Mathematical Models Used in The Drug Release Studies

MATHEMATICAL MODELS USED

IN THE DRUG RELEASE STUDIES

ASSIGNMENT-3
SUBMITTED FOR INTERNAL EVALUATION FOR
THE DEGREE IN MASTER IN PHARMACY
BY
BIBEK SINGH MAHAT, M. PHARM STUDENT,
1ST YEAR, 1ST SEMESTER, BATCH OF 2009
SUBMITTED TO:
DR. PANNA THAPA

DEPARTMENT OF PHARMACY
SCHOOL OF SCIENCE
KATHMANDU UNIVERSITY
DHULIKHEL, NEPAL
(Page No. 0 of 26)

Mathematical Models used in Drug Release Studies by Bibek S. Mahat 2010

TABLE OF CONTENTS:
1. INTRODUCTION:-
2. MATHEMATICAL MODELS APPLIED FOR DRUGS RELEASE STUDIES
A. DIFFUSION MODELS
I. FICK’S FIRST LAW
II. FICK’S SECOND LAW
B. ZERO ORDER KINETICS
C. FIRST ORDER KINETICS
D. HIGUCHI MODEL
E. KORSMEYER- PEPPAS MODEL (THE POWER LAW)
F. HIXON-CROWELL MODEL
G. WEIBULL MODEL
H. BAKER – LONSDALE MODEL
I. HOPFENBERG MODEL
J. SEQUENTIAL LAYER MODEL
K. OTHER EMPIRICAL AND SEMI-EMPIRICAL MODELS
I. MODEL DEVELOPED BY PEPPAS AND SAHLIN
II. MODEL INVESTIGATED BY COUARRAZE

3. SELECTION OF BEST MODEL
4. CONCLUSION
5. REFERENCES
(Page No. 1 of 26)


1. INTRODUCTION:-
In the last 100 years, drug delivery systems have enormously increased their performances,
moving from simple pills to sustained/controlled release and sophisticated programmable
delivery systems. Meanwhile, drug delivery has also become more specific from systemic to
organ and cellular targeting.
Traditional delivery systems (TDS) are characterized by immediate and uncontrolled drug
release kinetics. Accordingly, drug absorption is essentially controlled by the body’s ability to
assimilate the therapeutic molecule and thus, drug concentration in different body tissues such as
the blood, typically undergoes an abrupt increase followed by a similar decrease. As a
consequence, it may happen that drug concentration dangerously approaches the toxic threshold
to subsequently fall down below the effective therapeutic level.
Unfortunately, also the strategy of repeated administrations does not completely prevent the
above-mentioned drawbacks of TDS.
On the contrary, the purpose of controlled release systems (CRS) is to maintain drug
concentration in the blood or in target tissues at a desired value as long as possible. In other
words, they are able to exert a control on the drug release rate and duration. For this purpose, in
general, CRS initially release part of the dose contained in order to rapidly get the drug effective
therapeutic concentration. Then, drug release kinetics follows a well defined behavior in order to
supply the maintenance dose enabling the attainment of the desired drug concentration.
According to the release behavior, CRS can be subdivided into three different categories:
A. Passive pre-programmed,
B. Active pre-programmed and
C. Active self-programmed.
While in the first category (passive preprogrammed) release rate is predetermined and is
irresponsive to external biological stimuli, in the second category (active preprogrammed),
release rate can be controlled by a source external to the body as in the case of insulin delivery.
The last category, representing the future of CRS, is characterized by delivery systems whose
1
release rate is controlled by biological stimuli such as sugar concentration in blood.
While until 15 years ago the majority of CRS fell into the first category, nowadays the
importance of the last two categories has become recognized. In the light of wide versatility (for
example, application in the contraception, ophthalmic and odontoiatric field, in the treatment of
cancer, alcoholism, diabetes, thrombosis and resthenosis, CRS are unavoidable tools for the
exploitation of the modern concept of therapeutic treatment whose aim is to increase drug
effectiveness and patient compliance, two variables strictly related, to the administration
2
frequency and side effects connected to dosing.
Thus, mathematical modeling, whose development requires the comprehension of all the
phenomena affecting drug release kinetics, has a very important value in CRS optimization. The
model can be simply thought as a “mathematical metaphor of some aspects of reality” that, in
this case, identifies with the ensemble of phenomena ruling release kinetics.
(Page No. 2 of 26)


The major objectives of mathematical modeling are as listed below:
1. Designing the new drug delivery system based on general release expression.
2. Prediction of the exact behavior of drug or drug release rates from and drug diffusion
behavior through polymers, thus avoid excessive experimentation.
3. Optimization of the release kinetics.
4. Elucidation of the physical mechanism of drug transport by simply comparing the release
data to mathematical models.
2. MATHEMATICAL MODELS APPLIED FOR DRUGS RELEASE STUDIES:-
Several mathematical models are proposed by various workers depending upon the nature and
properties of the drug delivery systems. One of the models assumes a combination of effect of
drug dissolution, diffusion, and immobilization caused by adsorption of the drug to the tablet
constituents which is applicable to tablets that disintegrate into a number of approximately
spherical fragments. Consideration of the physiological parameters for modeling is also
necessary for a complete model of drug release. Besides the consideration of the excipients and
(3, 4, 5)
its effect on the release pattern also requires the mathematical assumptions.
Some of the empirical and semi-empirical mathematical models can be categorized as follows:-
A. Diffusion Models
B. Zero order Kinetics Models
C. First order Kinetics Model
D. Higuchi Models
E. Korsmeyer–Peppas Models (The power law)
F. Hixson–Crowell Models
G. Weibull Models
H. Baker–Lonsdale Models
I. Hopfenberg Models
J. Sequential Layer Models
K. Other Models
(Page No. 3 of 26)


