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 INTRODUCTION
 Concepts of Dissolution
 The Need of Dissolution Testing
 Theories of Dissolution
 Application of Dissolution Testing
 Compendial Dissolution Apparatus
 Biopharmaceutical classification system
 Selection of dissolution medium and medium composition
 Experimental testing condition
 Dissolution specification
 In vitro-In vivo correlation (Level A-C correlation)
 Challenges in dissolution tests
 Comparative dissolution testing
 Summary
 References

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 The earliest reference to dissolution can probably be found
in an article by Noyes and Whitney in 1897
"The Rate of Solution of Solid Substances in Their Own Solution.“
 The most prominent of these investigations that deserve recognition are
those of Nernst and Brunner in 1904 for their application of Fick's law
of diffusion to the Noyes-Whitney equation, and those of Hixson and
Crowell in 1931 for their development of the famous cube-root law of
dissolution.

 In the late 1960s dissolution was awarded compendial status and

dissolution testing became a mandatory U.S. pharmacopoeia
requirement for several dosage forms.

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 Dissolution is defined as the process by which a solid
substance enters in the solvent to yield a solution by
which a solid substance dissolves.

 It depends up on several physicochemical processes

 Physicochemical character of dosage forms
 The wet ability of the dosage unit
 Penetration ability of the dissolution medium
 The swelling process
 Disintegration and deaggregation of the dosage form

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 Dissolution testing is an official testing used by the
pharmacopeias for evaluating drug release of solid and
semi solid dosage forms.
 This process is rate-limiting.
 Due to the critical role that dissolution plays in the
bioavailability of the drug, in vitro dissolution can serve
as a relevant predictor of the in vivo performance of the
drug product.

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 has a major impact on its rate and extent of absorption.

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 Despite the large success of several reported in vitro-in
vivo correlation studies, dissolution is not a predictor of
therapeutic efficiency.

 Dissolution can best be described as a qualitative tool that

can provide valuable information about the biological
availability of a drug product.
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 In vitro dissolution testing serves as an important tool for
characterizing the biopharmaceutical quality of a product at
different stages in its lifecycle.
 e.g. as regards dose dumping, food effects on bioavailability
or interaction with other drugs, which influence
gastrointestinal environmental conditions

 In vitro dissolution data are supportive in the evaluation and

interpretation of possible risks, especially in the case of
controlled/modified-release dosage forms.

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 Biopharmaceutical aspects are as important for stability
concerns as they are for batch release after production, in
vitro dissolution being of high relevance in quality control
and quality assurance

 None of these purposes can be fulfilled by an in vitro test

system without sufficient reliability.

 Some investigators argue that the best dissolution test

device of any system is the system itself.

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 Evaluation of Bio availability.
 Development of more efficacious and therapeutically optimal
dosage forms.
 Minimizes use of humans as test subjects
 Ensures quality of the product
 Correlation between dissolution results & bioavailability of
product between batches.
 Product development, quality control and research and
application.
 Screening of formulations during product development .
 Batch to batch drug release uniformity.
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 There are three theories of dissolution namely:
 Diffusion Layer Model (Film Theory)
 Danckwert’s Model(Penetration or Surface Renewal
Theory)
 Interfacial Barrier Model (Double Barrier Mechanism
OR Limited Solvation Theory)

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It is a simplest model where dissolution of crystal,
immersed in liquid takes place without involving reactive or
electrical forces.

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 This theory assumes that solid-solution equilibrium is achieved
at interface and mass transport is slow step in dissolution
process.

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Interfacial Barrier Model (Double Barrier or
Limited Solvation Theory)

 The Diffusion layer model and the Dankwert’s model

were based on two assumptions:
 The rate determining step that controls dissolution is
the mass transport.
 Solid solution equilibrium is achieved at the
solid/liquid interface.
 G = ki (Cs – Cb)Where G = dissolution per unit area
Ki = effective interfacial transport constant
 According to interfacial barrier model, an intermediate
concentration can exist at the interface as a result of
solvation mechanism and is a function of solubility
rather than diffusion.
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 It follows zero order dissolution rate

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 For obtaining IVIVC sink condition can be achieved by:
 Bathing the dissolving solid in fresh solvent from time to
time.
 Increasing the volume of dissolution fluid..
 Adding a water miscible solvent such as alcohol to the
dissolution fluid.
 By adding selected adsorbents to remove the
dissolution drug.
 In vitro sink condition is so maintain that Cb always less
than 10% of Cs.

