Dissolution f1 and f2 Analysis and IVIVC

COMPARISON OF DISSOLUTION PROFILE BY
DIFFERENT METHODS
&
IVIVC
Presented By
Mr.Akash Gujarathi
M.Pharm 1st sem
Dept. of Pharmaceutics
1
Poona College Of Pharmacy,
Centre of Advanced Research In Pharmaceutical
Sciences
Guided By
Dr. Mrs. V.B. Pokharkar,
Vice Principal and
Head Of Department of
Pharmaceutics

CONTENTS….
 Definition
 Objectives
 Importance
 Different methods used for dissolution comparison
 Comparison of different methods
 IVIVC
 References
2

DEFINITION:
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.
3

OBJECTIVE:
 To Develop invitro-invivo correlation which can help to
reduced costs, speed-up product development and
reduced the need of perform costly bioavailability human
volunteer studies.
 Demonstrating equivalence after change in formulation of
drug product
 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.
4

IMPORTANCE OF DISSOLUTION
PROFILE
 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
 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.
5

METHODS TO COMPARE DISSOLUTION PROFILE
6
Grafical
Method
Statistical
Analysis
Model
Dependent
Method
Model
Independent
Method
Zero
order
First
order
Hixson-
crowell
Higuchi
model
Korsemeyar
and peppas
model
Baker-
Lonsdale
model
Ratio Test
Procedure
Pair Wise
Procedure-
(f1andf2)
Multivariate
Confidence
regionProcedure
t Test ANOVA

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

GRAPHICAL COMPARISON OF DISSOLUTION
PROFILE
8

MODEL DEPENDENT METHODS
1) Zero order kinetics (osmotic system
,transdermal system)
 Zero order A.P.I.release contributes drug release from
dosage form that is independent of amount of drug in
delivery system. ( i.e., constant drug release)i.e.,
A0-At = kt
Where ,A0 = initial amount of drug in the dosage form;
At = amount of drug in the dosage form at time‘t’
k = proportionality constant
 Application: Transdermal systems as well as matrix
tablets with low solubility drugs in coated forms,
osmotic systems.etc 9

2) FIRST ORDER KINETICS (WATER SOLUBLE DRUGS IN
POROUS MATRIX)
 Using Noyes Whitney’s equation, the rate of loss of drug
from dosage form (dA/dt) is expressed as;
-dA/dt = k (Xs – X)
Assuming that,
sink conditions = dissolution rate limiting step for in-vitro
study
absorption = dissolution rate limiting step for in-vivo study.
Then (1) turns to be:
-dA/dt = k (Xs ) = constant
So it becomes,
A = Ao × e-k
Applications: This relationship can be used to described the
drug dissolution in phaarmaceutical dossage forms
containing water soluble drugs in porous matrices
10

3)HIGUCHI MODEL (DIFFUSION MATRIX
FORMULATION)
 Higuchi in 1961 developed models to study the release of water
soluble and low soluble drugs incorporated in semisolid and solid
matrices.
 To study the dissolution from a planer system having a
homogeneous matrix the relation obtained was;
A = [D (2C – Cs)Cs × t]1/2
Where A is the amount of drug released in time‘t’ per unit
area,
C is the initial drug concentration,
Cs is the drug solubility in the matrix media
D is the diffusivity of drug molecules in the matrix
substance.
Applications: Modified release dossage forms, transdermal systems
and matrix tablets with water soluble drugs
11

4) BAKER-LONSDALE MODEL(MICROSPHERES ,
MICROCAPSULES)
 In 1974 Baker-Lonsdale (Baker and Lonsdale, 1974)
developed the model from the Higuchi model and
describes the controlled release of drug from a spherical
matrix that can be represented as:
3/2 [1-(1-At/A∞)2/3]-At/A∞ = (3DmCms) / (r02C0) X t
Where At is the amount of drug released at time’t’
A∞ is the amount of drug released at an infinite time,
Dm is the diffusion coefficient,
Cms is the drug solubility in the matrix,
ro is the radius of the spherical matrix
Co is the initial concentration of the drug in the matrix. 12

5) HIXON – CROWELL MODEL (ERODIBLE MATRIX
FORMULATION)
 To evaluate the drug release with changes in the surface
area and the diameter of the particles /tablets
 The rate of dissolution depends on the surface of
solvent - the larger is area the faster is dissolution.
 Hixon-Crowell in 1931 ( Hixon and Crowell, 1931)
recognized that the particle regular area is proportional
to the cubic root of its volume, desired an equation as
Wo
1/3-W1/3 = K × t
where, Wo= original mass of A.P.I.particles
K = cube-root dissolution rate constant
W = mass of the A.P.I at the time ‘t’
 This model is called as “Root law”. 13