A. Diffusion Models :-
Diffusion is defined as the process of mass transfer of individual molecules of a substance,

brought about by random molecular motion and associated with a concentration gradient. The
transfer of solute can be achieved by either simple molecular permeation or by movement
through pores and channels. Diffusion is concerned with the escaping tendency of the solute
molecules. The diffusion phenomenon can be observed if a droplet of dye is placed in the beaker
of water. The dye molecules tend to diffuse throughout the water and given uniform color. The
dye molecules are in state of continuous random motion with equal probability to move in any
direction. There are more dye molecules at the source than the bulk solution initially, so
molecules diffuse away from their source. At equilibrium, when a uniform color exists
throughout the beaker of water, the dye molecules are uniformly distributed and no further net
movement is observed.
Fig. 1: Diffusion
I. Fick’s First Law

Fick's first recognized the analogy among diffusion, heat conduction, and electrical conduction
and described diffusion on a quantitative basis by adopting the mathematical equations of the
Fourier's law for heat conduction or Ohm's law for electrical conduction. Fick’s First and second
law are based on the assumption of steady state diffusion across a barrier. The first law states that
the flux of the solute passing through a unit cross section area in a unit time is proportional to the
concentration gradient across the barrier.
(Page No. 4 of 26)


∂c ………………………………… (1)
J = Aj = − AD
∂x
Where J is total flux, A is the area through which diffusion occurs, j is the flux per unit area, x is
distance, and D is diffusion coefficient. In some cases, such as diffusion in dilute solutions, D
can be reasonably considered as constant, while in concentrated solution D may depends on
concentration. Fick’s first law asserts that steep gradients in concentration will result in rapid
diffusion, while no diffusion will occur when the concentration gradient is completely flat.
In cylindrical and spherical coordinates the form of Fick’s law for radial diffusion is
∂c J
J = −D ……………………………….. (2)
∂r
The negative sign in the above equation signifies that diffusion occurs in the direction opposite
to the increasing concentration. This signifies that diffusion occurs in the direction of decreasing
concentration of diffusant and hence the flux is always positive.
This equation is a first order process because the rate depends on the concentration of one
chemical species. This law describes the transfer of molecules from an area of higher
concentration to an area of lower concentration. Passive diffusion does not require that energy be
added to the system. This process is responsible for the movement of most molecules in the
body.
II. Fick’s Second Law
Fick’s first law is concise mathematical statement; however, is not directly applicable to solution
of most pharmaceutical problems. Fick’s second law presents more general and useful equation
in resolving most diffusion problems. It is derived from fick’s first law. For unsteady state
situations, where concentration is changing with time, we use Fick's second law, which assumes
constant D and constant boundaries. Fick’s second law states that the rate of change in
concentration in a volume within the diffusional field is proportional to the rate of change in
spatial concentration gradient at that point in the field; the proportionality constant is the
diffusion coefficient and represented as:
(Page No. 5 of 26)


∂C ∂ 2C ……………. …………. (3)

=D
∂t ∂x 2
Equation (3) is the general representation of the Fick’s 2nd Law. The second law of diffusion thus
states that the change in concentration with time in a particular region is proportional to the
change in concentration gradient at that point.
The representation of the Fick’s 2nd law in Cartesian coordinate is represented by:
⎛ 2 2 2 ⎞
∂C ⎜∂ C ∂ C ∂ C⎟
= D⎜ + + ⎟ …………………….. (4)
∂t ⎜ ∂x 2 ∂y 2 2
∂z ⎟
⎝ ⎠
Where the coordinate x, y & z represents exact the position of the diffusing species in space.
III. APPLICATIONS OF FICK’S LAW IN PHARMACEUTICAL SCIENCES:-

a. Membrane Diffusion:
Membrane transport reflects a major application of mass transport theory in the pharmaceutical
sciences. Since, convection is not generally involved; we will use Fick’s first and second laws to
find flux and concentration across the membranes. Mass transport problems can be categorized
as “steady “or “unsteady”. In steady mass transport there is no change of concentration with time
which is mathematically denoted as;
∂C
=0
∂t
In contrast, unsteady mass transport implies that there exists a concentration change with time.
Mathematically denoted as;
∂C
≠0
∂t
Since membrane diffusion involves one dimensional diffusion in medium bounded by two
parallel planes it can be referred as ‘diffusion in a plane sheet”.
(Page No. 6 of 26)


b. DISSOLUTION RATE OF DRUGS:

Dissolution is the process of putting a solute into true solution. The dissolution process can be
described by the Fick's First Law diffusion model. This theory explained the dissolution of a
solid in a liquid.
When a tablet or other solid drug form is introduced into a beaker of water or into the
gastrointestinal tract, the drug begins to pass into the solution from the intact solid. The solid
matrix disintegrates into granules, and these granules de-aggregate in turn into fine particles.
Disintegration, de-aggregation, and dissolution may occur simultaneously with the release of a
drug from its delivery form. So, the dissolution of a solid in a liquid undergoes two consecutive
steps.
1) First, the solution of the solid at the interface forms a thin stagnant layer of film n, around the
particles.
2) Second is the diffusion from this layer at the boundary to the bulk of the fluid.
In the first step, solution is almost instantaneous; the second diffusion is much slower and
therefore is the rate-limiting step. The rate of diffusion will obey Fick’s law of diffusion. Noyes
and Whitney developed an equation based on Fick’s Second law, to describe the dissolution
phenomenon as below:
dM DS
= (Cs − Cb ) …………………………… (5)
dt h
Where, dM/dt is the rate of dissolution
D= Diffusion coefficient of the solute in solution
S= Surface area of the exposed solid.
h= Thick ness of the diffusion layer.
Cs= concentration in a saturated liquid layer
Cb = Concentration of solute in the bulk solution at time t
Cs – Ct = Concentration gradient
(Page No. 7 of 26)


