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Department of Pharmacy (Pharmaceutics) | Sagar savale

Drug release kinetics and


mathematical models

Mr. sagar Kishor savale


Department of Pharmaceutics
avengersagar16@gmail.com
2015-2016
CONTENTS.
Introduction.
Mathematical models.
Ficks first law.
Ficks second law.
Zero order release model.
First order release kinetics.
Hixson - Crowell release equation.
Korsmeyer-peppas equation.
Peppas & Sahlin equation.
wiebull equation.
Baker and Lansdale model.
Hopfenberg Model
Drug release from slab, sphere and cylinder.
Drug release from erosion controlled matrix.
Drug release from lipophilic matrix.

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WHAT DO MEAN BY DRUG RELEASE?
It is a process by which a drug leaves a drug product
& is subjected to ADME & eventually becoming
available for pharmacological action.

It involves the study of drug release rate, dissolution


/diffusion/erosion studies and the study of factors
affecting release rate of the drug.

WHAT DO MEAN BY DRUG RELEASE


KINETICS?
o Drug release kinetics is application of
mathematical models to drug release process.
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Drug diffusion from the
non-degraded polymer
(diffusion-controlled
system).

Drug
release
form
matrix

Drug release due


to polymer Enhanced drug
degradation and diffusion due to
erosion (erosion- polymer swelling
controlled (swelling-controlled
system). system)

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Diffusion
Non-Biodegradable Concentration
polymer matrix gradient
Matrix swelling

Matrix erosion
Biodegradable Hydrolytic
cleavage of
polymer polymer chains
Diffusion

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MATHEMATICAL MODELS-
1. Zero order release model
2. First order release model
3. Hixson-crowell release model
4. Higuchi release model
5. Korsmeyer peppas release model.
6. Korsmeyer-peppas equation.
7. Peppas & Sahlin equation.
8. wiebull equation.
9. Baker and Lansdale model.
10. Hopfenberg Model

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FICKS FIRST LAW
J = dM
s dt

dM = change in mass of material.


S = barrier surface area.
dm/dt = rate of mass transfer.
J = flux. Fig. diffusion cell .donor compartment
contains diffusant at conc. c

Deals with the mass diffusing across a unit


area of barrier in unit time .

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FICKS SECOND LAW
An equation for mass transport that emphasizes the
change in concentration with time at a definite
location.
It states the change in conc. with time in particular
region is proportional to change in conc. gradient at
that point in the system.

dC = D dc
dt dx

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ZERO ORDER RELEASE MODEL
The equation for zero order release is
Qt = Q 0 + K0 t
Q0 = initial amount of drug
Qt = cumulative amount of drug
release at time t.
(released occurs rapidly
after drug dissolves.)
K0 = zero order release constant.
t = time in hours
INDEPENDENT OF
DRUG RELEASE RATE CONCENTRATION.

GRAPHICAL % CDR VS TIME.


REPRESENTATIONsagar kishor
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savale LINE OBTAIN. 9
Matrix tablet
Oral control with low
release solubility
drug

Implantable
depot Suspension

Examples
Oral osmotic
Transdermal Zero pressure
order

CONSTANT RELEASE same amount of


drug release per unit time.
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First order release kinetics
The first order release equation is-
Log Qt = Log Q0+ Kt /2.303
or Qt =Q0e-Kt
Q0 = initial amount of drug.
Qt = cumulative amount of drug
release at time t.
K = first order release constant.
t = time in hours.
DRUG RELEASE Depends on the
RATE concentration.
GRAPHICAL log of % drug remaining vs
REPRESENTATION time
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Matrix
diffusion Sustained
controlled release
release

Matrix
dissolution
Solution
controlled First
release order
release
system

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HIXSON CROWELL RELEASE EQUATION.
The Hixson - Crowell release equation is
What makes this
equation different from
noyes Whitney's
Q0 = Initial amount of drug.
Qt = Cumulative amount of drug release
at time t.
KHC = Hixson Crowell release constant.
t = Time in hours.