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 These methods are known as the USP basket (method
Ι) and paddle (method ΙΙ) methods and are referred to
as “closed-system” methods because a fixed volume of
dissolution medium is used.

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 This Method replaces the basket as the source of
agitation. As with the basket apparatus, the shaft should
position no more than 2mm at any point from the
vertical axis of the vessel and rotate without significant
wobble

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 Both the USP Apparatus 1 and 2 share some common
advantages and disadvantages.
 Advantages include:
 i) widely accepted apparatus for dissolution test,
 ii) apparatus of first choice for solid oral dosage forms,
iii) standardized,
 iv) easy to operate,
 v) robust and
 vi) broad experience.

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 Disadvantages include:
 i) limited volume of the dissolution media,
 ii) simulation of the gastrointestinal transit is not
possible
 iii) hydrodynamic conditions are not known.

 Dissolution results obtained with USP Apparatuses 1

and 2 may be significantly affected by shaft wobble,
location, centering, and coning

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 The design of USP apparatus 3 is based on the disintegration
tester.
 The assembly of USP apparatus 3 consists of a set of cylindrical,
flat-bottomed glass outer vessels; a set of glass reciprocating
inner cylinders; and stainless steel fittings and screens that are
made of suitable material and that are designed to fit the tops
and bottoms of the reciprocating cylinders.
 USP Apparatus 3 offers advantages like
 i) programmed for dissolution in various media for various time,
ii) the media can be changed easily,
 iii) may start at pH 1 and then pH 4.5 and then at pH 6.8 and
 iv) attempts to mirror pH changes and transit times in the GI
tract.

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 But it has got some disadvantages too,
i) Disintegrating dosage forms show too low results,
ii) surfactants cause foaming and
iii) volume of dissolution media is too small.
 Not accepted b Japanese Pharmacopeias.

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 USP Apparatus 4 can be operated under different
conditions such as open or closed system mode,
different flow rates and temperatures.

 It is the method of choice for extended release and

poorly soluble products.
 USP Apparatus 4 requires the sampling pump to be on
continuously throughout the analysis, as the dissolution
rate is directly proportional to the flow rate of the
medium that is pumped into the flow through cell.

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 Advantages of the apparatus include:
 i) no limitation regarding the volume of media used for
the dissolution test,
 ii) suitable for low soluble drugs,
 iii) gentle hydrodynamic conditions,
 iii) simulation of the gastrointestinal transit and
 iv) suitable for special dosage forms such as powder
and granules, implants.

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 But the apparatus has got limited experience;
 pump precision may influence the results and
 fractioned primary data lead to greater experimental
error when computed to cumulative profiles

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 In Paddle-over-Disk method the paddle and vessel
assembly from Apparatus 2 with the addition of a
stainless steel disk assembly designed for holding the
transdermal system at the bottom of the vessel.
 The temperature is maintained at 32°C ± 0.5°C. The
disk assembly holds the system flat and is positioned
such that the release surface is parallel with the bottom
of the paddle blade.

 The apparatus is used to test transdermal patches.

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 This is a modification of the basket apparatus (USP
Apparatus 1).
 It uses the vessel assembly from Apparatus 1 except to
replace the basket and shaft with a stainless steel
cylinder stirring element.

 The apparatus is used to test transdermal patches.

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 Originally introduced in the USP as a small-volume
option for small transdermal patches, the reciprocating
disk apparatus was later renamed the reciprocating
holder apparatus with the adoption of four additional
holders for transdermal systems, osmotic pumps, and
other low-dose delivery systems.

 The apparatus is used to test transdermal patches.

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 The Biopharmaceutical classification system (BCS)
is a scientific framework for classifying a drug substance
based on their solubility ratio, dissolution and intestinal
permeability.
 It allows
 Predicting the in vivo pharmacokinetic performance
 Reduces its costs
 can be applied to NDA and ANDA approvals
 scale up, and post approval changes

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 Expands the regulatory application of the BCS and
recommends methods for classifying drugs.

 Explains when a waiver for in vivo bioavailability and

bioequivalence studies may be requested based on the
approach of BCS.

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 The drug can be classified into four classes of the BCS

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 BCS is based on scientific framework describing three rate
limiting steps in oral absorption.