This equation is almost identical to Fick's first law but the terms are defined differently. The
Noyes Whitney Equation is a first order expression because the rate of dissolution is a function
of the concentration of one chemical species.
In dissolution, it is assumed that an aqueous diffusion layer or stagnant liquid film of thickness h
exists at the surface of a solid undergoing dissolution. The thickness h represents a stationary
layer of solvent in which the solute molecules exist in concentration from Cs to Cb. the gradient,
or change in concentration across the diffusion layer, is constant which is represented by (Cs –
Cb)/h. when Cb is considerably less than the drug’ solubility, Cs, the system is represented by
“sink conditions” i.e under no influence of the concentration gradient, and concentration Cb may
be eliminated from equation (5).
dM DSCs
= ………………………………………….. (6)
dt h
Such sink condition may arise in vivo when the drug is absorbed from its solution in the
gastrointestinal fluid at a faster rate than it dissolves in the fluid
IV. LIMITATION OF FICK’S LAW OF DIFFUSION:
Many drug delivery systems follow Fick's laws of diffusion. Many mathematical models are
derived based on Fick’s law by different scientists like Higuchi’s equation, Hixon & crowell
cubic root law etc. But there are some limitation in diffusion of drug having heterogeneous
structure, non-Fickian diffusion, moving boundary condition & ionic species. In heterogeneous
structure, each layer is made from different material. In such case diffusion coefficient cannot be
assumed to be constant through out the system. Similarly in case of polymer diffusion, rate of
drug release follows Fickian law under equilibrium condition but during swelling process, they
will not exist in equilibrium & the diffusion follows non-fickian.
(Page No. 8 of 26)


B. ZERO ORDER KINETICS

The superposition of various different mass transport phenomena such as water and drug
diffusion, polymer swelling and polymer degradation can lead to overall zero-order drug release
kinetics. In this case, an empirical model just gives a zero-order release equation. All mass
transfer processes involved in controlling drug release are assumed to add up to a single zero-
order process (characterized by a rate constant, k) confined to the surface area of the system [9,
234]. The system can be represented mathematically as:
W t − W 0 = k 0 t --------------------------- (7)
Where Wo is the initial amount of drug in the pharmaceutical dosage from, Wt is the amount of
drug in the pharmaceutical dosage form at time t and k is a proportionality constant. Dividing
this equation by Wo and simplifying
Wt
1− = k 0t = f t -------------------------- (8)
W0
Where ft = 1 – (Wt /Wo) and ft represents the fraction of drug dissolved in time t and ko; the
apparent dissolution rate constant or zero order release constant. In this way, a graphic of the
drugs dissolved fraction versus time will be linear if the previously established conditions were
fulfilled. This model is applicable to studies on drug release from different modified release
pharmaceutical dosage from like transdermal system, matrix based tablet with poorly soluble
drug, osmotic sustained system, and coated sustain release form in which there is a constant
release rate of drug and is independent of the amount of drug present in the dosage form. This is
the ideal method of drug release to achieve prolonged pharmacological action. The above
equation can be modified to following simple form
Q1 = Qo + Ko t---------------------------------------- (9)
Where
Q1= Amount of drug dissolved in time t and the Qo = Initial amount of drug in the solution, which
is often zero and Ko is the zero order release constant.
The equations mentioned above are used extensively in describing the drug dissolution of several
types of controlled release drug delivery systems. The pharmaceutical dosage form following
this profile release the same amount of drug in unit time and it is the ideal method of drug release
in order to achieve a prolonged therapeutic action.
(Page No. 9 of 26)


C. FIRST ORDER KINETIC MODEL
This model was first proposed by Gibald & Feldman (1967) later by Wagner (1969). The
pharmaceutical dosage forms containing water-soluble drugs in porous matrices follow first
order release kinetics, and can be expressed by the equation:
Qt = Q0e− k t …………………………………. (10)

1
Where Qt is the amount of drug released inn time t, Q0 is the initial amount of the drug in the
solution and k1 is the 1st order release constant.
The above equation in decimal logarithm will take the form,
k1t
log Qt = log Q0 − ……………………. (11)
2.303
This equation implies that a graphic of the decimal logarithm of the amount of drug versus time
will be linear. The dosage forms that follow this dissolution profile release the drug in a way that
is proportional to the amount remaining in the interior of the dosage form, in such a way that the
amount of drug released by unit of time diminishes.
Thus any system obeying this model releases the drug in such a way that the remaining amount
in the system governs the rate of release of drugs.
(Page No. 10 of 26)


D. HIGUCHI MODEL:-

In 1961 Higuchi introduced the most famous and often used mathematical equation to describe
the release rate of drugs from matrix system initially; it was valid only for planar systems. It was
later modified and extended to consider different Geometries and matrix characteristics including
porous structure. Higuchi developed an equation for the release of a drug from an ointment base
and later applied it to diffusion of solid drugs dispersed in homogeneous and granular matrix
dosage system. (6)
Depletion Zone

Static Diffusion Surrounding
Layer Aqueous Layer

A
Matrix (Perfect Sink)
Cs
h
h + dh
Receding
Boundary
Fig. 2. Schematic of the solid matrix and its receding boundary as drug diffuses out
from the dosage from.
From Martin, Page 335
In this model, it is assumed that solid drug dissolves from the surface layer of the device first;
when this layer becomes exhausted of drug, the next layer begins to be depleted by dissolution
through the matrix to the external solution. In this way the interface between the regions
containing dissolves drug and that containing dispersed drug moves into the interior as a front.
(Page No. 11 of 26)


