2. CONTENTS:
INTRODUCTION
IMPORTANCE OF DISSOLUTION PROFILE COMPARISON
OBJECTIVE OF DISSOLUTION PROFILE COMPARISON
METHODS USED TO COMPARE DISSOLUTION PROFILE
GRAPHICAL METHOD
STASTITICAL METHOD
MODEL DEPENDENT METHODS
MODEL INDEPENDENT METHODS
CONCLUSION
REFERENCES
2
3. 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.
3
4. Importance of dissolution profile Comparison :
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
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
5.
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.
5
6. METHODS TO COMPARE DISSOLUTION PROFILE
Graphical
method
Statistical
method
t- Test
Model independent method
(Pair Wise Procedure)
ANOVA
f1 and f2 comparison
Model dependent methods
Zero order
First order
Hixsoncrowell law
Higuchi
model
Korsemeyar and
peppas model
6
7. 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.
7
8. Statistical Analysis:
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.
8
9. 2. ANOVA method (ANALYSIS OF VARIENCE)
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.
9
10. ANOVA table.
Source of
variance
Between columns
Between rows
Within group/
error
Total
S2
df
M2
F value
No. of
columns-1
No. of rows -1
dfbetween
columns×
dfbetween rows
(No. of columns
×No. of rows)-1
Compare the calculated F- value with the tabulated value at particular degrees
of freedom and level of significance. If the calculated value is less than the
tabulated value, then degrees of variance is insignificant.
10
11. 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.
11
12. Zero order Plot:
100
cumulative percent of drug released
90
80
70
60
50
TEST
R² = 0.959
REFERENCE
40
R² = 0.965
30
20
10
0
0
5
10
Time (h)
15
20
25
12
13. 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 cumulative percentage 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.
13
18. Korsmeyer - Peppas model:
• The KORSEMEYER AND PEPPAS described this method..
It is given by the equation :
Mt/Ma = Ktn
where Mt / Ma 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.
18
19. Some models with linear equation for graphical presentation:
Model
Zero order
First order
Linear equation
Hixon crowell
Mt/Ma = Ktn
On Y-axis
Time
Cumulative
amount
of drug released
Time
log cumulative
percentage
of drug
cumulative
percentage
drug release
Time
log C = log C0 - Kt / 2.303
On X-axis
Square root of
Time
Qt = Q0 + K0t
Higuchi model
KorsmeyerPeppas model
Plot
cube root of
drug percentage
remaining
Log Time
log cumulative
percentage drug
release
19
20.
Model Independent Approach Using a Similarity 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=1n |R-T|] / [Σ t=1n 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
21. 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=1n (R-T) 2]-0.5 ×100
Limits for similarity and difference factors
Difference
factorf1
0
Similarity
factor f2
100
Inference
Dissolution profiles are similar
Similarity or equivalence of
two
≤15
≥50
profiles.
21
22. 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 point used.
(2) If the test and reference formulation are inter changed , f2 is
unchanged but f1 Is not yet differences between the two mean profile
remain the same.
(3) The basis of the criteria for deciding the difference or similarity
between dissolution profile is unclear.
22
23. conclusion:
Graphical method is first step in comparing dissolution profile and it
is easy to implement but it is difficult to make definitive conclusions
from the it.
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
profiles of drugs.
23
24. References:
1. Hussain L,Ashwini D,Sirish D. Kinetic modeling 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.
24
25. 3.
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/comparison_
of_dissolution_profile.pdf (accessed 15 November 2013).
4.
U.S. Department of Health and Human Services Food and Drug
Administration
Center
for
Drug
Evaluation
and
Research
(CDER). Guidance for Industry Dissolution Testing of Immediate
Release
Solid
Oral
Dosage
Forms.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm070237.pdf (accessed 15 November 2013).
25