Drug releases by dissolution


Changes in surface area
Changes diameter of the particles
release is not by diffusion
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GRAPHICAL cube root of % remaining vs
REPRESENTATION time (hrs)

For spherical particle


Wt1/3 = W0 k1/3t
Wt = particle weight at time t
W0 = initial particle weight
k1/3 = dissolution rate constant
Under sink condition
k1/3 = (4/3p2)1/3 .DCs/h

For multiparticulate system


wt = w01/2 k1/2t
Under sink condition
k1/2 = (3/2p)1/2. DCs/k
K = proportionality constant between diffusion layer
thickness and particle size

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HIGUCHIS EQUATION / MODEL
The equation for Higuchis
For drug release through matrix
Q = KH t1/2
0r
1/2
Mt / M0 = kt
Q = cumulative amount of drug
release at time t
KH = Higuchi constant
t = time in hours

Graphical Amount of drug released


representation Vs square root of time. .
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What is the significance HIGUCHIS
EQUATION / MODEL .
It describes the drug release as a diffusion process
based on the Ficks law which is square root time
dependent.

water soluble drug pentoxyphylline


Poorly water soluble
drug morphine.
semisolids Diclofenac gel.
Solids.
some Transdermal
patches

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KORSMEYER-PEPPAS EQUATION
Korsmeyer peppas equation is

F = (Mt /M ) = Km tn

F = Fraction of drug released at time t


Mt = Amount of drug released at time t
M = Total amount of drug in dosage form
Km = Kinetic constant
n = Diffusion or release exponent
t = Time in hours
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Graphical representation log % CDR vs log time taken .

n is estimated from linear regression of log ( Mt/M ) versus log t


n INDICATION

Less than 0.45 Quasi fickian

0.45 fickian diffusion


0.45<n<0.89 anomalous
diffusion or non-
fickian diffusion.
0.89-1 case-2 relaxation
Zero order. or non fickian
case 2.
>1 Non fickian super
case 2 Fig:This plot explains diffusion
mechanism by which drug
diffuses from dosage form.
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n= 0.5
Diffusion release
Square root of time depended.
Fickian release.

n= 1
Swelling controlled
Release rate independent of time.
Zero order/case II .

n= between 0.5-1
Diffusion and swelling
Release is time depended.
First order/anamolus /non-
fickian.
fig:- graph of drug release kinetics

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What is the significance KORSMEYER-
PEPPAS EQUATION.
Release behavior of drug from hydrophilic
matrix.
Diffusion Anomalous diffusion
Erosion controlled Release or
release rate
Rate non-fickian diffusion

Diffusion and
dissolution controlled Swellable & erodible
dosage form polymer.

Case-2 Erosion of polymeric chain.


relaxation stresses and state-transition in
or hydrophilic glassy polymers
super case which swell in water or
transport-2 biological fluids
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This equation can be used to analyze the first
60% of a release curve, regardless of geometric
shape.

Fickian diffusional release and a Case-II


relaxation release, are the limits of this
phenomenon.

Hence modification was need for above stated


condition

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PEPPAS & SAHLIN EQUATION
diffusional Case 2
contribution transport
m 2m
Mt / M0 = Kdt + K rt
Kd = Diffusion constant
Kr = Relaxation constant
m = Purely fickian diffusion exponent for
device of any geometrical shape, which exhibit
controlled release.

Used
for???
when release of drug depends
upon its diffusion as well as on
fickian relaxation of polymer.
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Table :- Describes the limits of this analysis.

Diffusion exponent (m) Mechanism


Film Cylinder Sphere

0.50 0.45 0.43 Fickian


diffusion

0.50 < m< 1.00 0.45 < m< 0.43 < m< 0.85 Anomalous
0.89 transport

1.00 0.89 0.85 Case-II


transport

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WIEBULL DISTRIBUTION

m - accumulated fraction,
b = 1 indicates exponential curve,
a - time scale process, b= 2 indicates sigmoid curve,
Ti -lag time ( generally zero), b= 3 indicates parabolic curve.
b - shape factor.