The following assumptions are made in deriving the mathematical model:-

1. A pseudo-steady is maintained during release.
2. The total amount of drug present per unit volume in the matrix, Co, is substantially greater
than the saturation solubility of the drug per unit volume in the matrix Cs, which means that
the excess of solute is present.
3. The release medium is a perfect sink at all times.
4. Drug particles are much smaller in diameter than the average distance of diffusion.
5. The diffusion coefficient remains constant.
6. No interaction occurs between the drug and the matrix.
With reference to the figure, the change in amount of drug released per unit area, ∂ M, with a
change in the depleted zone thickness, ∂ h, is given by:
∂ M=Co. ∂ h - (Cs/2) ∂ h -------------------------- (12)
Where Co and Cs are as defined in the second assumption.

Now, from the fick’s law,
∂M
= (DmCs)/h
∂t
or, ∂ M= {( DmCs) / h}∂t ---------------(13)
Where, Dm is the diffusion coefficient in the matrix.

Now, if we equate the equations (12) and (13), integrate and solve for “h”, we get
( Dm C s / h)∂t = (Co − C s / 2)∂h
or, ∫ (2C o − C s ) / h( 2 Dm C s )∂h = ∫ ∂t
or, (2Co-Cs)/(2DmCs) ∫ h ∂h = ∫ ∂t
or, (2Co-Cs) h2/(4DmCs) = t
h = 2 [( Dm Cs t ) /(2Co − Cs)]
1/ 2
or, -------------(14)
(Page No. 12 of 26)


Now if we
w integrate the
t equationn (12) and suubstitute the value
v of h frrom equationn (14),
We get, ∫ ∂M = ∫ (CCo − Cs / 2)∂h

or, M = (2Co - Cs)h/2
or, M = (2 Co – Cs) 2 [(Dm Cs t)/ (2Co- Cs)]1/2
or, M = [(2Co – Cs)Dm Cs t]1/2
1
……………
…………..(15)
This equaation is calleed Higuchi equation.

e Thhis equation can
c be modified to repreesent drug reelease
from a poorous or gran nular matrixx as:-
M = [(2Co - ∈ Ca) Ds Ca t ( ∈ / τ )] 1/2…………..

… (116)
Where, ∈ is the poro osity of the matrix,

m τ is the Tortuosiity, Ca is thee solubility of
o the drug in
i the
release medium,
m Ds is the diffusiion coefficieent of drug inn release meedium. In thiis system, drrug is
leached from the matrix
m throuugh channel or pores. For the puurpose of simplicity in data
treatmentt, equations (15) and (166) are convenniently reducced to:-
M = kt1/2…………………
………. (17)
Where, k is the consttant, so that a plot of am
mount of druug released versus
v the sqquare root off time
should be linear if thhe release off the drug frrom the matrrix is diffusiion- controllled. The releeased
rate of thhe drug from
m such devicee, however, isi not zero order.
o
This equuation describes release by pure difffusion of a drug out of an encapsullating matrixx (no
erosion occurring).
o The analytiical expressiion allows experimentaal determinaation of connstant
parameteers, k` = (22ADCs) ½ from
f early release curvves when Higuchi
H connditions aree still
prevailinng.
(Pagee No. 13 of 26)

Mathematical Modells used in Dru
ug Release Stu udies by Bibek
k S. Mahat 2010

Applications:-
• The application of materials used in the preparation of matrix devices is insoluble plastics,
hydrophilic polymers, and fatty compounds.
• Plastic matrices include methylacrylate-methylmethacrylate, polypolyviny1 chloride, &
polyethylene.
• Hydrophilic polymers include methylcellulose, HPMC, sodium CMC, and carbopol 934.
Fatty compounds include carnauba wax and glyceryl tristearate.
E. KORSMEYER- PEPPAS MODEL (THE POWER LAW):-

Power law equation is more comprehensive very simple and semi-empirical equation developed
by Korsmeyer- Peppas which can be used to analyze data of drug release from polymers. The
equation implies that; the fractional release of drug is exponentially related to release time.
Mt
= kt n …………. (18)
M∝
Where, M & M ∞ are the absolute cumulative amounts of drug released at time t and infinity
respectively k is a constant incorporating structural and geometrical characteristics of the device
and n is the exponent, indicative of the mechanism of drug release.
∂C ∂ 2C
The Fick’s second law equation =D , can be used to express water soluble drug
∂t ∂x 2
diffusion from a controlled release polymeric device with the form of plane sheet of thickness.
Here, the diffusion coefficient of the drug, D, is assumed to be concentration independent.
Under skin condition, the initial and boundary conditions can be written as,
t=0 - δ /2 < x < δ /2 c = c0
t>0 x = ± δ /2 c = c1
Where c0 is the initial concentration of drug loading in the slab, and c1 is the constant external
concentration at the polymer / water interface.
(Page No. 14 of 26)


