2. 2 Development of Dissolution Test
in regards to Bioequivalence
3. 3 Development of Dissolution Test
in regards to Bioequivalence
4. Biopharmaceutics Classification System (BCS)
High Solubility - High Permeability Drugs
Low Solubility - High Permeability Drugs
High Solubility - Low Permeability Drugs
Low Solubility - Low Permeability Drugs
FDA: This classification can be used as a
basis for setting in vitro dissolution
specifications and can also provide a basis
for predicting the likelihood of achieving a
successful in vivo-in vitro correlation
(IVIVC).
4 Development of Dissolution Test
in regards to Bioequivalence
5. BCS applications
♦ Highly Soluble API should not have any bioavailability
problems if, in addition, the dosage system is rapidly
dissolved in the physiological pH-interval expected after
product administration and the excipients are known not
to affect the dissolution, stability and absorption
processes.
A bioequivalence study may in those situations be waived
based on similarity of dissolution profiles which are based
on discriminatory testing, provided that the other
exemption criteria in Appendix III are met.
♦ Low Soluble API If an active substance is considered to
have a low solubility, the rate limiting step for absorption
may be dosage form dissolution. This is also the case
when one or more of the excipients are controlling the
release and subsequent dissolution step of the active
substance. In those cases a variety of test conditions is
recommended and adequate sampling should be
performed until either 90% of the drug is dissolved or an
asymptote is reached.
5 Development of Dissolution Test
in regards to Bioequivalence
6. DISSOLUTION STUDIES
♦ In vitro dissolution studies are used to
assess the product quality.
♦ In vitro dissolution rate should correlate
with in vivo bioavailability.
♦ A dosage form with a rapid dissolution
rate is likely to have a rapid rate of drug
bioavailability in vivo.
♦ Bioavailability is not dependent only on
the dissolution of the drug product, but
also on the permeability and solubility of
the drug substance.
6 Development of Dissolution Test
in regards to Bioequivalence
7. FDA has defined bioequivalence as "the absence of a
significant difference in the rate and extent to
which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug
action when administered at the same molar dose
under similar conditions in an appropriately
designed study."
♦ Bioequivalence studies are for determination of
the therapeutic equivalence between the
pharmaceutically equivalent generic drug product
and a corresponding reference listed drug.
♦ Bioequivalence studies provide information on
product quality and performance when there are
changes in components, composition and method of
manufacture after approval of the drug product.
7 Development of Dissolution Test
in regards to Bioequivalence
8. Testing of product quality
♦ To get information on the test batches used in
bioavailability/bioequivalence studies and pivotal
clinical studies:
- To investigate batch to batch consistency of both
test and reference products, to be used as basis for
the selection of appropriate batches for the in vivo
study.
- to support setting specifications for quality control.
♦ To be used as a tool in quality control to demonstrate
consistency in manufacture.
♦ To support the assumption of similarity between
products provided that the manufacturing process,
composition and specifications are similar.
♦ To demonstrate similarity between different
formulations of an API and the reference product
(biowaivers e.g., variations, formulation changes
during development and generic products).
8 Development of Dissolution Test
in regards to Bioequivalence
9. In-vitro dissolution test complementary to bioequivalence studies
“The results of in-vitro dissolution tests at pH
1.2, 4.5, 6.8 and the media intended for drug
product release (QC media), obtained with the
batches of test and reference products that
were used in the bioequivalence study should
be reported.”
“Unless otherwise justified, the specifications
for the in vitro dissolution to be used for quality
control of the product should be derived from
the dissolution profile of the test product batch
that was found to be bioequivalent to the
reference product.”
9 Development of Dissolution Test
in regards to Bioequivalence
10. Biowaiver
10 Development of Dissolution Test
in regards to Bioequivalence
11. In vitro dissolution test in support
of biowaiver and/or strengths
♦ pH 1.2, 4.5, 6.8
♦ Particular dosage forms may require
investigations using physiologically relevant
experimental pH conditions.
♦ Similarity of in vitro dissolution should be
demonstrated at all conditions:
- between strengths used for
bioequivalence testing,
- between additional strengths of the
developed product and corresponding
strengths of the reference product.
11 Development of Dissolution Test
in regards to Bioequivalence
12. Pharmacopoeial Test or
Alternative?
♦ The test methodology should be in
accordance with pharmacopoeial
requirements unless those requirements
are shown to be unsatisfactory and/or do
not reflect the in vivo dissolution (i.e.
biorelevance).
♦ Alternative methods can be considered
when justified that these are
discriminatory and able to differentiate
between batches with acceptable and non-
acceptable performance of the product in
vivo.
12 Development of Dissolution Test
in regards to Bioequivalence
13. Dissolution Techniques - Critical Parameters
♦ Knowledge of dissolution properties under
different conditions e.g. pH, agitation, ionic
strength, surfactants, viscosity, osmotic
pressure is important since the behavior of
the solid system in vivo may be critical for
the drug dissolution independent of the
physico-chemical properties of the active
substance.
♦ An appropriate experimental statistical
design may be used to investigate the
critical parameters and for the optimization
of such conditions.
13 Development of Dissolution Test
in regards to Bioequivalence
14. Similarity Calculation
In this equation ƒ2 is the similarity factor, n is the
number of time points, R (t) is the mean percent
drug dissolved of e.g. a reference product, and T(t)
is the mean percent drug dissolved of e.g. a test
product.
