THEORIES AND MECHANISMS OF

DISSOLUTION TESTING

By
D.Narender
Semester

M.pharmacy 1 st

DEPARTMENT OF PHARMACEUTICS
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES
KAKATIYA UNIVERSITY

OUT LINE
Definitions
Theories of Dissolution
Mechanisms of drug release

Wagner theory

Zero order release

First order release

Hixon -Crowel model

Higuchi model

Peppas model

Weibull model

Conclusion

Definitions:
Dissolution:
Dissolution is defined as a process in which a solid
substance solubilizes in a given solvent i.e. mass transfer
from solid surface to the liquid phase.
Dissolution rate:
Dissolution rate is defined as the amount of solute
dissolved in a given solvent under standard conditions of
temperature, pH, solvent composition and constant solid
surface area.
It is a dynamic process
The rate of dissolution of drug substance is determined by
the rate at which solvent-solute forces of attraction

Drug Dissolution Process

THEORIES OF DISSOLUTION:
3 Theories
1) Diffusion layer model / Film theory

2)

Danckwerts model (penetration or surface renewal theory)

3)

Interfacial barrier model (double barrier or limited solvation theory)

Diffusion layer model

Assumes that there is a stagnant layer or diffusion layer which is saturated with the drug at the
solid liquid interface.
From this stagnant layer, diffusion of soluble solute occurs to the bulk of the solution.

Cs

Film boundary

c
bulk
solution

Stagnant layer
Diffusion layer model
Here ,the dissolution is diffusion controlled where the solvent-solute
interaction is fast when compared with the transport of solute into bulk of
solution
Once the solute molecules pass the liquid film-bulk film interface rapid
mixing occurs and concentration gradient is destroyed. The rate of solute
movement and therefore the dissolution rate are determined entirely by the
Brownian motion diffusion of molecules in liquid film.

The rate of dissolution when the process is diffusion controlled is given by

noyes-whitney equation
Equation:
dC/dt =D.A.Kw/o (Cs Cb)\ v.h
dC/dt = dissolution rate of the drug.
D = diffusion coefficient of the drug.
A = surface area of the dissolving solid
Kw/o = water/oil partition coefficient of drug
V = volume of dissolution medium
h = thickness of stagnant layer
CsCb = concentration gradient of diffusion of drug

Limitation : Assumes that surface area of the dissolving solid remains

constant during dissolution which is practically not possible.
To account for particle size ,Hixson and Crowell cube root law was
developed
Equation: w01/3 w1/3 = k .t
W=mass of drug remaining to be dissolvedat time t
K=dissolution rate constant

w0 =original mass of the drug.

2) Danckwert model:

Did not approve the existence of stagnant layer as said by

diffusion layer theory
Instead, said that turbulence existed in dissolution medium near
solid liquid interface. Due to agitation, mass of eddies or packets
reach the solid liquid interface and absorb the solute and carry
to bulk of solution

since solvent molecules are exposed to new solid surface each

time, the theory is called surface renewal theory
Equation: V.dC/dT= dm/dt = A ( Cs-Cb). (.D)1/2
m=mass of solid dissolved

3) Interfacial layer model

Film boundary

Cs
C

Bulk solution

Stagnant layer
In this model it is assumed that the reaction at solid surface is not
instantaneous i.e. the reaction at solid surface and its diffusion across the
interface is slower than diffusion across liquid film.
therefore the rate of solubility of solid in liquid film becomes the rate
limiting than the diffusion of dissolved molecules
equation : dm/dt = Ki (Cs C )

K = effective interfacial transport rate

constant

Biopharmaceutical Classification System

HighSolubility
(DoseVol.NMT
250mL)

LowSolubility
(DoseVol.>250
mL)

HighPermeability
(Fract.Abs.NLT
90%)

CLASS

CLASSII

e.g.Propranolol
metoprolol

e.g.piroxicam,
naproxen

LowPermeability
(Fract.Abs.<90%)

