Mathematical Modeling and Drug

release kinetics
 computation of desired release rate and dose for controlled release DDS,
 pharmacokinetic design for DDS – intermittent, zero order & first order
release.
Introduction
• Over the past three decades, there have been significant advances in the area
of drug delivery with the development of controlled release dosage forms.
• Drug release is an important property of a therapeutic system, constituting a
prerequisite to absorption of the therapeutic agent and one that contributes
to the rate and extent of active availability to the body.
• The release patterns comprise the zero- and first-order rate.
• In addition, there are those that provide an initial rapid dose, followed by
zero- or first-order release of the sustained component.
• The aim of these systems is to maintain the concentration of the therapeutic
agent in the blood or in target tissues at a desired value as long as possible,
exerting a control on the drug release rate and duration.
• Therefore, the controlled release system can initially release a fraction of the
dose contained in order to attain rapidly the effective therapeutic
concentration of the drug (burst release).
• After, a well-defined behavior of drug release kinetics can supply the
maintenance of effective drug concentration level.
• Therefore, controlled release dosage forms enable pharmacists and
engineers to work together with the aim of designing controlled drug
delivery systems.
• To provide particular, predetermined release profiles, it is necessary to
know the exact mass transport mechanisms involved in drug release, and
to predict quantitatively the resulting drug release kinetics.
• Many times, it is possible to acquire a mathematical equation that describes the
dependence of release in function of time.
• The use of this tool is very useful to predict the release kinetics before the
release systems are realized.
• This analytical solution conduces to many models that have been used to design
a number of simple and complex drug delivery systems and devices and to
predict the overall release behavior.
• Mathematical models are an important tool to design pharmaceutical
formulations, evaluate drug release processes in vitro and in vivo and, in
general, come up with the optimal design for new systems.
• They allow the measurement of some important physical parameters (e.g.,
drug diffusion coefficient) and resort to model fitting on experimental release
data.
• The amount and type of active agent, polymer and adjuvants as well as the
size and shape of the system designed to achieve a certain drug release profile
can be predicted theoretically.
• It is very important to know how to use these equations to understand the
different factors that affect the dissolution velocity and how the dissolution
behaviors can vary and influence the efficiency or the therapeutic regimen of
patients.
• Mathematical equations enable the quantitative interpretation of the values
obtained from a dissolution or drug release assay.
• The equation needs to have the ability to transform the release curve in
function of some other parameter related to the dosage form under analysis.
• Therefore, the models have been used mainly to predict the release of the
encapsulated molecule(s) in function of time.
• Therefore, mathematical evaluation of drug release kinetics adds value,
ensuring optimal design of pharmaceutical formulation(s) as well as
understanding release mechanism(s) through experimental verification
• The precise combination of experimental observations with models that
make it possible to acquire the underlying physics will provide the
understanding about the release mechanism.
• When the analytical solutions are explicit, it is possible to relate the
dependent and independent variables.
• However, this dependence is not obvious in the case of implicit
analytical solutions.
• The understanding of the effect of certain independent variables on
particular dependent variables is much easier, compared to numerical
solutions.
• Physically more realistic models are mathematically more complex, and
very often it is difficult to find analytical solutions of the respective set of
equations .
• At this point, it is clear that the development of mathematical modeling
requires the comprehension of all the phenomena affecting drug release
kinetics.
• The model can be simply considered a mathematical metaphor of some
aspects of reality that, in this case, identifies with the ensemble of
phenomena ruling release kinetics.
• According to what was previously described, the drug release from a
modified release system can be controlled by various methods, such as
dissolution, diffusion, partitioning, osmosis, swelling, and erosion.
• Diffusion of the active agent is a strong function of the structure through
which the diffusion takes place, and diffusion equations can be predicted by
many existing models.
• For example, it is important to consider the polymer morphology
• Generally, when a hydrophilic drug is incorporated in a matrix, the release occurs
easily by diffusion, compared to another hydrophobic or less water-soluble drug.
• The hydrophobic drug release normally is associated with swelling and/or matrix
erosion.
• Differences in solubility, in the factors that determine the solubility and the
participation of different processes explain why the same active agent, when
incorporated in a polymeric matrix, can present different behaviors.
• Considering that qualitative and quantitative changes in a system may alter drug
release and in vivo performance, the development of tools that facilitate product
development by reducing the necessity of biostudies is always desirable.
• In this regard, the use of in vitro drug dissolution data to predict in vivo
bioperformance can be considered the rational development of controlled
release formulations
• Statistical methods can be used to investigate the kinetics of drug release from
controlled release formulation, using the exploratory data analysis method,
repeated measures design and multivariate approach (e.g., multivariate
analysis of variance (MANOVA)).
• The exploratory data analysis method is the first step to compare dissolution
profile data in both graphical and numerical form, constituting a useful manner
to obtain improved understanding of the dissolution data of the controlled
release system.
• Briefly, the release profile data are illustrated graphically by plotting the mean
release profile data for each preparation, with error bars extending to two
standard errors at each dissolution time point.
• The data of the dissolution profiles are summarized numerically, and 95%
confidence intervals for the differences in the mean dissolution profiles at each
dissolution time point are evaluated
• The complexity of the involved process justifies the frequent utilization of
empirical equations.
• However, statistical methods are recommended when the aim is to evaluate
the similarities between dissolution/release behaviors
• Methods independent of model (e.g., difference factor (f1), similarity factor
(f2)) are also utilized.
• However, model-dependent methods, based on different mathematical
functions, are very useful to describe the release profile.
• Once a suitable function has been selected, the dissolution profiles are
evaluated depending on the derived model parameters.
• Between the main-release kinetic models are zero order, first order, Higuchi,
Hixson–Crowell, Korsmeyer–Peppas, Baker–Lonsdale, Weibull, Hopfenberg,
and Gompertz.
 • MODELLING AND COMPARISON OF DISSOLUTION PROFILE

