Unit:6

Kinetics and evaluation of

controlled released
formulations
Achyut Bikram Thapa
1. Fick’s Law of diffusion
• The pioneer mathematical modeling for the diffusion is
given by Adolf Fick in 1885, and Fick’s first law and second
law of diffusion are being widely accepted for the
modeling of Fickian drug release system.

• Fick’s first law in its one dimension form is mathematically

expressed as:

– where, “D” is diffusion coefficient of a penetrant,

cm2/sec
– “dC” is change in concentration of material, g/cm3
– “dx” is change in distance, cm in “x” dimension  
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 Fick’s 2nd law of diffusion is expressed mathematically in its three
dimensional form as:

– where, “dC” = change in concentration of material, g/cm3

– “D” = diffusion coefficient of a penetrant, cm2/sec
– “dx”, “dy”, “dz” = change in distance, cm in “x”, “y”, “z” dimension

• Fick’s law has found its application in various branches of

pharmaceutical sciences like in study of drug synthesis, pre-
formulation studies, dosage form design, manufacturing,
analysis, drug absorption, drug distribution, drug metabolism,
drug excretion etc.
• In drug release mathematical modeling family, a lot of
mathematical models derived from the Fick’s law are found.
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 Fick’s Law of diffusion
Solid undergoing dissolution is covered by an aqueous stagnant
diffusion layer having uniform thickness ‘h.’

Now, as per the Fick’s law of diffusion, a concentration gradient is

present in the diffusion layer having concentration varying from Cs &
C beyond the diffusion layer, mixing is supplied to occur uniformly,
throughout the bulk.

Above equation is commonly known as Noyes – Whitney equation.

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 2. Kinetics model
a. Zero Order Kinetics Model
Assumptions: 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. Here, the sink
condition prevails throughout the process.

Mathematical expressions: Q 1 = Q o + Ko t
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

Applications: study of drug release from different modified release

pharmaceutical dosage from like transdermal system, matrix tablet
formulations with less soluble drugs, osmotic sustained system and coated
sustained release forms 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.
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 2. Kinetics model
b. First Order Kinetic Model
Assumptions:
Any pharmaceutical dosage forms containing water-soluble drugs in porous
matrices follow first order release kinetics.
Mathematical statement: Qt = Qoe-kt
Where, Qt is the amount of drug released in time t. Qo is the initial amount
of drug in the solution and k is the first order release constant.
In decimal logarithm, above equation can be expressed as following:
Log Qt = log Qo + kt/ 2.303
This equation implies that a graph of the decimal logarithm of the amount
of drug versus time will be linear. Thus any system following this model
releases the drug in such a way that the remaining amount in the system
governs the rate of release of drugs.
Applications:
Commonly used to describe absorption and elimination of drugs. Specially,
applied
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formdrug delivery
design-unit 6 systems where water
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 3. Higuchi Model
• Higuchi developed models to study the release of both the
water soluble and lower soluble drugs incorporated in
semisolid and solid matrices. To study the dissolution from a
planer system having a homogeneous matrix, the relation
obtained was;

• Where “Mt” and “M∞” are cumulative amount of drug release

at time “t” and infinite time “∞”, and “KH” is the Higuchi
constant of drug release (Fickian diffusion).
• When the drug release obeys Higuchi model a plot of “M t/M∞”
versus “t1/2” will be a straight line passing through the origin
with a slope of “KH”.

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 3. Higuchi Model
Similarly, the release from the granular matrices involves the
simultaneous penetration of the surrounding liquid, dissolution of
drug, and leaching out of the drug through interstitial channels or
pores. A granule is in fact a porous rather than a homogenous
matrix. The volume and the length of the opening in the matrix must
be accounted during the mathematical treatment. Thus the classical
Higuchi equation takes the following form
 

Where, ε is the porosity of the matrix and τ is the tortousity of the

capillary system on the granular matrix, both of the parameters
being the dimensionless quantity.