What the need of this equation?


It can be widely used for the analysis and characterization of
DRUG DISSOLUTION process from different dosage form.

APPLICABLE FOR Almost all systems

GRAPHICAL Log of dissolved amt Vs log time


REPRESENTATION
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Baker and Lansdale model
(Mt /M) 2/3 - Mt /M = (3DmCms t)/ (r02C0)
where Mt is the amt of drug released at time t and M is amt of
drug released at time

Graphical representation Mt/M Vs Time.


For Controlled release from a spherical matrix.

Hopfenberg Model
Mt /M = 1 [1 (kot)/ (C0a0)] n
Mt is the amt of drug dissolved in time t.
Ko is erosion rate constant.
drug release from slabs, spheres and infinite cylinder displaying
heterogeneous erosion

Graphical representation
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Mt/M Vs Time.
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HOW DO WE COME TO
KNOW WHICH MODEL IS
HOW DO WE
FIT.
USE THESE CAN ONE FORMULATION
MODELS FOLLOW DIFFERENT
EQUATIONS AT A TIME

The kinetic model that best fits the dissolution data is


evaluated by comparing the correlation coefficeint ( r ) values
obtained in various models.
The model that gave higher r value is considered as best fit
model.
yes ,one model can follow two types of release systems.

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Sr No. Model Graph

1. Zero Order Cummulative Release Vs


Time
2. First Order Log Cummulative Release
Vs Time

3. Weibull Model Log Cummulative Release


Vs Log Time

4. Higuchi Model % Cummulative Release Vs


(Time)

5. Korsemeyer Peppas Model % CRt/CR Vs (Time)1/2

6. Hixson Crowell Model (Unreleased fraction)1/3 Vs


Time

7. Baker-Lonsdale Model Mt/M Vs Time

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Article review
Formulation, and Evaluation of Pentoxifylline-
Loaded Poly (-caprolactone) Microspheres :-

Table 1:-yield , drug entrapment and avg. particle


size of pentoxyphylline loaded poly(-
caprolactone) microspheres.
Formulation Drug : % yield Drug Avg .
code polymer entrapped Particle
size
F1 1:3 79.63 73.14 59.3
F2 1:4 80.97 76.92 65.6
F3 1:4 83.34 74.69 78.52
F4 1: 5 81.28 71.96 86.22
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TABLE 2:- VALUE OF R FROM RELEASE DATA OF
VARIOUS FORMULATIONS FOR DIFFERENT MODELS.

MODEL F1 F2 F3 F4

ZERO 0.853 0.865 0.883 0.877


ORDER

FIRST 0.994 0.983 0.965 0.954


ORDER

HIGUCHI 0.987 0.985 0.978 0.979

THE VALUES LISTED ARE THE VALUES OF COEFFICIENT


RELATED (R) OBTAINED FROM RELEASE DATA OF VARIOUS
FORMULATIOS FOR DIFFERENT MODELS OF MECHANISM OF
DRUG RELEASE.

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ZERO ORDER FIRST ORDER

HIGUCHI

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By applying In vitro release data to various kinetics models
the drug release mechanism was found to be

Microspheres were diffusion controlled as plots of the


amount released versus square root of time was found to be
linear.

The correlation coefficient (r2) was in the range of 0.978-


0.987 for various formulations.

When log percentage of drug remaining to be released vs.


time was plotted in accordance with first order equation,
straight lines were obtained (r2 >0.95) indicated that drug
release followed first order kinetics.