Several theories and kinetic models are described for the drug release characteristics of

immediate release and modified release dosage forms, by using dissolution data and

quantitative interpretation of values obtained in dissolution assay if facilitated by the

usage of the generic equation dosage form that mathematically translates the dissolution

curve in function of some parameters related with pharmaceutical dosage form.

• Mathematical models for the drug release studies plays a significant role as it
establishes a mechanism of drug release and provides more general
guidelines for the development of other systems.
• It is accepted that numerous successful drug delivery systems have been
developed as a result of an almost arbitrary selection of components,
configurations and geometrics.
• Various models:
Zero order Kinetics Model
First order Kinetics Model
Higuchi Model
Korsmeyer–Peppas Model
Hixson–Crowell Model
Objectives of Mathematical Model
 Designing of new drug delivery system based upon the general release
expression.
 Prediction of the drug release rate form and drug diffusion behavior through
polymers, thus avoid excessive experiment.
 Optimization of the release kinetic.
 Physical mechanism of drug transport is determined by the compare the
release data with mathematical models.
 Prediction of the effect of design parameters viz. shape, size and
composition on the overall drug release rate.
 Accurately prediction of drug release profile and improve overall
therapeutic efficacy and safety of these drug
• Application of Mathematical Model

i. The mathematical model equation can be used to design new systems by selecting the optimal geometry,
method of formulation and size.

ii. Mathematical modeling aids in predicting the drug release rates and diffusion behavior from these
systems by the solution of an appropriate model, thereby reducing the number of experiments needed.

iii.Mathematical modeling of controlled drug delivery can help provide a scientific knowledge base
concerning the mass transport mechanisms which are involved in the control of drug release.

iv. Mathematical modeling can significantly facilitate the optimization of existing and the development of
new Pharmaceutical products.

v. The systematic use of models can save money and time.

vi.The mathematical approaches may help researchers to develop highly effective drug formulations and
more accurate dosing regimens.
Assumption for deriving Mathematical Model

 During the release of drug, pseudo-steady is maintained.

 Total amount of drug present per unit volume in the matrix, C 0, is greater than the

saturation solubility of the drug per unit volume in the matrix C s, which indicates excess amount of

solute present.

 At all times the release media is under perfect sink condition.

 Drug particles smaller in diameter than the average distance of diffusion.

 The value of diffusion coefficients is constant.

 Between the drug and matrix, no interactions are occurred.

Diffusion Parameters, Dissolution Parameters and Pharmacokinetic parameters
Diffusion Model
Diffusion refers to the process by
which molecules intermingle as a
result of their kinetic energy of
random motion.
the diffusion of drug molecule in our body which can be well
explained by Fick’s laws of diffusion.
i. Fick’s first law of diffusion: Fick's first law relates the
diffusive flux to the concentration under the assumption of
steady state. It postulates that the flux goes from regions of
high concentration to regions of low concentration, with a
magnitude that is proportional to the concentration gradient. In
one dimension, the law is
J = - D (dC / dx)
Where,
J is the amount of substance passing perpendicularly through a
unit surface area per time,
D is the diffusion coefficient and
dc / dx is the concentration gradient
The negative sign in the above equation signifies that diffusion
occurs in the direction opposite to the increasing concentration.
 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.
Fick’s second law of diffusion:
It is derived from Fick’s first law for unsteady
state situations, where concentration is
changing with time.
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:

Thus it states that the change in concentration

with time in a particular region is proportional to
the change in concentration gradient at that
point.
Applications of diffusion models
 Fick’s first and second laws are applied to find flux and
concentration across membranes.
 Dissolution of a solid in a liquid is well explained by the
modified Fick’s law, i.e Noyes-Whitney equation:

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
Limitations of Fick’s laws

There are some limitations in diffusion of drugs having

heterogeneous structure, moving boundary condition, non-
Fickian diffusion, and ionic species.

In case of heterogeneous structure, each layer is made up by

different material.

In such type of condition diffusion

coefficient cannot be considered to be constant throughout the
system.