 Release of drug from dosage forms

 Maintenance of dissolved state through Gastro-intestinal

(G.I) tract;

 Permeation through G.I. membrane into hepatic

circulation.

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 Examples of Drugs belonging to different
Classes of BCS [1][2][6]
Class I: Chloroquine, Paracetamol,
Class II: Glibenclamide, Ketoconazole, Phenytoin
Class III: Acyclovir, Atenolol, Captopril,
Class IV:Furosemide, Ritonavir, Saquinavir, Taxol,

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 The selection of an appropriate dissolution medium is a
fundamental stage of the dissolution test
 Before selecting the dissolution medium
 Physical and chemical data for the drug substance
and dosage unit need to be determined
 When deciding the composition of the medium for
dissolution testing
 influence of buffers, pH value, and surfactants on the
solubility and stability of the drug need to be
evaluated.

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 The choice of volume and composition of the dissolution
medium is very much dependent on the solubility of the
drug..
 The volume of the dissolution medium is 500 mL to
1000 mL, with 900 mL as the most common volume
when using the basket or paddle apparatus.
 The standard temperature for the dissolution medium is
37±0.5°C for oral dosage forms.
 Lower temperatures such as 32±0.5 °C are utilized for
topical dosage forms such as trans-dermal patches and
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 Dissolution media should be deaerated immediately
before use to avoid air bubbles forming on the compact
or die surface.

› Bubbles on the dosage unit may decrease the

dissolution rate by decreasing the available surface
area.
 For very poorly soluble compounds, aqueous solutions
may contain a percentage of a surfactant
 The use of enzymes in the dissolution medium is
permitted
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 Ideally, a dissolution medium should be formulated as
close as possible to the pH anticipated in in vivo fluids
› Meets sink conditions
› must not affect the stability of the drug
› simple composition required to permit
› automation of the method
› easy to be prepared
› inexpensive
› preferably non-organic

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 simulated gastric fluid (with or without enzymes)
o This medium contains hydrochloric acid and sodium
chloride and water
o has a pH of 1.2 as well as it may contain pepsin.
 Simulated Intestinal Fluid (SIF) with or without enzymes
o buffer solution containing potassium dihydrogen
phosphate
o The pH of this medium is 6.8 and falls within the
range of normal intestinal pH.
o Pancreatin may also be added if amore biorelevant
form of the medium is required.

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 Bio-relevant media- is the media that represent the
conditions same as that of the in-vivo condition.

 These media are primarily used to establish in vitro-in

vivo correlation during formulation development and to
assess potential food effects

 The fed and fasted state may have significant effects on

the absorption or solubility of a compound

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 This media reflect changes in the pH, bile concentration
and osmolarity after meal intake and therefore have a
different composition than that of typical compendial
media.
 Examples of biorelevant media include fasting state and
fed state simulated intestinal fluids consisting of bile
salt–phospholipid mixed micelle systems

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 Water, and surfactants (with or without acids or buffers)

 Purified water is often used as the dissolution medium,

but is not ideal for several reasons.

 The quality of the water can vary depending on the

source of the water, and the pH value of the water is
not controlled.
 the pH of water may vary with its source, and water
has no buffer capacity

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 For very poorly soluble compounds, aqueous solutions
may contain a percentage of a surfactant that is used to
enhance drug solubility.
 Surfactants can be used either as wetting agents or to
solubilize the drug substance.
 dilute hydrochloric acid, and buffers in the physiologic
pH range of 1.2 to 7.5, are also The most commonly
used dissolution media

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 Dissolved gases- can alter the pH of media

› distilled water, pH 6;

› deareated water, pH 7.2

 With the change in temperature, the dissolved gases

may be released in the form of bubbles.

› These bubbles can alter the flow patterns associated

with particles or the dosage form itself, disturbing the
boundary layer at the solid-liquid interface

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 pH of the Dissolution medium-
 dissolution media contains various ions and salts, has
significant effect on dissolution of drugs.
 Eg-Dissolution rate of benzoic acid from tablet
decreases, when various concentrations of sodium
chloride, sodium sulfate & dextrose are present in
dissolution media.
 This effect occurs due to change in PH associated with
addition of salt.

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 Viscosity of dissolution media:-
 Dissolution rate decreases with increase in viscosity of
dissolution medium in case of diffusion controlled dissolution
process.