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 3. Higuchi Model
Assumptions for CR systems to follow Higuchi model
I.The initial drug concentration in the system is much higher than the
solubility of the drug.
II.Mathematical analysis is based on one-dimensional diffusion. Thus,
edge effects must be negligible.
III.The suspended drug is in a fine state such that particles are much
smaller in diameter than the thickness of the system.
IV.Swelling or dissolution of the polymer carrier is negligible.
V.The diffusivity of the drug is constant.
VI.Perfect sink conditions are maintained.

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 3. Higuchi Model
Applications
This model is used to describe the release rate of drugs from matrix
system.
Initially, it was valid only for planar systems but later it was 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.

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 4. Hixson-Crowell Model
Assumptions:
I.Applicable for drug delivery systems consisting of uniformly shaped &
sized particles.
II.The release rate is limited by the drug particles dissolution rate and not
by the diffusion.
III.The radius of the particle is diminishing and the rate of dissolution
depends on the weight of the particles
IV.The particle diminishes proportionately with time such that the shape is
not distorted over the period of dissolution.

Mathematical statement:
Where, k is cube root of dissolution constant =
Applications:
This model is applicable to the dosage forms such as tablets, where the
dissolution occurs in planes that are parallel to the drug surface if the tablet
dimensions diminished proportionately.
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 5. Power law
• Korsmeyer et al. developed a simple, semi-empiric model, when diffusion
is the main drug release mechanism, relating exponentially the drug
release to the elapsed time (t).

• where, “K” is constant incorporating structural and geometrical

characteristic of the dosage form, “n” is the release exponent, indicative
of the drug release mechanism and the function of “t” is “M t/M∞”
(fractional release of drug).
• Peppas used the “n” value in order to characterize different release
mechanisms.
• As can be seen, the classical Higuchi equation as well as the above
described short time approximation of the exact solution of Fick’s second
law for thin films represent the special case of the power law where n =
0.5.
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 Interpretation of diffusion release
mechanism from polymeric films
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 t n-1

( Anomalous transport)

1 Case-II transport Zero order release

>1
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Super Case-II transport
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t n-1 13
 Interpretation of drug release mechanism from polymeric
controlled delivery systems of different geometry

Exponent, “n” Drug release

Thin film Cylinder Sphere mechanism

0.5 0.45 0.43 Fickian diffusion

0.5<n<1.0 0.45<n<0.89 0.43<n<0.85 Anomalous transport

1.0
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0.89 0.85
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Case-II transport 14
The Power Law continued…
The power law can be seen as a generalization of the observation that
superposition of two apparently diffusion independent mechanisms
of drug transport, a Fickian diffusion and a case II transport
describes in many cases dynamic swelling of and drug release from
glassy polymers, regardless of the form of the constitutive equation
and the type of coupling of relaxation and diffusion. It is clear from
Eq.
Ft = Kot
that when the exponent n takes a value of 1.0, the drug release rate is
independent of time. This case corresponds to zero order release
kinetics. For slabs, the mechanism that creates the zero-order
release is known among polymer scientists as case-II transport.

Where, Ft = 1 – (Wt /Wo) and Ft represents the fraction of drug dissolved

in time t and ko is the apparent dissolution rate constant or zero
order release constant. Dosage form design-unit 6
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 Mathematical Model of release (Summary)
x y
zero Time cum. Drug release

First Time log cum % drug remaining

Higuchi
Sq.rt. Time cum. % Drug release
(Square root)
Hixson-Crowell cube root of drug %
Time
(cube root) remaining
korsmeyer peppas log cumulative% drug
Log time
(Power Law) release

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 Evaluation of CR formulations
Physical parameters to be evaluated in CR formulations are
A. Weight variation
B. Breaking force
C. Friability
D. Thickness and diameter/ length / width variation

Disintegration time (DT), a common parameter of IPQC in

conventional tablets is not a parameter to be evaluated
for sustained release formulations.
Assay, content uniformity and In-vitro drug release
(dissolution) studies for CR formulations are important
parameters to be tested. The time for evaluation of drug
release for CR formulations depend upon the nature of
dosing as BD/ OD regimen.
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 Evaluation of CR formulations
• Pharmacopeial products are tested at time frame
mentioned in individual monograph.
• For non-pharmacopeial products, specifications for drug
release at 3 or more test-time points is set.
• The first point should be set after a testing period
corresponding to a dissolved amount of typically 20-30%
to show that there is no dose dumping at start hour.
• The second point should define the dissolution pattern
and should be set at around 50% release.
• The final point should ensure almost complete release
that is generally understood as more than 80% release.

