Definition, importance, objectives, methods to compare, applications, advantages and disadvantages, references.

1. Similarity and Difference
Factors in Dissolution Studies
By: Jessica Fernandes
Reg. No. 150617004
Department of Pharmaceutics
Guided By Mr. Lalit Kumar
Assistant Professor-senior scale
Department of Pharmaceutics
MCOPS, Manipal

2. 2
Definition
It is graphical representation [in terms of concentration vs.
time] of complete release of drug 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.

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Importance of dissolution profile Comparison
 Dissolution profile of an A.P.I. reflects its release pattern under
the selected condition sets.
 FDA has placed more emphasis on dissolution profile
comparison in the field of post approval changes.
 The most important application of the dissolution profile is that
by knowing the dissolution profile of particular product of the
BRAND LEADER, we can make appropriate necessary
change in our formulation to achieve the same profile of the
brand leader.

4. 4
Objective of dissolution profile Comparison
• To Develop in-vitro in-vivo correlation which can help
to reduce costs, speed-up product development and
reduce the need to perform costly bioavailability human
volunteer studies.
• 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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METHODS TO COMPARE DISSOLUTION PROFILE
Graphical
method
Statistical
method
t- Test ANOVA
Zero order First order Hixson-
crowell law
Higuchi
model
Korsemeyar and
peppas model
f1 and f2 comparison
Model independent method
(Pair Wise Procedure)
Model dependent methods

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Graphical method
 In this method we plot graph of Time V/S concentration
of solute (drug) in the dissolution medium or biological
fluid.
 The shape of two curves is compared for comparison of
dissolution pattern and the concentration of drug at each
point is compared for extent of dissolution.
 If two or more curves are overlapping then the
dissolution profile is comparable.
 If difference is small then it is acceptable but higher
differences indicate that the dissolution profile is not
comparable.

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Statistical Analysis
1. Student’s t-Test
Following tests are commonly used…
a) Paired t-test
b) Unpaired t-test
𝑡 =
𝐷
𝑆𝐸
Calculated ‘t’ value is compared with tabulated value of ‘t’ if
the calculated value exceeds the tabulated value, then the null
hypothesis should be rejected and vice versa.

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2. ANOVA METHOD (Analysis of Variance)
 This test is generally applied to different groups of data.
Here we compare the variance of different groups of data
and predict whether the data are comparable or not.
 Minimum three sets of data are required. Here first we
have to find the variance within each individual group and
then compare them with each other.

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Model dependent methods
 Zero order kinetics
Qt = Q0+K0t
Where,
Qt is the amount of drug dissolved in time t
Q0 is the initial amount of drug in the solution
K0 is the zero order release constant expressed in units of
concentration/time
.
Plot: Cumulative amount of drug released versus time.
Applications: Transdermal systems, as well as matrix tablets
with low solubility drugs in coated forms, osmotic systems, etc.

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R² = 0.9652
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25
cumulativepercentofdrugreleased
Time (h)
Zero order Plot:

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First order model
log C = log C0 - Kt / 2.303
Where
C0 is the initial concentration of drug,
K is the first order rate constant, and
t is the time.
Plot: log concentration of drug remaining vs. time which would
yield a straight line with a slope of -K/2.303.
Application: This relationship can be used to describe the drug
dissolution in pharmaceutical dosage forms such as those
containing water soluble drugs in porous matrices.

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R² = 0.9333
94
95
96
97
98
99
100
101
0 5 10 15 20 25 30
Logconcentration
Time (h)
First order plot

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Higuchi model (Diffusion matrix formulation)
• This is given by Higuchi.
𝑄 = 𝐾 𝑇
Where Q is the amount of drug released in time‘t’ per unit
area,
K is higuchi constant
T is time in hr.
Plot: The data obtained is to be plotted as cumulative
percentage drug release versus Square root of time.
Application:
modified release pharmaceutical dosage forms, transdermal
systems and matrix tablets with water soluble drugs.