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 For all applications, in-vitro dissolution data should at
least allow some interpretation with regard to in-vivo
biopharmaceutical performance.

 In general, an aqueous medium is used.

 The composition of the medium is chosen on the basis

of
 the physico-chemical characteristics of the active substance(s)
and excipient(s) .

 The pH of the dissolution medium is usually set

between pH 1 and pH 8.
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 dissolution media may contain enzymes, surfactants,
further inorganic substances and organic substances.

 For the testing of preparations containing poorly

aqueous-soluble active substances,

 Gases dissolved in the dissolution medium can affect

the results of the dissolution test.

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 is expressed in terms of the quantity (Q) of active
substance dissolved in a specified time,

 expressed as a percentage of the content stated on the

product label.

 For immediate-release products, a single-point

specification is used to ensure prompt dissolution;

› normally no less than 75% of the drug must be

dissolved within 45 minutes.

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 Gastro-resistant dosage forms require at least 2
specification points in a sequential test and 2 different
specifications in a parallel test.

 In a sequential test, the 1st specification point

represents an upper limit and is set after 1 h or 2 h in
acidic medium, and the 2nd after a pre-set time period
of testing in an adequate buffer solution (preferably pH
6.8)

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 The dissolution test acceptance criteria for prolonged-
release dosage forms is normally expected to consist of
3 or more points.
› 1st specification point is intended to prevent
unintended rapid release of the active substance
(‘dose dumping’).
 It is therefore set after a testing period
corresponding to a dissolved amount typically of 20
per cent to 30 per cent.

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 2nd specification point defines the dissolution pattern
and so is set at around 50 per cent release.

 The final specification point is intended to ensure almost

complete release, which is generally understood as
more than 80 per cent release.

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 E.G.H 57
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 From biopharmaceutical standpoint, correlation
could be referred to as the relationship between
appropriate in vitro release characteristics and in
vivo bioavailability parameters.
Terminology
A. In vitro dissolution : refers to the process of dissolution
(release) of drug from dosage form as measured in an in
vitro dissolution apparatus.
B. In vivo dissolution: refers to the process of dissolution of
drug in the gastrointestinal tract.
C. Correlation: is a relationship between in vitro dissolution
rate and in vivo input (absorption rate) as used in
bioequivalence guidance.

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 United State Pharmacopoeia (USP) definition
 The establishment of a rational relationship between a biological
property/a parameter derived from a biological property
produced by a dosage form, and a physicochemical
property/characteristic of the same dosage form.
Food and Drug Administration (FDA) definition
 IVIVC is a predictive mathematical model describing the
relationship between an in vitro property of a dosage form and a
relevant in vivo response.
 Generally,
In-vitro properties are rate or extent of drug released under a given
set of conditions.
In-vivo properties are plasma drug conc. expressed in terms of Cmax,
AUC.

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 Reduction of regulatory burden : IVIVC can be used as
substitute for additional in vivo experiments, under certain
conditions.
 Optimization of formulation: The optimization of formulations
may require changes in the composition, manufacturing process,
equipment, and batch sizes.
 Justification for “therapeutic’ product quality: IVIVC is often
adequate for justification of therapeutically meaningful release
specifications of the formulation.
 Scale up post approval changes (Time and cost saving during
the product development): Validated IVIVC is also serves as
justification for a biowaivers , either during scale up or post
approval, as well as for line extensions (e.g., different dosage
strengths).
 IVIVC as surrogate for in vivo bioequivalence and to support
biowaivers (Time and cost saving)

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 point-to-point relationship between in vitro dissolution
rate and in vivo input rate of the drug from the dosage
form.
 Usually Correlations are linear
 Comparison of fraction of drug absorbed (Fa) and
fraction of drug dissolved (Fd) in-vitro to obtain a linear
correlation.
 Formulations showing Level A correlation require no
additional human studies to justify change in
manufacturing site, raw material supplier or minor
formulation changes.
 Most informative and very useful from a regulatory
perspective.
 PURPOSE – DEFINE DIRECT RELATIONSHIP
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Importance of level A correlation
The in vivo dissolution serves
as in vivo indicating quality
control procedure for
predicting dosage form
performance.
Determining stable release
characteristics of the product
over time.
A point to point correlation is
developed
an in vitro dissolution curve
can serve as a surrogate for
in vivo performance.