Crank’s solution to the Fick’s second law equation under the above boundary conditions can be
expressed as:-
Mt / M ∞ = 2(Dt/ δ 2)1/2 { π -1/2 + ∑ ∞

n-1 (-1) n ierfe (n δ / 2 Dt )}……… (19)
A sufficiently accurate expression can be obtained for small valves of t and since the equation
disappears. Then it becomes,
Mt / M ∞ = 2(Dt/ δ 2)1/2 = Kt ½ …………….. (20)
Hence plots of the initial drug release data of experiments conducted under a perfect skin
conditions versus the square root of release time should be a straight line if Fickian diffusion is
the predominant mechanism of release.
The mechanism of diffusion deviates from the Fickian equation and follows a Non-fickian or
anomalous (irregular) behavior in many cases including the case of drug release from swell-able
polymeric systems. For these cases, a general equation can be used,
Mt
= Ktn ……………….. (21)
M∞
Where, K is an experimentally determined parameter characteristic of structure and geometry of

the dosage form.
Peepas used the n value in order to characterize different release mechanisms as shown in the
table below.
RELEASE EXPONENT(n) DRUG TRANSPORT MECHANISM RATE AS A fx OF Time
0.5 FICKIAN DIFFUSION t-.5
0.5<n<1 NON-FICKIAN DIFFUSION tn-1
1 CASE –II TRANSPORT Zero order release
HIGHER THAN 1 SUPER CASE –II TRANSPORT tn-1
(Page No. 15 of 26)


Mt
= kt n
M∝
This equation has two distinct physical realistic meaning in the two special cases of n = 0.5
(indicating diffusion- controlled drug release) and n = 1 of n between 0.5 and 1 can be regarded
as an indicator for the superposition of both phenomena (anomalous transport). It has to be kept
in mind that the two extreme values for the exponent n, 0.5 and 1.0 are only valid for slab
geometry. For spheres and cylinders different values have been derived.
Assumptions:-
i. The generic equation is applicable for small values of t or short times and the portion of
release curve where Mt/M ∞ < 0.6 should only be used to determine the exponent n.
ii. Drug release occurs in a one dimensional way.
iii. The system’s length to thickness ratio should be at least 10.
When the release mechanism is not well known or when more than one type of release
phenomena could be involved, this model can be used to analyze the release of poly-metric
dosage form. This equation was later modified to accommodate the lag time (L) in the beginning
of the drug release from the pharmaceutical dosage form:-
M t −1
= a (t – l) n. ……………….. (22)
M∝
And when there is possibility of burst effect (b),
Ml
= at n. + b ……………….. (23)
M∝
Whenever there is absence of lag time and burst effect l and b value would be zero and only Kt n
is used. This mathematical model has been frequently used to describe the drug release from
different modified release dosage forms.
(Page No. 16 of 26)


F. HIXON-CROWELL MODEL:-
On the basis of theory that the particle regular area is proportional to the cubic root of its volume,
Hixson & Crowell derived an equation as given below,
Wo1/3 – Wt1/3 = Ks t …………….. (24)
Where, Wo is the initial of drug in the pharmaceutical dosage form, Wt is the remaining amount
of drug in the pharmaceutical dosage form at time t and Ks is the a constant incorporating the
surface- volume relation.
This expression applies to pharmaceutical dosage form such as tablets, where the dissolution
occurs in planes that are parallel to the drug surface is the tablet dimensions diminish
proportionally, in such a manner that the initial geometry form keeps constant all the time.
Above equation can be written as:
1/3
K t N 1/3 DC s t
Wo – Wt1/3 = ………… (25)
δ
Where, N is the number of particles, Kt is a constant related to the surface, the shape and the
density of the particle, D is the diffusion coefficient, Cs. is the solubility in the equilibrium (at
experience temperature ) and δ is the thickness of the diffusion layer.
Dividing equation (24) by Wo1/3 and simplifying,
(1-ft) 1/3 = 1 - K β t………………. (26)
Where ft = 1 – (Wt - Wo) and ft represent the drug dissolved fraction at time t and K β is the
release constant. Then, a graphic of the cubic root of the unreleased fraction of the drug versus
time will be linear if the following conditions are fulfilled:-
• The equilibrium conditions are not reached and
• The geometrical shape of the pharmaceutical dosage form diminishes proportionally over
time.
Assumption:
When this model is used, it is assumed that the release rate is limiting by the drug particles
dissolution rate and not by the diffusion that might occur through the poly-metric matrix. This
model has been used to describe the release profile keeping in the mind the diminishing surface
of the drug particles during the dissolution.
(Page No. 17 of 26)


G. WEIBULL MODEL
Weibull introduced a general empirical equation which is highly applied to drug dissolution or
release from pharmaceutical dosage forms. The accumulated fraction of the drug m in solution at
time t is given by Weibull equation:
⎡ − (t − Ti )b ⎤
m = 1 − exp⎢ ⎥ ………………. (27)
⎣ a ⎦
In this equation a, defines the time scale of the process. The location parameter, Ti , represents
the lag time before the onset of the dissolution or release process and in most cases will be zero.
The shape parameter, b, characterizes the curve as either exponential (b = 1) (case 1), sigmoid, S-
shaped, with upward curvature followed by a turning point (b>1) (case 3). This equation may be
rearranged into:
Log [-In (1-m)] = b log (t – Tt) – log a ……………………. (28)
From this equation a linear relation can be obtained for a log-log plot of – In (1 – m) versus time
t. the shape parameter (b) is obtained from the ordinate value (1/a) at time t = 1. The parameter a
can be replaced by the more informative dissolution time Td that is defined by a = (Td) b and is
read from the graph as the time value corresponding to the ordinate – In (1 – m) = 1.
Since –In (1 – m) =1 is equivalent to m = 0.632, Td represents the time interval necessary to
dissolve or release 63.2% of the drug present.
In the pharmaceuticals systems following this model, the logarithm of the dissolved amount of
drug versus the logarithm of time plot will be linear.
Limitations:-

i. There is not any kinetic fundament and could only describe, but doesn’t adequately
characterize, the dissolution kinetic properties of the drug.
ii. There is not any single parameter related with the intrinsic dissolution rate of the drug and
iii. It is of limited use for establishing in vivo/in vitro correlation.
(Page No. 18 of 26)