GUIDANCE FOR INDUSTRY
To allow application of these models to comparison of
dissolution profiles, the following procedures are suggested:
1. Select the most appropriate model for the dissolution profiles from the standard,
prechange, approved batches. A model with no more than three parameters
(such as linear, quadratic, logistic, probit, and Weibull models) is recommended.
2. Using data for the profile generated for each unit, fit the data to the most
appropriate model.
3. A similarity region is set based on variation of parameters of the fitted model for
test units (e.g., capsules or tablets) from the standard approved batches.
4. Calculate the MSD (Multivariate Statistical Distance) in model parameters
between test and reference batches.
5. Estimate the 90% confidence region of the true difference between the two
batches.
6. Compare the limits of the confidence region with the similarity region. If the
confidence region is within the limits of the similarity region, the test batch is
considered to have a similar dissolution profile to the reference batch. 14

MODEL INDEPENDENT METHODS
PAIRED WISE PROCEDURE
 DIFFERENCE FACTOR (f1) & SIMILARITY FACTOR (f2)
 The difference factor (f1) as defined by FDA calculates the %
difference between 2 curves at each time point and is a
measurement of the relative error between 2 curves.
f1 = × 100
where, n = number of time points
Rt = % dissolved at time t of reference product (pre change)
Tt = % dissolved at time t of test product (post change) 15
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1

 The similarity factor (f2) as defined by FDA is logarithmic
reciprocal square root transformation of sum of squared error
and is a measurement of the similarity in the percentage (%)
dissolution between the two curves
f2 = 50 ×
Limits for similarity and Difference factors
16
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1
log )(
1
1
5.0
n
r
TtRtwt
n
Difference
Factor
Similarity Factor Inference
0 100 Dissolutions
profile are similar
≤15 ≥50 Similarity or
equivalence of
two profiles

Advantages:
1. They are easy to produce
They provide 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 interchanged, f2
is unchanged but f1 is not, yet difference between two
mean profiles remains same
3. The basis of criteria for deciding the difference or
similarity between dissolution profile is unclear
17

The evaluation of similarity between dissolution profile is based
on following conditions
 Minimum of three dissolution time points are measured
 Number of drug products tested for dissolution is 12 for both
test and reference
 Not more than one mean value of >85% dissolved for each
product
 Standard deviation of mean of any product should not be
more than 10% from 2nd to last dissolution time point
18

RESEARCH ARTICLE:
A Comparative Study for Evaluation of
Different Brands of Metformin
Hydrochloride 500 Mg Tablets
Marketed in Saudi Arabia
 Corresponding author
Samar A. Afifi1&2
1 Department of Pharmaceutics, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia
 Life Science Journal 2012;9(4)
http://www.lifesciencesite.com 19

Abstract:
The physicochemical equivalence of six brands of
Metformin hydrochloride tablets were determined through the
evaluation of both official and non-official standards according to
the USP pharmacopoeia including uniformity of weight, friability,
hardness,disintegration, dissolution rate and drug content.
All the six brands evaluated in this study could be
considered biopharmaceutically and chemically equivalent and
therefore they can be substituted with the innovator product in
clinical practice except Glucare®. Therefore, patients can safely
switch from one brand to another.
20

MATERIALS
Metformin hydrochloride brands having label
strength of 500 mg (Table 1) were purchased from a retail
pharmacy in Riyadh city, Saudi Arabia. All tests were
performed within product expiration dates.
The reagents used were potassium dihydrogen
orthophosphate (WINLAB chemicals, UK) and sodium
hydroxide pellets (Poole BH15, UK).
All reagents used were of analytical grade. Distilled
water was used throughout the work.
21

EXPERIMENTAL CONDITUIONS:
 stimulated intestinal fluid pH 6.8
 Apparatus-ERWEKA DT600 dissolution apparatus
(Heusenstamm,Germany)
 Volume-1000ml
 Temperature-37 ± 0.5 °C
 Speed-100 rpm
 Sample Withdrawing Intervals-10 min
 Each of the withdrawn sample was filtered with syringe filter
0.45μm, the filtrate diluted.
 The absorbance was measured at λ max 233nm using Uv-
visible spectrophotometer.
 The concentration was determined against standard solution
having a known concentration of Metformin hydrochloride RS
in the same medium.
23