CLASSIII

CLASSIV

e.g.ranitidine
cimetidine

e.g.furosemide
hydrochlorothiazide

Mechanisms of dissolution
Wagner theory
Wagner interpreted the percent dissolved time plots derived from
the in vitro testing of regular tablets and capsules.
this concept relates to the apparent first order kinetics under
sink conditions to the fact that a percent dissolved value at time
t may be equivalent to the percent surface area generated at same
time.
Wagner utilized the following mathematical method to desribe
his theory for the dissolution kinetics of conventional tablets and
capsules assuming that surface area available for dissolution
decreases exponentially with time according to the equation;
S = S0 e-ks ( t-to)

-------------------------------->

Where So is the surface area at time to.

But we know that

dW/dt = K.S.Cs ------------------------(2)
Substitution for S from equation (1) ,we get
dW/dt = K.Cs.So.e-ks(t-to) ------------------------(3)
Integration of above equation gives
w= w0+K/ks Cs So [1-e-ks(t-to)] ------------------------(4)
If it is assumed that W is the amount in solution at infinite
time and M= K/ks.Cs.So,then
W = Wo+M and W-W = M e-ks(t-to) -------------------(5)
Applying log to both sides ,we get,
log (W - W) = log M ks/2.303( t to) ------------(6)
Where W - w is the amount of undissolved drug.

Zero order release:

Zero order refers to the process of constant drug release from a drug delivery
device such as oral osmotic tablets,transdermal systems,matrix tablets with low
soluble drugs
constant refers to the same amount of drug is released per unit time.
drug release from pharmaceutical dosage forms that donot disaggregate and
release the drug slowly can be represented by the following equation
W0 Wt = K .t ------------------- 1
W0 = initial amount of drug in the dosage form.
Wt = amount of drug in the pharmaceutical dosage form at time t
K = proportionality constant.
Dividing this equation by W0 and simplifying
ft = K0 .t
where ft = 1-(Wt/W0)
Ft = fraction of drug dissolved in time t and Ko the zero order release constnat.
A graphic of the drug dissolved fraction versus time will be linear.

Applications:
Zero order kinetic model can be used to describe the
drug dissolution of several types of modified release
pharmaceutical dosage forms, as in case of some trans
dermal systems ,as well as matrix tablets with low
soluble drugs, coated forms ,osmotic systems etc.

First order release:

If the amount of drug Q is decreasing at a
rate that is proportional to he amount of
drug Q remaining ,then the rate of release of
drug Q is expressed as
dQ/dt = -k.Q -----------------1
Where k is the first order rate constant.
Integration of above equation gives,
ln Q = -kt + ln Q0 ---------------- 2
The above equation is aslo expressed as
Q = Q0 e-kt ------------------------ 3

Inference
The pharmaceutical dosage forms following this
model, such as those drugs containing water
soluble drugs in porous matrices, release the drug
in a way that is proportional to the amount of drug
remaining in its interior.
This model has been also used to describe
absorption and elimination of drugs.

Higuchis mechanism.
Higuchi developed an equation for the release of drug from an ointment base and
applied it to diffusion of solid drugs dispersed in homogenous and granular
matrix devices.
Higuchi pointed out that to develop mathematical relationship for the release of
drugs from matrix tablets, two systems are considered.
a) first, when the drug particles are dispersed in homogeneous uniform matrix,
which acts as diffusional mechanism

b) When the drug particles are incorporated in granular matrix and released by
leaching action of penetrating solvent.