H. BAKER – LONSDALE MODEL:-
Baker and Lonsdale developed a model from the Higuchi model and describe the drug controlled
release from a spherical matrix, being represented by the following expression:
3⎡ ⎛ ⎤ M
2
M ⎞ 3
3D C
⎢1 − ⎜⎜1 − t ⎟⎟ ⎥ − t = 2m ms t ……………………. (29)
2 ⎢ ⎝ M∝ ⎠ ⎥⎦ M ∝ r0 C0
⎣
Where Mt is the drug release amount at time t and M ∞ is the amount of drug released at an
infinite time. Dm is the diffusion coefficient, Cms is the drug solubility in the matrix, r0 is the
radius of the spherical matrix and Co is the initial concentration of drug in the matrix.
3 M M 3D f C fs ε
[1 − (1 − t ) 2 / 3 ] − t = 2 t …………………….. (30)
2 M∞ M∞ r 0 Coτ
Where Df is the diffusion coefficient, Cfs is the drug solubility in the liquid surrounding the
matrix, τ is the Tortuosity factor of the capillary system and ε is the prosperity of matrix. The
matrix prosperity can be described by (Desai et al... 1966):
ε = ε o + K Co …………………………………. (31)
Where, ε o is the initial porosity and K is the drug specific volume. If ε o is small, equation (30)
can be rearranged as:
3 M M 3D f KC fs
[1 − (1 − t ) 2 / 3 ] − t = t ……………. (32)
2 M∞ M∞ r 2 0τ
In this way a graphic relating the left side of the equation and time will be linear if the
established conditions were fulfilled and the Baker-Lonsdale model could be define as:
3 M M
f t = [1 − (1 − t ) 2 / 3 ] − t = kt ………….. (33)
2 M∞ M∞
The release constant k corresponds to the slope of the graph. This equation has been used to the
linearization of release data from several formulations of microcapsules or micro-spheres.
(Page No. 19 of 26)


I. HOPFENBERG MODEL:-
The release of drugs from surface-eroding devices with several geometries was analyzed by
Hopfenberg. He developed a general mathematical equation describing drug release from slabs,
spheres and infinite cylinders displaying heterogeneous erosion (Hopfenberg, 1976;
Katzhendleret al., 1997)
n
Mt ⎛ k .t ⎞
= 1 − ⎜⎜1 − 0 ⎟⎟ ………….. (34)
M∝ ⎝ C0 .a ⎠
Where Mt is the amount of drug dissolved in time t, M ∞ is the total amount of drug dissolved
when the pharmaceutical dosage form is exhausted, Mt/ M ∞ is the fraction of drug dissolved, ko
is the erosion rate constant, Co is the initial concentration of drug in the matrix and ao is the
initial radius for a sphere of cylinder or the half-thickness for a slab.
The value of n is 1, 2 and 3 for a slab, cylinder and sphere, respectively.
A modified form of this model was developed (El-Arini and Leuenberger, 1998) to
accommodate the lag time (l) in the beginning of the drug release from the pharmaceutical
dosage form:
Mt
= 1 − [1 − k t t (t − 1)] n ………………. (35)
M∞
• Where, kt is equal to ko/CoAo. This model assumes that the rate-limiting step of drug release
is the erosion of the matrix itself.
• The time depended diffusion resistances, (internal or external to the eroding matrix) does not
influence it.
(Page No. 20 of 26)


J. SEQUENTIAL LAYER MODEL:-

A detailed description of the mathematical analysis was presented before by Siepmann &
Peppas. Briefly, the “sequential layer” model considers the following physicochemical
phenomena occurring during drug release from hydrophilic matrix tablets:
At early times, significant water concentration gradients are formed at the matrix/water interface
leading to water imbibitions into the system. This process is taken into account considering:-
a. The exact geometry of the tablet;
b. The axial and radial direction of the mass transport; and
c. The significant dependence of the water diffusion coefficient on the matrix swelling ratio
d. Due to the imbibitions of water HPMC swells, resulting in dramatic changes of polymer and
drug concentrations, and increasing dimensions of the system.
e. On contact with water the drug dissolves and (due to concentration gradients) diffuses out of
the device.
f. With increasing water content the diffusion coefficient of the drug increases substantially.
g. In the case of poor water-solubility, dissolved and un-dissolved drug co-exist within the
polymer matrix. Un-dissolved drug is not available for diffusion.
h. In the case of high initial drug loadings, the inner structure of the matrix changes
significantly during drug release, becoming more porous and less restrictive for diffusion on
drug depletion.
i. Depending on the chain length and degree of substitution of the hydrophilic polymer used,
the polymer itself dissolves more or less rapidly.
j. A dissolution rate constant, kdiss, was considered characterizing the polymer mass loss
velocity normalized to the actual surface area of the system:
M pt = M po − k diss At t ………………. (36)

Here, Mpt and Mp0 are the dry polymer matrix mass at time t, and t = 0, respectively; At denotes
the surface area of the device at time t. Water and drug diffusion were described using Fick’s
second law of diffusion.
∂C ⎛ 2 2 2 ⎞
k = D ⎜∂ C + ∂ C + ∂ C⎟
∂t k ⎜ ∂x 2 ∂y 2 ∂z 2 ⎟
⎝ ⎠
Here, Ck and Dk are the concentration and diffusion coefficient of the diffusing species (k= 1 for
water, k = 2 for the drug), respectively; and t represents time. According to the free volume
theory of diffusion, an exponential dependence of the diffusion coefficients on the water content
of the system was taken into account:
(Page No. 21 of 26)


⎡ ⎛ C ⎞⎤
Dk = Dkcrit exp ⎢− β k ⎜⎜1 − 1 ⎟⎟⎥ ………………. (37)
⎣ ⎝ C1crit ⎠⎦
Where; β1 and β2 are dimensionless constants characterizing this concentration-dependence. Also