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 utilizes the principles of statistical moment analysis.
 It compares
 1) MDT vitro to MATvivo,
 2) MDT vitro to MRT,
 3) In-vitro Dissolution Rate Constant (kd) to Absorption Rate Constant (ka).
 it is not considered to be a point-to point correlation,
since there are a number of different in vivo curves that
will produce similar mean residence time values.
 Therefore, one cannot rely upon a level B correlation
alone to justify
› formulation modification,
› manufacturing site change,
› excipient source change, etc.

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Limitations
 does not uniquely
reflect the actual in
vivo plasma level
curves.
 Therefore it fails to
justify the formulation
modifications.

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 Predictive mathematical model
which relates one dissolution time
point (e.g.t50%) to one
pharmacokinetic parameter that
characterizes in-vivo time course.
(e.g., Cmax, Tmax, T1/2 or AUC).
 Level C correlations can be useful
in the early stages of formulation
development when pilot
formulations are being selected.
 Lowest correlation level
 Does not reflect a complete shape
of plasma concentration time
curve.

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 relates one or several pharmacokinetic parameters of interest
(Cmax, AUC, or any other suitable parameters) to the amount of
drug dissolved at several time points of the dissolution profile.
 may be used to justify a bio waiver, provided that the correlation
has been established over the entire dissolution profile with one
or more pharmacokinetic parameters of interest.
 A relationship should be demonstrated at each time point at the
same parameter such that the effect on the in vivo performance
of any change in dissolution can be assessed.
 If achievable, then the development of a level A correlation is
also likely.
 should be based on at least three dissolution time points
covering the early, middle, and late stages of the dissolution
profile

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LEVEL IN VITRO IN VIVO

A Dissolution curve Input(absorption curves)

B Statistical moments: mean Statistical moments: mean

dissolution time(MDT) residence time(MRT), mean
absorption time(MAT) .

C Disintegration time, time to Maximum observed

have 10%, 50%, 90% dissolved, concentration( cmax ),
dissolution rate, dissolution observed at time( tmax ),
efficiency(DE) absorption constant(ka), time
to have 10,50,90% absorbed,
AUC(total or cumulative)

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 Both bio relevance and technique variability are used to
challenge the validity of dissolution testing.
1. lack of bio relevance
 The most significant challenge for many dissolution methods
used as a nominal performance measure stems from the lack of
bio relevance (physiologically based).
 Scientists have stated that developing a dissolution method and
setting associated specifications that are not linked to in vivo
performance may limit the value of testing.
 It is not difficult to see that the vortex in the current design of
USP apparatus is not the same as in a churning stomach.
 The majority of dissolution testing is carried out in a simple salt
medium at a particular pH

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 The gastrointestinal lumen is significantly different, containing a plethora
of biomolecules and salts in a changing pH environment.
 A lack of a bio relevant (physiologically based) dissolution system and
specification often leads to data that are disconnected from in vivo results.
 Few cases have been found where the method is appropriately
discriminating.
 A dissolution method that is developed solely as a quality control tool for
manufacturing is much less desirable than one that has bearing on patient
safety or efficacy.
 If measurements have no bearing on the pharmacokinetic impact, then
testing is not controlling the most important aspect of performance.

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 Variability associated with dissolution testing is another area receiving a great
deal of attention.
 These sources can be divided into four subsets
1. The physical or mechanical setup of the test.
 Tolerances allowed in operating the apparatus are defined by the USP.
 The definitions are designed to allow the apparatus to function with acceptable
method variability, but even when operating within these limits, different
dissolution profiles for the same drug product may result.
 Other physical factors are not controlled by the USP description but have an
effect.
 Among the parameters in this class are shaft or basket wobble, vessel/shaft tilt,
shaft centering, shaft height in vessel, and rotational speed.
 Vessel roundness, surface uniformity, or other hydrodynamic effects fall into
this class and impact results.
 Even small changes in basket mesh size seem to have an influence on results.

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2. Operational differences.
 Parameters in this group are incidental vibration, the extent of
degassing, inconsistent tablet placement in vessels, and
inconsistent use of clips or sinkers.
3. Variability comes indirectly from performance differences in
calibrator tablets that are real, operator induced, or from
excipient deposition.
 As the name implies, calibrator tablets are used to verify overall
system precision to qualify apparatus and control system
variability.
 However, different disintegration mechanisms between
calibrator and sample tablets are cited as a source of variability.
 Proposed remedies for calibrator tablet variability are
mechanical calibration, project specific manufacturer calibrator
tablets possessing similar processing and mechanistic
disintegration qualities or non-USP apparatus.