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 Hixson-Crowell model
Hixson and Crowell described this
W0
1
3
− Wt
1
3
= Kt
Where W0 is the initial amount of drug
Wt is the remaining amount of drug at time t .
Plot: Data is to be plotted as cube root of drug percentage
remaining in matrix versus time.
Application: This expression applies to pharmaceutical dosage
form such as tablets, where the dissolution occurs in planes
that are parallel to the drug surface if the tablet dimensions
diminish proportionally in such a manner that the initial
geometrical form keeps constant all the time.

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 Korsmeyer - Peppas model
The KORSEMEYER AND PEPPAS described this method..
It is given by the equation :
Mt /M∞ = Ktn
where Mt / M ∞ is fraction of drug released
t = time
K=constant includes structural and geometrical characteristics
of the dosage form
n= release component which is indicative of drug release
mechanism
where , n is diffusion exponent.
If n= 1 , the release is zero order .
n = 0.5 the release is best described by the Fickian diffusion
0.5 < n < 1 then release is through anomalous diffusion or case
two diffusion. In this model a plot of percent drug release
versus time is linear.

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Model Independent Approach
Moore and Flanner proposed a model independent mathematical
approach to compare the dissolution profile using two factors, f1
and f2.
1. Difference Factor
The difference factor (f1 ) calculates the percent (%)
difference between the two curves at each time point and is a
measurement of the relative error between the two curves:
f1= {[Σ t=1
n |R-T|] / [Σ t=1
n R]} ×100
where n is the number of time points, R is the dissolution
value of the reference (prechange) batch at time t, and T is
the dissolution value of the test (postchange) batch at
time t.

20. Applications
• F1 is specially used to compare two dissolution profiles,
being necessary to consider one of them as the reference
standard product.
• It can measure the percent of error between two curves
over all time points.

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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 two curves.
f2= 50×log {[1+ (1/n) Σ t=1
n (R-T) 2]-0.5 ×100
2. Similarity Factor
PARAMETERS VALUES
Difference Factor (f1) 0 – 15
Similarity Factor (f2) 50-100

22. Applications
• This method is more appropriate when more than three or
four dissolution time points are available.
• 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.
• Nevertheless, with a slight modification in the statistical
analysis, similarity factor would definitely serves as an
efficient tool for reliable comparison of dissolution
profiles.

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Advantages
1. They are easy to compute.
2. They provide a single number to describe the comparison
of dissolution profile data.
Disadvantages
1. The values of f1 and f2 are sensitive to the number of
dissolution time points used.
2. The basis of the criteria for deciding the difference or
similarity between dissolution profile is unclear.

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Conclusion
 Graphical method is first step in comparing dissolution
profile and it is easy to implement but it is difficult to make
definitive conclusions.
 Various model dependent methods can be used to compare
the dissolution profile but selecting the model, interpretation
of model parameters and setting similarity limit is difficult.
 f1 and f2 comparison is easy and this is most widely used
method to compare dissolution profiles. This is also
recommended by FDA.
 By using all the above given models we can compare
dissolution profile of drug.

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References
1. Hussain L, Ashwini D, Sirish D. Kinetic modelling and
dissolution profiles comparison: an overview. Int J Pharm
Bio Sci. 2013; 4(1): 728 - 737.
2. Thomas O’H, Adrian D, Jackie B and John D. A review of
methods used to compare dissolution profile
data. PSTT. 1998; 1(5): 214-223.

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3. U.S. Department of Health and Human Services Food and
Drug Administration Centre for Drug Evaluation and
Research (CDER). Guidance for industry dissolution testing
of immediate release solid oral dosage forms.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceR
egulatoryInformation/Guidances/ucm070237.pdf. Accessed
on 15 November 2015.
4. Jignesh A, Maulik P, Sachi P. Comparison of dissolution
profile by model independent & model dependent methods.
http://pharmaquest.weebly.com/uploads/9/9/4/2/9942916/com
parison_of_dissolution_profile.pdf. Accessed on 15
November 2015.

27. ThankYou