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Mathematical models for diffusion-controlled
systems
RESERVOIR SYSTEM.
Mt = 4 RRi Dci
t (R-Ri)
R-Ri = layer of thickness.
Cr = drug concentration in the reservoir.
Mt/t = Cumulative amount of drug release.
MATRIX SYSTEM.
Mt = 6 Dt 3Dt for Mt < 0.4
M r r M
Mt/M = Cumulative amount of drug release. DISSOLVED
D = diffusion coefficient. DRUG (Co<Cs)
Mt = 1 6 - Dt
For Mt > 0.6
M exp r M

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Mt = 1- r FOR DISPERSED SYSTEM
(Co > Cs)
M R

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DRUG RELEASE FROM SWELLING CONTROLLED SYSTEM .
Imbibing water
Polymer concentration decrease

Polymer disentanglement
Swelling/rubbery gel layer
Disentanglement + dissolution
Non fickian release

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LEE AND PEPPAS MODEL.
Glassy rubbery
Swelling Thermodynamic Front (R)

equilibrium
Rubbery- solvent
Front (S)

Water penetration
Fig: one dimensional swelling processlee fig.

Early-time final dissolution


Initial thickness of late-time swelling process
the carrier swelling

R moves inward. Thermodynamic Both fronts Rubber region is


attend at S . moves inwards. only present.
S moves outward
S starts dissolves. R diminishes as
S moves inwards the glassy core
(shrinks). disappears

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Fickian
No polymer
water diffusion
Relaxation
Glassy matrix

Non fickian
water Case ii Zero order
transport

Diffusion +
Anomalous First order
Dissolution

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MATHEMATICAL MODELS FOR EROSION-
CONTROLLED SYSTEMS

Empirical Mechanistic

No
physiochemical physiochemical
phenomenon. phenomenon.

Surface erosion. Surface erosion.


that exhibits zero Involving mass
order. transfer +
chemical reaction

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EMPIRICAL MODEL -
Weibull equation.
Hofenbergs equation.
Hixson-crowell cube root law.
MECHANISTIC MODEL -
Diffusion and reaction Diffusion + chemical
model erosion model
Mechanistic
Cellular automata Random erosion

For diffusion and reaction model.


C = De dc + 2dc k( cs-c)
t dr rdr
C - drug concentration .
De - effective diffusivity in liquid-filled pores .
k - drug dissolution rate constant
- porosity of the polymer matrix
Cs - equivalent drug saturation concentration in the solution in pores.
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Modified higuchi equation.
dmt = s 2pco
dt 2 t
S -surface area on both sides of the planar film,
C0 - initial drug concentration(loading) in the polymer,
P - permeability of the drug inside the polymer matrix.

Mt = (1-b) xa(t)a,o + xb(t) b,o p +B


M a,o + b,o p
xa = release mass fraction for fast eroding matrix
xb = release mass fraction for slow eroding matrix
a,o = surface fraction for fast eroding matrix
b,o = surface fraction for slow eroding matrix
p = ratio of drug conc in matrix
B = bust release

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Cellular automata
max

Mt =0 (, )d
M
- dispersion parameter .
- porosity of the device.
- pore size parameter, exact geometry and the encapsulated
drug .

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DRUG RELEASE FROM LIPOPHILIC MATRIX
DEPENDING ON DRUG : POLYMER RATIO IT CAN
FOLLOW
Zero order release
First order release
Higuchi square root time model = Mt/M = kt 1/2
Hixson and Crowell cube-root equation
Weibull distribution

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LACTOSE
solubility STARCH
Diluents MCC
Lubricants

wetting
Salt
formation
Factor
affecting
drug release
Form / state mechanism
of drug Temp

Viscosity HPMCK4M
Binders HPMC K100M
GELATIN
EC particle
size
griseofulvin
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Release profile comparison
Statistical methods-ANOVA, MANOVA
Model independent method- AUC, etc.
Model dependent methods- all stated models.

Similarity factor(f2)

It Calculates similarity in the % dissolution between two


curves & it is a logarithmic reciprocal square root
transformation of the sum of squared error, value between 50 to
100.
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Dissimilarity factor(f1)
Calculates % difference between two curves at each time
point & is measurement of the relative error between two
curves, value between 0 to 15.

R & T = Dissolution measurements at n time points of the


reference and test, respectively.
n = no. of time points.
t = Time
Rescigno Index may also be used for comparison.