The difference factor (f1) and similarity
factor (f2) was calculated for each local brand
respect to the reference brand (Glucophage®)
equation (1) and (2), respectively.
The percentage of drug released from
Glucophage® as an innovative was compared
with the percentage of drug released from each
brand individually using the f1 and f2 formula
24

 Five generic brands of Metformin hydrochloride tablets,
namely Formit® , Glucare®, Dialon®,Metaphage® and Metfor®
together with the innovative (Glucophage®) have been
subjected to analysis according to the monograph of USP 32
Pharmacopoeia.
 The results have shown that all the tested brands satisfied the
USP requirements in terms of identification, assay and
dissolution.
 Dissolution profiles revealed differences between the different
generics. Four generic products could be said to be equivalent
to the originator (Glucophage®) while the Glucare® was
nonequivalent.
 According to the present study patients can safely switch from
one brand to another but with consulting them of the
possibility of some minor GIT complications that may occur
after the treatment with new alternative brand.
25
Conclusion

IN VITRO IN VIVO CORRELATION (IVIVC)
 In IVIVC, "C" denotes "Correlation", which means
"the degree of relationship between two variables".
 IVIVC is defined as the predictive mathematical
model that describes the relationship between an
in-vitro property(such as rate and extent of
dissolution) of dossage form and an in-vivo
response (such as plasma drug concentration)
26

DEFINATION
 The Food and Drug Administration (FDA) defines
 “A predictive mathematical model describing the
relationship between an in-vitro property of a dosage
form and an in-vivo response”.
 The United States Pharmacopoeia (USP) also defines
 “The establishment of a relationship between a
biological property, or a parameter derived from a
biological property produced from a dosage form,
and a physicochemical property of the same dosage
form”.
27

IMPORTANCE OF IVIVC
 To serve as a surrogate(alternate) for in vivo bioavailability.
 To support biowaivers for bioequivalence testing.
 To validate the use of dissolution methods and set the
dissolution specifications.
 IVIVC proves an important research tool in the development
of drug delivery systems.
 The IVIVC model facilitates the rational development &
evaluation of immediate or extended release dosage forms.
Hence it acts as a tool for formulation screening.
 To assist quality control for certain scale-up and post-
approval changes (SUPAC).
28

1. CORRELATIONS BASED ON THE PLASMA LEVEL
DATA:
Parameters used for correlating In Vitro Dissolution
with Plasma Data
29
In vitro dissolution parameters In vivo plasma data parameters
Time for specific amount of drug to dissolve
(e.g. 50% of the dose)
Amount dissolved at a specific time point
Mean dissolution time
Parameter estimated after modeling the
dissolution process
AUC, Cmax
Fraction absorbed, absorption rate constant Ka
Mean residence time, mean dissolution time,
mean absorption time
Concentration at time t, amount absorbed at time
t

2. CORRELATION BASED ON THE
URINARY EXCRETION DATA
Dissolution parameters are correlated to the amount of
drug excreted unchanged in the urine, cumulative
amount of drug excreted as a function of time, etc.
30
An acute pharmacological effect such as LD50 in
animals is related to any of the dissolution parameters.
3. CORRELATION BASED ON THE
PHARMACOLOGICAL ACTION

FACTORS AFFECTING IVIVC
Complexity of the
delivery system.
Composition of
formulation.
Physicochemical
properties of
drug.
Dissolution
method
Method of
manufacture 31

BASIC DEFINATIONS ABOUT IVIVC
•The mean time for which the drug resides in the body. Also known as mean transit time.
•MRT = AUMC / AUC
•where, AUMC = Area under first moment Curve (Concentration*time Vs time)
•AUC = Area under curve (Concentration Vs time)
•Both AUMC & AUC can be obtained by using Trapezoidal rule.
Mean Residence Time:
•The mean time required for drug to reach systemic circulation from the time of drug
administration.
•MAT = MRT oral – MRT i.v.
Mean Absorption Time:
•It reflects the mean time for drug to dissolve in-vivo. For solid dosage form:
•MDT solid = MRT solid – MRT solution
Mean In-vivo Dissolution Time:
•% PE = [(Observed value – Predicted value) / Observed value] x 100
Percent Prediction Error: 32

LEVELS OF IVIVC
Level A
• Most
informative &
recommended
Level B
• Least useful in
regulatory
purpose
Level C
• Useful for
early stages
of formulation
development
Multiple
Level C
• Useful as
Level A
33

34
 It is defined as a hypothetical model describing the
relationship between a fraction of drug absorbed and
fraction of drug dissolved.
 In order to develop a correlation between two parameters
one variable should be common between them.
 The data available is in vitro dissolution profile and in vivo
plasma drug concentration profile whose direct comparison is
not possible.
 To have a comparison between these two data, data
transformation is required.
 It is considered as a predictive model for relationship
between the entire in vitro release time courses.
Level A Level B Level C Multiple C

35
Advantages:
1. A point to point correlation is developed. The in vitro dissolution curve serves as
a surrogate for in vivo performance. Any change in manufacturing procedure or
modification in formula can be justified without the need for additional human
studies.
2. The in vivo dissolution serves an in vivo indicating quality control procedure for
predicting dosage form’s performance.

