drug absorption from a solid dosage form after controlling step and a limited IVIVC may be
oral administration depends on the release of possible. Drugs in case 4 present significant
the drug substance from the drug product, the problems for oral drug delibery.
dissolution or solubilization of the drug under
physiological conditions, and the permeability
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The dissolution profile comparison may be → EMEA guidelines: (4)

carried out suing model independent or model
dependent methods: (3) A simple model Dissolution studies can serve several purposes
independent approach uses a difference factor as, for example, to be used as a tool in quality
(f1) and a similarity factor (f2) to compare control to demonstrate consistency in
dissolution profiles. manufacture, to demonstrate similarity between
reference products from different Member
f1 = {[St=1n (Rt -T t)] / [St=1 n Rt]} * 100 States, to demonstrate similarity between
different formulations of an ac tive substance
f2 = 50 * log {[1+(1/n)St=1 n (Rt -T t)2]-0.5 * 100} (variations and new, essentially similar products
There is a specific procedure to determine included) and the reference medicinal product.
difference and similarity factors as follows: If an active substance is considered highly
1. Determine the dissolution profile of two soluble, it is reasonable to expect that it will not
products (12 units each) of the test and cause any bioavailability problems. A
reference products. bioequivalence study may in those situations be
waived based on case history and similarity of
2. Using the mean dissolution values from dissolution profiles. The similarity should be
both curves al each time interval, calculate justified by dissolution profiles, covering at least
the difference factor (f1) and similarity three time points, using three different buffers.
factor (f2) using the above equations. For
curves to be considered similar, f1 values If an active substance is considered to have a
should be close to 0, and f2 valuesshould low solubility and a high permeability, the rate
be close to 100. Generally, f1 values up to limiting step for absorption may be the dosage
15 (0-15) and f2 valuesgreater than 50 (50- form dissolution. In those cases a variety of test
100) ensure sameness or equivalence of conditions is recommended and adequate
the two curves. sampling should be performed until 90 % of the
This model independent method is most drug is dissolved or an asymptote is reached.
suitable for dissolution profile comparison Any methods to prove similarity if dissolution
when three to four or more dissolution time profiles are accepted as long as they are
points are available. The following justified.
recommendations should alsom be considered: The similarity may be compared by model-
- The dissolution measurements of the test independent or model-dependent methods e.g.
and reference batches should be made by linear regression of the percentage
under the same conditions. The dissolution dissolved at specified time points, bu statistical
time points for both the profiles should be comparison of the parameters of the Weibull
the same. The reference batch used function or by calculating a similarity factor as
should be the most recently manufactured f2:
prechange product. f2 = 50 * log {[1+(1/n)St=1 n (Rt -T t)2]-0.5 * 100}
- Only one measurement should be
considered after 85 % dissolution of both In this equation f2 is the similarity factor, n is teh
the products. number of time points, R(t) is the mean percent
- To allow use of mean data, the percent drug dissolved of e.g. a reference product, and
coefficient of variation at the earlier time T(t) is the mean percent drug dissolved of e.g.
points (e.g., 15 minutes) should not be a test product. The evaluation of similarity is
more than 20 %, and at other time points based on the conditions of:
should not be more than 10 %.
- A minimun of three time points (zero
excluded).
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- 12 individual values for every time points References

for each formulation.
- Not more than one mean value of > 85 % 1. Amidon, G.L., H. Lennemäs, V.P. Shah,
dissiolved for each formulation. and J.R. Crison; A Theoretical Basis for a
- That the standard desviation of the mean Biopharmaceutics Drug Classification: The
of any product should be less than 10 % Correlation of In Vitro Drug Product
from second to last time points. Dissolution and In Vivo Bioavailability,
Phamaceutical Research 12, 413-420,
An f2 value between 50 and 100 suggests that 1995.
the two dissolution profiles are similar. In cases
where more than 85 % of the drug are 2. Guidance For Industry: Waiver of In Vivo
dissolved within 15 minutes, dissolution profiles Bioavailability and Bioequivalence Stidies
may be accepted as similar without further for Inmediate-Release Solid Oral Dosage
mathematical evaluation. Forms Based on a Biopharmaceutics
Classification System. FDA, 2000.
A new approach on the use of the similarity
factor f2 3. Guidance for Industry: Dissolution Testing
of Inmediate Release Solid Oral Dosage
In researchments carried out in our department Forms. FDA, 1997.
(5), it has been demonstrated that similarity
factor (f2) is a simple measure for the 4. Note for Guidance on the Investiagation of
comparison of two dissolution profiles, but 2f Bioavailability and Bioequivalence. EMEA.
factor is a slanted and conservative estimator of London, 2001.
similarity factor real value. The statistical
distribution of the f2 metrics has been simulated 5. Prior A., Frutos P., Frutos G., Torrado
using the Bootstrap method. A relatively robust Susana, Correa C.; Estudio Comparativo
distribution and a statistical correction of the de los Medicamentos Integrantes del
slant were obtained. Grupo Homogéneo “Alopurinol 300 mg 30
comprimidos”, V Spanish-Portuguese
In conclusion, it is plain that the use of Conference on Controlled Drug Release,
Bootstrap confidence intervals is an useful tool Abstract Book, 159-160, 2002.
in order to simulate the confidence the
confidence interval for similarity factor f2.