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PROCEDURE SET BY FDA FOR DISSOLUTION
PROFILE COMPARISON:
At least 12 units of reference & test product used.
Use mean dissolution values from both curves at each
time interval to calculate f1 & f2 .
Measurement should be carried out under same test
conditions.
f1 & f2 values are sensitive to number of dissolution time
points.
For rapidly dissolving products comparison is not
necessary.
For curves to be considered similar, f1 values should be
close to 0 & f2 close to 100.

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Drug release from thin polymer film.
Mt = 4 Dt
Assumptions
M L Perfect sink
condition.
Mt = mass of drug release at time t. One dimensional
isothermal solute
M = mass of drug release at . release.
D = diffusion coefficient.
L = thickness of the film.
Fickian diffusional release from a thin film is characterize by an
initial t time dependence of the drug released.
The short-time approximation is valid for the first 60% of the
total released drug (Mt/ M 0.06)

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Semi-empirical equation for drug
release from thin polymer slabs.
Mt / M = k t if release order is zero
Mt/M = 1 - exp( - kt) if release order is first
k = constant.
t = square root of time.

Fickian diffusion
THEORETICAL For slab ,
STANDPOINT
may be defined by spheres,cylinder
an initial t time

Fickian diffusion dependence on t


time valid only for first 15% release for Practical
sphere and cylinder stand point
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RELEASE FROM CYLINDERS/ SPHERES
By coupling of fickian and non fickian mechanism-
Mt = kt
M
n = diffusional exponent.
t = square root of time.
k = constant (characteristics of macromolecule
specifically geometry).
Above equ. Shows that the relationship between the diffusional
exponent n and the corresponding release mechanism is clearly
dependent upon the geometry.

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References
1. Davis Yohanes Arifin , Lai Yeng Lee , Chi-hwa Wang ; Mathematical Modeling
And Simulation Of Drug Release From Microspheres: Implications To Drug
Delivery Systems ; Advanced Drug Delivery Reviews 58 (2006) 12741325.

2. Philip L. Ritger And Nikolaos A. Peppas ; A Simple Equation For Description


Of Solute Release Fickian And Non-fickian Release From Non-swellable
Devices In The Form Of Slabs, Spheres, Cylinders Or Discs ; Journal Of
Controlled Release, 5 (1987) ;elsevier Science Publishers B.V. ;Amsterdam; 23-
36.

3. Nikolaos A. Peppas and Jennifer J. Sahlin; A simple equation for the


description of solute release.Iii. Coupling of diffusion and relaxation;
International Journal of Pharmaceutics, 57 (1989) 169-172.

4. Tamizharasi S, Rathi JC, Rathi V. Formulation and evaluation of


Pentoxifylline-loaded Poly(-caprolactone) microspheres . Ind J of Pharm Sci,
2008may; 70(3):333-5.

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5. Edith Mathiowitz. Encyclopedia of controlled drug delivery. 1stedition, Volume.II, pg: 698-29.

6. Martins physical pharmacy &pharmaceutical sciences, fifth edition, Patrick J. sinko ,lippincott
Williams & Wilkins publication ,p.337-349.

7. Compaction properties, drug release kinetics and fronts movement studies from matrices
combining mixtures of swellable and inert polymers, International Journal of Pharmaceutics,
September 2007, 6173.

8. Desai S.J, Sing P, Simonelli A.P, Higuchi W.I, Investigation of Factors Influencing Releaese of
Solid Drug Dispersed In Inert Matrices, III, Quantitative Studies involving the Polyethylene
Plastics Matrix, Journal of Pharmaceutical Sciences, 1966a, 55, 1230-1234.

9. Higuchi W.I, Analysis of Data on the Medicament Release from Ointments, J. Pharm. Sci,
1962, 51, 802 804.

10. Judit Dredin*, Istvin Antal, Istvin R/lcz .Evaluation of mathematical models describing drug
release from lipophilic matrices ,International,Journal of Pharmaceutics.

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