C1crit denotes the water concentration, D1crit and D2crit the respective diffusion coefficients of
water and drug at the interface matrix/release medium, where polymer disentanglement occurs.
Ideal mixing was assumed (no volume contraction on mixing drug, polymer and water), and the
total volume of the system at any instant was given by the sum of the volumes of the single
components.
K. OTHER EMPIRICAL AND SEMI-EMPIRICAL MODELS:-
(i) Model developed by Peppas and Sahlin:
Mt
= k t t m + k 2t 2 m ………………. (38)
M∝
Where; k1, k2 and m are constants. The first term on the right hand side represents the Fickian
diffusional contribution, F, whereas the second term the case-II relaxational contribution, R. The
ratio of both contributions can be calculated as follows:
R k 2t m
= ………………. (39)
F k1
(Page No. 22 of 26)


(ii) Model investigated by Couarraze :-

It focuses on drug release from bulk eroding polymer films, considering polymer degradation
and drug diffusion simultaneously. Their assumptions for modeling were a pseudo-steady state
approach, for initial drug loadings well above the solubility of the drug within the matrix was
assumed
• Polymer chain cleavage follows first-order kinetics and
• drug diffusion coefficients, D, increase exponentially with time t:
D = D0 exp( k .t ) ………………. (40)

Where; D0 is the diffusion coefficient of the drug at t=0 (prior to degradation); and k is the
polymer degradation rate constant. The following equation for the cumulative absolute amount
of drug released, Q, versus time was derived:
2C 0 C s D0 [exp( k .t ) − 1]
Q=S ………………. (41)
k
Where, S is the surface area of the film exposed to the release medium; and C0 and Cs are the
initial drug concentration and the solubility of the drug in the system, respectively.
3. SELECTION OF BEST MODEL:-

The selection of the appropriate model in the drug release studies is critical to ensure the
effectiveness of the study. There are various criteria for the selection of the mathematical
models which are based on the statistical treatments. The most widely used method employs the
coefficient of determination, R2, to assess the fit of the model equation. This method can be used
when the parameters of the model equations are similar. But when the parameters of the
comparing equations increased; a modification is incorporated in this technique where an
adjusted coefficient of determination (R2adjusted) given by:
n −1
R 2 adjusted = 1 − (1 − R 2 ) ………………. (42)
n− p
Where n is the number of dissolution data points and p is the number of parameters in the model.
Hence, the best model is the one with the highest adjusted coefficient of determination.
Similarly other statistical tools like correlation coefficient (R), Analysis of Variance (ANOVA)
and Multivariate analysis of variance (MANOVA) are used for the comparison and selection of
the models.
(Page No. 23 of 26)


4. CONCLUSION:-
Over recent years, drug release/dissolution from solid pharmaceutical dosage forms has been the
subject of intense and profitable scientific developments. Whenever a new solid dosage form is
developed or produced, it is necessary to ensure that drug dissolution occurs in an appropriate
manner. The pharmaceutical industry and the registration authorities do focus, nowadays, on
drug dissolution studies.
The quantitative analysis of the values obtained in dissolution / release tests is easier when
mathematical formulas that express the dissolution results as a function of some of the dosage
forms characteristics are used. In some cases, these mathematic models are derived from the
theoretical analysis of the occurring process. In most of the cases the theoretical concept does not
exist and some empirical equations have proved to be more appropriate. Thus, the mathematical
model is an important cursor for prediction and elucidation of the exact behavior of drug or drug
release profile from a specific drug delivery system.
Drug dissolution from solid dosage forms has been described by kinetic models in which the
dissolved amount of drug (Q) is a function of the test time, t or Q=f(t). Some analytical
definitions of the Q(t) function are commonly used, such as zero order, first order, Hixson–
Crowell, Weibull, Higuchi, Baker–Lonsdale, Korsmeyer–Peppas and Hopfenberg models.
Mathematical models explain to the path to predict the fundamental theory of controlled release
drug product design. The model can definitely ensure batch to batch uniformity and the success
of the intended therapy with the expected quality, safety and efficacy of the product. The model
can have the control over all critical parameters, which will lead to predictability &
reproducibility of the drug release profile of a dosage form. It can also significantly facilitate the
optimization of existing product as well as the development of new products. In addition to the
prevention from excessive experimentation, it will not only help to bring down the cost but also
save the time.
(Page No. 24 of 26)


5. REFERENCES :-
1. Robinson, J. R.; Lee, V. H. L.; eds. Controlled drug delivery, Marcel Dekker, Inc. New
York, Basel, 1987.
2. Sefton, M. V.; Allen, D. G.; Horvath, V.; Zingg, W. In Recent advances in drug delivery,
Anderson, J. M.; Kim, S. W. eds.Plenum Press, New York, 1984, pp. 349-365.
3. Mathematical Modeling and Controlled Drug Delivery: Matrix Systems; Mario Grassi and
Gabriele Grassi
4. A Basic Guide to the Double-Barrelled Dissolution Equations; Karl Malcolm PhD , Queen's
University Belfast
5. Comparison of In Vitro Dissolution Profiles of Oxcarbazepine-HP b-CD Tablet Formulations

with Marketed Oxcarbazepine Tablets; Nirav Patel1,5, Narendra Chotai2, Jayvadan Patel3,
Tejal Soni1,Julan Desai1, and Rajnikant Patel4
6. Novel Mathematical Method for Quantitative Expression of Deviation from the Higuchi
Model Submitted: July 7, 2000; Accepted: October 25, 2000Mukesh C. Gohel*, Maulik K.
Panchal, and Viral V. Jogani, Department of Pharmaceutics, L. M. College of Pharmacy,
P.O. Box. No. 4011, Navrangpura, Ahmedabad–
7. Monte Carlo simulations for the study of drug release from cylindrical matrix systems with
an inert nucleus; Lizbeth Martíneza, Rafael Villalobosa, Marisol Sáncheza, Jeny Cruzb,
Adriana Ganema, Luz María Melgozab
8. Modeling and comparison of dissolution profiles; Paulo COSTA, Jose Manuel Sousa Lobo
9. Mathematical models describing polymer dissolution: consequences for drug delivery; Balaji
Narasimhan
10. J. Siepmann & N.A.Peppas, Mathematical Modelling of Controlled Drug Delivery,