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4. Source of variability comes from manufacturing
and is due to lot-to-lot or tablet-to tablet processing
or handling differences of the drug product.
 It includes particle size distribution and polymorph
changes during drug substance manufacture.
 Changes in excipient characteristics are known to
impact results.
 The variability from this cause is independent of the
method but is reflected in the results.
 Sorting out the origin among all the potential sources
of variability can be problematic.

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 It is graphical representation [in terms of concentration vs. time]
of complete release of A.P.I. from a dosage form in an
appropriate selected dissolution medium. I.e. in short it is the
measure of the release of A.P.I from a dosage form with
respect to time.
Objective:
 To develop in-vitro-in-vivo correlations which can help to
reduced costs, speed-up product development and reduced the
need of perform costly bioavailability human volunteer studies.
 To stabilize final dissolution specification for the
pharmacological dosage form
 Establish the similarity of pharmaceutical dosage forms, for
which composition, manufacture site, scale of manufacture,
manufacture process and/or equipment may have changed
within defined limits.

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 Dissolution profile of an A.P.I. reflects its release pattern under the
selected condition sets. I.e. either sustained release or immediate
release of the formulated formulas.
 For optimizing the dosage formula by comparing the dissolution
profiles of various formulas of the same A.P.I
 Dissolution profile comparison between pre change and post change
products for SUPAC (scale up post approval change) related changes
or with different strengths, helps to assure the similarity in the product
performance and green signals to bioequivalence.
 FDA has placed more emphasis on dissolution profile comparison in
the field of post approval changes and bio waivers (e.g. Class I drugs
of BCS classification are skipped off these testing for quicker approval
by FDA).
 The most important application of the dissolution profile is that by
knowing the dissolution profile of particular product of the
BRANDLEADER, we can make appropriate necessary change in
our formulation to achieve the same profile of the BRAND LEADER

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 Comparison of 2 or more products or batches containing the same API
› by means of multipoint dissolution (comparing profiles)
 The strength of products / batches may OR may not be the same
depending on purpose of test
 The dissolution conditions must be similar, (e.g. Apparatus, medium,
volume, rotation speed & temperature and Minimize possible
experimental differences in conditions)
 Samples are taken at the same time points for data comparison
 In the presence of minor changes, single point dissolution tests have
been employed in evaluating scale-up and post-approval changes.
 For major changes, a dissolution profile comparison performed under
identical conditions for the product before and after the change is
recommended.
 Dissolution profile comparison may be carried out using the model
dependent or model independent methods.
 One such model independent approach is subsequently explained

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 This approach uses a difference factor (f1) and a
similarity factor (f2) to compare the dissolution profiles.
The difference factor (f1) calculates the percent (%)
difference of the two curves at each time point and is a
measurement of the relative error between the two
curves:

 where n is the number of time points, Rt is the

dissolution value of the reference batch (pre-change) at
time t, and Tt is the dissolution value of the test (post-
change) batch at time t.
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 The similarity factor (f2) is a logarithmic reciprocal square root
transformation of the sum of squared error and is a measurement of
the similarity in the percent (%) dissolution between the curves:

 To calculate the difference and similarity factor, first, the

dissolution profile should be done for 12 units each of the pre-
change and the post-change products.
 The difference factor (f1) and similarity (f2) can be calculated
using the mean dissolution values from both curves at each time
interval.
 For the curves to be considered similar, f1 values should be close to
0, and f2 values should be close to 100.

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 This model independent method is most suitable for
dissolution profile comparison, when three or four more
dissolution time points are available.

 If both the test and reference product show ≥ 85%

dissolution within 15 minutes,
› the profiles are considered to be similar
 No calculations are required
 If this is not the case, apply point 2 (next point)
 Calculate the f2 value (similarity factor):
› If f2 ≥ 50
 the profiles are regarded similar
 No decimal required (f2 = 49.51 ≡ 50)

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 n = number of time points
 Rt = % API dissolved of reference product at time point x
 Tt = % API dissolved of test product at time point x
 Minimum of 3 time points (zero excluded)
 12 units (one / vessel) for each batch (for “official”
purposes)
 Only one measurement should be considered after the
reference product has reached 85 % dissolution (or
asymptote is reached
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