Applications
Fick‟s first and second law applied to fluid flux and
concentration across the membrane.
 Zero order kinetics model
Drug dissolution from dosage forms that do not disaggregate and
release the drug slowly can be represented by the equation:
Q0 - Qt = K0t
Rearrangement of above equation,
Qt = Q0 + K0t
Where,
Qt is the amount of drug dissolved in time t,
Q0 is the initial amount of drug in the solution (most times, Q 0 = 0)
K0 is the zero order release constant expressed in units of
concentration/time. To study the release kinetics, data obtained from
in vitro drug release studies, are plotted as
cumulative amount of drug released versus
time.
Application:
This relationship can be used to describe the drug dissolution of several types of modified release
pharmaceutical dosage forms, as in the case of some transdermal systems, as well as matrix tablets with
low soluble drugs in coated forms, osmotic systems, etc
Such model is particularly important in certain classes of medicines intended, for example, for antibiotic
delivery, heart and blood pressure maintenance, pain control and antidepressants.
First order kinetics model
This model is used to describe absorption and elimination of some drugs,
although it is difficult to conceptualize this mechanism on a theoretical
basis. The release of the drug which follows first order kinetics can be
expressed by the equation:
= -KC
Where, K is first order rate constant expressed in units of time -1
Above equation can be expressed as:
log C = log C0 - Kt / 2.303 (6)
where,
C0 is the initial concentration of drug,
k is the first order rate constant, and
t is the time.
The data obtained are plotted as 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.
Higuchi model
Higuchi proposed this model in 1961 to describe the drug
release from matrix system. Higuchi model is based on the
hypotheses that:
(i) initial drug concentration in the matrix is much higher
than drug solubility
(ii) drug diffusion takes place only in one dimension (edge
effect must be negligible)
(iii) drug particles are much smaller than system thickness
(iv) matrix swelling and dissolution are negligible
(v) drug diffusivity is constant and
(vi) perfect sink conditions are always attained in the
release environment.
Higuchi model is given by the equation:

where,
Q is the amount of drug released in time t per unit area A,
C is the drug initial concentration,
Cs is the drug solubility in the matrix media and
D is the diffusivity of the drug molecules (diffusion coefficient) in
the matrix substance.
Application:
This model can be used to describe the drug
dissolution from several modified release
dosage forms like, some transdermal
systems and matrix tablets with water
soluble drugs.
Korsmeyer–Peppas Model (The power law)
A simple relationship which described drug release from a polymeric system
equation was derived by Korsmeyer et al. in 1983.
Korsmeyer-Peppas model:
Mt / M∞ = Ktn
Where,
Mt / M∞ is a fraction of drug released at time t,
k is the release rate constant and
n is the release exponent.
The n value is used to characterize different release for cylindrical shaped
matrices and the value of n characterizes the release mechanism of drug as
described in Table below:
Release Drug transport Rate as a function
exponent (n) mechanism of time

0.5 Fickian diffusion t-0.5

0.5<n<1 Non Fickian diffusion tn-1
1 Case II transport Zero order release
Higher than 1 Super Case II tn-1
transport
 For cylindrical shaped matrices:(Like Tablets)

Diffusion exponent (n) Overall solute diffusion mechanism 0.45

Fickian diffusion

0.45 < n < 0.89 Anomalous (non-Fickian) diffusion

0.89 Case-II transport

n > 0.89 Super case-II transport

N is estimated from linear regression of log (mt/M) Vs Log t

The following assumptions were made in this model:
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.
Hixson–Crowell Model A plot of the Cube root of the Initial concentration minus
the Cube root of % remaining Vs time in hours for the
According to Hixson-Crowell, regular area of particles is dissolution data
proportional to the cube root of its volume. i.e,
Q0 1/3 – Qt 1/3 = Ks t
Where
Q0 = Initial amount of drug
Qt = Cumulative amount of drug release at time “t”
Ks = Hixson crowell release constant
t = Time in hours.
It describes the drug releases by dissolution, with the changes in
surface area and diameter of the particles or tablets.

Application:
This expression applies to pharmaceutical dosage form such as
Tablets, where the dissolution occurs in planes that are parallel
to the drug surface if the tablet dimensions diminish
proportionally, in such a manner that the initial geometrical
form keeps constant all the time.
The plotted graph 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.
References:

1.Higuchi, W. I., Diffusional models useful in biopharmaceutics drug release rate processes. J. Pharm. Sci., 1967, 56:
315-324.
2. Noyes, A. A. and Whitney, W. R. The rate of solution of solid substances in their own solutions. J. Am. Chem.
Soc.,1897, 19: 930-934
3. Siepmann, J. and Peppas, N.A. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC).
Adv. Drug Deliv. Rev. 48, 2001,139-157.
4. Korsmeyer, R.W., Gurny, R., Doelker, E., Buri, P. and Peppas, N.A. Mechanisms of solute release from porous hydrophilic polymers.
Int. J. Pharm. 15, 1983, 25-35.
5. Costa P.et.al, Modelling and comparison of dissolution profiles, European Journal of Pharmaceutical Sciences, 13, 2001, pp 123-133.
6. Higuchi T; Mechanism of sustained medication, Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J
Pharm Sci., 1963; 84: 1464-77
Riger PL, Peppas NA; A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J
Control Rel., 1987; 5: 37. 40.
Siepmann J, Peppas NA; Preface: Mathematical modeling of controlled drug delivery. Adv. Drug Deliv. Rev., 2001; 48: 139