36
 Level B IVIVC uses the principles of
statistical moment analysis. The mean in
vitro dissolution time(MDTvitro) is compared
either to the mean residence time (MRT) or
to the mean in vivo dissolution time
(MDTvivo).
 Level B correlation, like a Level A, uses all of
the in vitro and in vivo data, but is not
considered to be a point-to-point
correlation.
 Level B correlation does not uniquely
reflect the actual in vivo plasma level curve,
because a number of different in vivo curves
will produce similar mean residence time
values.
 MATHS TOOL : MDTvitro VS MDTvivo or
MRTvivo

37
 In this level of correlation, one dissolution
time point (t50%, t90%, etc.) is compared to
on mean pharmacokinetic parameter such
as AUC, t max or C max.
 It represents a single point correlation and
doses not reflect the entire shape of the
plasma drug concentration curve.
 Level C correlations can be useful in the early
stages of formulation development when
pilot formulations are being selected.
 While the information may be useful in
formulation development, biowaiver is
generally not possible.

 A multiple level C correlation 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.
 A multiple point level C correlation 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.
38

VARIOUS PARAMETERS USED IN IVIVC
DEPENDING ON THE LEVEL
Level In vitro In vivo
A Dissolution curve
Input (absorption)
curves
B
Statistical Moments:
MDT
Statistical Moments:
MRT, MAT
C
Disintegration time,
Time to have 10, 50,
90% Dissolved,
Dissolution rate,
Dissolution efficiency
Cmax,
Tmax,
Ka,
Time to have 10, 50,
90% absorbed,
AUC (total or
cumulative)
39

APPLICATIONS OF IVIVC IN DRUG
DELIVERY
1. Early Stages of Drug Delivery & Development:
• Proof of Concept
2. Formulation Assessment:
• In Vitro Dissolution
3. Dissolution Specifications
4. Future Biowaivers
5 . IVIVC – Parenteral Drug Delivery
• Potent Drugs & Chronic Therapy
• Limited volume of tissue fluids and Area of absorption
40

SOFTWARES USED IN IVIVC
41
IVIVC
Software
WinNonlin-
IVIVC
Toolkit
GastroPlus
v. 6.1
IVIVCPlus
PDx-
IVIVC
DDDPlu
s v. 3.0
IVIVC
for R
Kinetica

REFERENCES
 Biopharmaceutics and Pharmacokinetics by D. M.
Brahmankar, 2nd edition 2009, page no. 432 to 434
 By Madhusmruti Khandai Research article of
International Journal of Pharmaceutical Sciences
Review and Research Volume 1, Issue 2, March – April
2010; Article 001
 Guidance for Industry Dissolution Testing of Immediate
Release Solid Oral Dosage Forms U.S. Department of
Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research
(CDER), August-2011
 International Journal of Pharmaceutical Science Vol-1,
Issue-1, page no.57-64, 2010 42

 Research Article on:A Comparative Study for Evaluation of
Different Brands of Metformin Hydrochloride 500 Mg Tablets
Marketed in Saudi Arabia;by-Samar A. Afifi1&2
Life Science Journal 2012;9(4) http://www.lifesciencesite.com
 Guidance for Industry; Extended Release Oral Dosage Forms:
Development, Evaluation, and Application of In Vitro/In Vivo
Correlations. www.fda.gov/cder/guidance/index.htm
 Dissolution, Bioavailability and Bioequivalence by Hamed M.
Abdou, Mack Publishing House.
 IVIVC: Methods and Applications in Modified-Release Product
Development; Harald Rettig and Jana Mysicka. Dissolution
Technologies | FEBRUARY 2008
 IVIVC: An Important Tool in the Development of Drug Delivery
Systems; Gangadhar Sunkara, PhD, and Dakshina M. Chilukuri,
PhD. http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=144 43

Dissolution f1 and f2 Analysis and IVIVC

Dissolution f1 and f2 Analysis and IVIVC

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