Advanced drug delivery Reviews 48(2001), www.elsevier.com/locate/drug deliv,pg137-138
11. Balaji Narshimhan, Accurate models in controlled drug delivery systems, Handbook of
Pharmaceutical Controlled Release Technology, Donlad L. Wise, New York & Basel.
12. Paula Costa and Jose M.S.Lobo, Modeling and comparision of dissolution profiles, European
Journal of Pharmaceutical Sciences, 13, (2001). pg 123-133.
(Page No. 25 of 26)


13. B.M. Silber, M.Bailer and A. Yacobi, Basis of controlled Drug Delivery, Controlled Drug
Delivery Fundamental & Application, Robinson, Vincent H L Lee, 2nd Edition 1987, Marcel
Dekker, New York & Basel. pg 233.
14. J. Siepmann & N.A.Peppas, Modeling of drug release from delivery systems based on
HPMC, Advanced drug delivery Reviews 48 (2001), www.elsevier.com/locate/drug deliv,
pg139-157
15. Web based survey:-
• www.elservier.com/locate/drugdelivery
• www.pharmscitech.com;
• http://www.tjpr.freehosting.net
• www.mse.kth.se-utbildning-4H1068-lect06-diffusion.pdf
• http://en.wikipedia.org/wiki/Diffusion
• http://cop.utmem.edu/pharmacy/phsc_111/HTML%20Pages/022.html
(Page No. 26 of 26)


Mathematical Models Used in The Drug Release Studies

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MATHEMATICAL MODELS USED

DR. PANNA THAPA

(Page No. 0 of 26)

B. ZERO ORDER KINETICS

C. FIRST ORDER KINETICS

E. KORSMEYER- PEPPAS MODEL (THE POWER LAW)

H. BAKER – LONSDALE MODEL

I. MODEL DEVELOPED BY PEPPAS AND SAHLIN

II. MODEL INVESTIGATED BY COUARRAZE

(Page No. 1 of 26)

(Page No. 2 of 26)

The major objectives of mathematical modeling are as listed below:

behavior through polymers, thus avoid excessive experimentation.

3. Optimization of the release kinetics.

data to mathematical models.

2. MATHEMATICAL MODELS APPLIED FOR DRUGS RELEASE STUDIES:-

(Page No. 3 of 26)

Diffusion is defined as the process of mass transfer of individual molecules of a substance,

I. Fick’s First Law

(Page No. 4 of 26)

II. Fick’s Second Law

(Page No. 5 of 26)

∂C ∂ 2C ……………. …………. (3)

III. APPLICATIONS OF FICK’S LAW IN PHARMACEUTICAL SCIENCES:-

(Page No. 6 of 26)

b. DISSOLUTION RATE OF DRUGS:

D= Diffusion coefficient of the solute in solution

S= Surface area of the exposed solid.

h= Thick ness of the diffusion layer.

Cs= concentration in a saturated liquid layer

Cb = Concentration of solute in the bulk solution at time t

(Page No. 7 of 26)

IV. LIMITATION OF FICK’S LAW OF DIFFUSION:

(Page No. 8 of 26)

B. ZERO ORDER KINETICS

(Page No. 9 of 26)

C. FIRST ORDER KINETIC MODEL

Qt = Q0e− k t …………………………………. (10)

(Page No. 10 of 26)

(Page No. 11 of 26)

The following assumptions are made in deriving the mathematical model:-

∂ M=Co. ∂ h - (Cs/2) ∂ h -------------------------- (12)

Where Co and Cs are as defined in the second assumption.

or, ∂ M= {( DmCs) / h}∂t ---------------(13)

Where, Dm is the diffusion coefficient in the matrix.

( Dm C s / h)∂t = (Co − C s / 2)∂h

or, ∫ (2C o − C s ) / h( 2 Dm C s )∂h = ∫ ∂t

or, (2Co-Cs) h2/(4DmCs) = t

(Page No. 12 of 26)

We get, ∫ ∂M = ∫ (CCo − Cs / 2)∂h

This equaation is calleed Higuchi equation.

M = [(2Co - ∈ Ca) Ds Ca t ( ∈ / τ )] 1/2…………..

Where, ∈ is the poro osity of the matrix,

(Pagee No. 13 of 26)

E. KORSMEYER- PEPPAS MODEL (THE POWER LAW):-

t=0 - δ /2 < x < δ /2 c = c0

(Page No. 14 of 26)

Mt / M ∞ = 2(Dt/ δ 2)1/2 { π -1/2 + ∑ ∞

Mt / M ∞ = 2(Dt/ δ 2)1/2 = Kt ½ …………….. (20)

Where, K is an experimentally determined parameter characteristic of structure and geometry of

RELEASE EXPONENT(n) DRUG TRANSPORT MECHANISM RATE AS A fx OF Time

0.5 FICKIAN DIFFUSION t-.5

0.5<n<1 NON-FICKIAN DIFFUSION tn-1