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 Evaluation of CR formulations
• The dissolution medium preferably is deaerated water
or, if substantiated by the solubility characteristics of the
drug or the formulation, buffered aqueous solutions
(typically pH 4 to 8) or dilute acid (0.001 N to 0.1 N
hydrochloric acid) may be used.
• Choice of dissolution medium depends upon the nature
of drug and site of absorption. The pH- and surfactant-
dependence of the dosage form should be evaluated by
in vitro testing in media of various compositions.
• The volume of medium will vary depending on the
apparatus used, rpm of apparatus and the formulation
under test.

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 In- vivo Evaluation of CR Formulations
• The assessment of safety and efficacy of a modified-
release dosage form is best achieved through observing
in vivo pharmacodynamics or pharmacokinetics
parameters.
• If there is a well-defined, predictive relationship
between the plasma concentrations of the drug or active
metabolites and the clinical response (therapeutic and
adverse), it may be possible to use plasma drug
concentration data alone as a basis for the approval of a
modified-release preparation that is designed to replace
an immediate-release preparation.
• In other cases, following in-vivo evaluation methods are
used.
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 In- vivo Evaluation of CR Formulations
1. Disposition parameters (clearance, volume of distribution, half-life,
mean residence time, or model-dependent or non compartmental
parameters).
2. Linearity or characterization of nonlinearity over the dose or
concentration range which could possibly be encountered.
3. Accumulation.
4. Metabolic profile and excretory organ dependence, with special
attention to the active metabolites and active enantiomers of
racemic mixtures.
5. Enterohepatic circulation.
6. Protein binding parameters and dialyzability.
7. The effects of age, gender, race, and relevant disease states.
8. Plasma/blood ratios.
9. A narrow therapeutic index or a clinical response that varies
significantly as a function of the time of day.
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 Comparison of two CR formulations
There are 3 different methods to compare dissolution profile of
two different Cr formulations one of which is the comparator
product and another is innovator product.

a. Model independent approach using similarity and dis-similarity

factor
b. Model Independent Multivariate Confidence Region Procedure
c. Model Dependent Approaches

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 Model independent approach
• Similarity and dissimilarity factor helps to compare the dissolution
profiles of two or more different sustained release products of the
same drug substance.
• FDA has defined two equations for difference or dis-similarity, FD
and similarity factor, Fs.
• The difference factor FD measure the percentage error between two
curves over all point of times where as similarity factor F S is a
logarithmic transformation of sum squared error of difference
between the test and reference product over all time points.
• The similarity factor fits the result for the values higher than 50 and
close to 100. It is 100 when the test and reference profiles are
identical and tends to 0 as the dissimilarity increases.
• The dissimilarity factor ranges between 15 and 0. This method is
more adequate to dissolution profile comparison when more than
three or four dissolution time points are available.
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 Model independent approach

• n is the sampling number,

• Rj is the percentage of dug dissolved of reference product at time
“j”
• Tj is the percentage of dug dissolved of formulated product at
time “j”

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 Model Independent Multivariate Confidence Region Procedure
In instances where within batch variation is more than 15% CV, a
multivariate model independent procedure is more suitable for
dissolution profile comparison. The following steps are suggested
1. Determine the similarity limits in terms of multivariate statistical
distance (MSD) based on interbatch differences in dissolution
from reference (standard approved) batches.
2. Estimate the MSD between the test and reference mean
dissolutions.
3. Estimate 90% confidence interval of true MSD between test and
reference batches.
4. Compare the upper limit of the confidence interval with the
similarity limit. The test batch is considered similar to the
reference batch if the upper limit of the confidence interval is less
than or equal to the similarity limit.
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 Model dependent approach
• Several mathematical models have been described in the literature
to fit dissolution profiles. 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 in model parameters between test and
reference batches.
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 Model dependent approach
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

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 THANK YOU
Achyut Bikram Thapa
a.abthapa@gmail.com

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