14 Development of Dissolution Test
in regards to Bioequivalence
15. Similarity Factor
The evaluation of the similarity factor is based on the
following conditions:
♦ A minimum of three time points (zero excluded): the first
time point before 15 minutes, the second one at 15
minutes and the third time point when the release is close
to 85%.
♦ In general five to eight sampling times within a 0-60
minutes interval are recommended to achieve meaningful
dissolution profiles.
♦ The time points should be the same for the two
formulations.
♦ Twelve individual values for every time point for each
formulation.
♦ Not more than one mean value of > 85% dissolved for any
of the formulations.
♦ The relative standard deviation or coefficient of variation of
any product should be less than 20% for the first point and
less than 10% from second to last time point.
15 Development of Dissolution Test
in regards to Bioequivalence
16. Similarity Factor Criteria
An f2 value between 50 and 100 suggests
that the two dissolution profiles are similar.
In cases where more than 85% of the drug
is dissolved within 15 minutes, dissolution
profiles may be accepted as similar without
further mathematical evaluation, except in
the case of gastro-resistant formulations
where the dissolution takes place in the
intestine and the 15 minutes for gastric-
emptying lacks of physiological meaning.
16 Development of Dissolution Test
in regards to Bioequivalence
18. 18 Development of Dissolution Test
in regards to Bioequivalence
19. 19 Development of Dissolution Test
in regards to Bioequivalence
20. Solubility of montelukast sodium in blank biorelevant
media and USP-buffers (Okumu et al)
A.Okumu et al, “Dynamic Dissolution Testing To Establish In Vitro/In Vivo Correlations
for Montelukast Sodium, a Poorly Soluble Drug”,
Pharmaceutical Research, 2008, Vol. 25 (12), 2778-2785
20 Development of Dissolution Test
in regards to Bioequivalence
21. Bio-relevant dissolution media
♦ USP SGF (simulated gastric fluid)
NaCl 2.0 g
Purified pepsin 3.2 g
HCl 7.0 mL
Purified water qs. 1000 mL
Media has a pH of about 1.2
♦ USP SIF (simulated intestinal fluid)
Monobasic potassium phosphate 6.8 g in Purified water 250 mL
NaOH (0.2 N) 77 mL and Purified water 500 mL
Pancreatin 10.0 g
Adjust with either 0.2 N NaOH or 0.2 N HCl to a pH of 6.8 ± 0.1.
Purified water qs. 1000 mL
♦ FeSSIF (fed state simulated intestinal fluid)
Sodium taurocholate 15 mM
Lecithin 3.75 mM
NaOH (pellets) 4.04 g
Glacial Acetic Acid 8.65 g
NaCl 11.874 g
Purified water qs. 1000 mL
Media has a pH of 5.00 and an osmolality of about 670 mOsmol/kg
♦ FaSSIF (fasted state simulated intestinal fluid)
Sodium taurocholate 3mM
Lecithin 0.75 mM
NaOH (pellets) 0.174 g
NaH2PO4.H2O 1.977 g
NaCl 3.093 g
Purified water qs. 500 mL
Media has a pH of 6.50 and an osmolality of about 270 mOsmol/kg
21 Development of Dissolution Test
in regards to Bioequivalence
22. Dissolution data in various
bio-relevant media
Pharmacokinetics (“Observed”)
overlayed with “GastroPlus”
models obtained from
dissolution data
22 Development of Dissolution Test
in regards to Bioequivalence
24. Example of flow through cell equipment for dynamic dissolution
M.McAllister “Dynamic Dissolution: A Step Closer to Predictive Dissolution Testing?”
Mol. Pharmaceutics, 2010, 7 (5), pp 1374–1387
24 Development of Dissolution Test
in regards to Bioequivalence
25. Guidances
♦ USP <711> Dissolution: Description of Apparatus 1, 2, 3, 4 . Procedures for
Immediate-Release Dosage Forms and for Extended-Release Dosage Forms
♦ USP <724> Drug Release: Description of Apparatus 5, 6, 7 for Transdermal
Delivery Systems
♦ USP <1088> In Vitro and In Vivo Evaluation of Dosage Forms
Dissolution Testing for Immediate and Modified-Release Dosage Forms.
♦ USP <1092> The Dissolution Procedure: Development and Validation
Medium, Volume, Deaeration, Enzymes, IVIVC (Biorelevant medium),
Apparatus, Sinkers, Agitation, Time Points, Observations, Sampling, Filters,
Centrifugation, Assay.
♦ FDA Guidance for Industry: Dissolution Testing of Immediate – Release
Solid Oral Dosage Forms, August 1997
♦ FDA Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage
Forms, September 1997
♦ FDA Guidance for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms
Based on a Biopharmaceutics Classification System, August 2000
♦ BP Appendix XII B. Dissolution and Ph.Eur. method 2.9.3
♦ EMEA. Note for Guidance on the Investigation of Bioavailability and
Bioequivalence London, 26 July 2001, CPMP/EWP/QWP/1401/98
♦ EMEA. Guidance on the Investigation of Bioequivalence DRAFT,
London, 24 July 2008, CPMP/EWP/QWP/1401/98 Rev. 1
25 Development of Dissolution Test
in regards to Bioequivalence
26. 26 Development of Dissolution Test
in regards to Bioequivalence
27. 27 Development of Dissolution Test
in regards to Bioequivalence