Higuchi demonstrated that during the initial release phase from a

spherical system until approximately 50% of drug content in vehicle
has been released,the square root of time behaviour is dominating and
then it depends on design of sustaine release system.
From Ficks first law,
dM/S.dt = dQ/dt = D.Cs/ h --------------------------(1)

As the drug passes out of a homogeneous matrix. the boundary of

drug( represented by the dashed vertical line), moves to the left by an
infinitesimal distance, dh. The infinitesimal amount ,dQ, of the drug
released because of this shift is given by
dQ = A.dh Cs dh -----------------------(2)
Substituting (2) in (1),we get
D .Cs /h = (A Cs) dh/dt --------------------(3)

The steps for derivation as given by higuchi are ,

2A Cs/2DCs h dh = dt ------------------ (4)
t = (2A Cs) h2/4DCs +C -------------------------(5)
The integration constant C,can be evaluated at t=0 at which
h=0.giving.
t = (2A Cs)h2/4DCs --------------------------------(6)
h = ( 4.D.Cs t / 2A Cs)1/2

------------------------------(7)

The amount of drug depleted per unit area of matrix .Q at

time t is obtained by integrating the equation (2) to yield,
Q = h.A -1/2 h.Cs ---------------------------- (8)
Substituting
Q = (D.Cs.t / 2A Cs)1/2 . (2A Cs)
or
Q = [D(2A-Cs)Cs.t]1/2 ------------------------------------- (9)

When the porosity and tortuosity of the matrix is concerned, the equation
is modified as ; ( for heterogeneous type matrix)
Q = [D/t( 2A - Cs)Cs.t]1/2 -------------------------------- (10)
The instantaneous rate of release of a drug at time t is obtained by
differentiating equation (10 ) to yield,
dQ / dt = [ D(2 A Cs)Cs/t]1/2 ------------------------ (11)
Ordinarily A is much greater that Cs and hence equation ( 9 ) reduces to
Q = (2.A.D.Cs.t)1/2 --------------------------- (12)
And hence equation ( 11) becomes .
dQ/dt = (A.D.Cs/2t)1/2 ---------------------------- (13)
Equation (12), indicates that the amount of drug released is proportional to
square root of A , the total amount of drug in unit volume of matrix; D. the
diffusion coefficient of the drug in matrix; Cs is the solubility of drug in
polymeric matrix and t the time.
Graph : graph is plotted between % drug release and square root of time.

Applications:
Higuchi describes the drug release as a diffusion
process based on Ficks law, square root time
dependent .
This model is useful for studying the release of
water soluble and poorly soluble drugs from variety
of matrices ,including solids and semi solids.

Hixon-crowell cube root law

HixonCrowellcuberootequationfordissolutionkineticsis
basedonassumptionthat:
a) Dissolutionoccursnormaltothesurfaceofthesolute
particles
b) Agitationisuniformallovertheexposedsurfacesandthere
isnostagnation.
c) Theparticleofsoluteretainsitsgeometricshape
The particle (sphere) has a radius r and surface
area 4 r2
Through dissolution the radius is reduced by dr
and the infinitesimal volume of section lost is
dV = 4 r2 . dr

------------------(1)

.dV, can be setequal to dW,

.dV = k.S.Cs.dt --------------------------- (5)
Equations (2) and (3) are substituted into equation (5) , to yield
-4 N r2 . dr = 4 N r2 . K .Cs .dt -------------(6)
Equation 6 is divided through by 4 N r2 to give
- . Dr = k Cs.dt -------------------------(7)
Integration with r = ro at t= 0produces the expression
r = ro kCs .t/ -----------------------------(8)
The radius of spherical particles can be replaced by the weight of N
particles by using the relationship of volume of sphere
W = N (/6)d3 ----------------------------(9)
Taking cube root of the equation (9) yield,
W

1/3

= [ N (/6)]1/3. d. ----------------------------(10)

The diameter d from equation (10) ,is substituted for 2r into equation 8
to give

W01/3 - W1/3 =k t ------------------(11)

Where k = [ N (/6)]1/3.2 k Cs/.
Wo is the original weight of drug particles .
Equation (11) is known as Hixson- Crowell cube root law ,and k is the
cube root dissolution rate constant.
Futher dividing euation (11) by w01/3 and simplifying,we get
( 1 ft )1/3 = k t
Where ft = 1-(w/w0) and it represents the drug dissolved fraction at time
t
And k is release constant.

Korsmeyer and peppas model

Also called as power law
To understand the mechanism of drug release
and to compare the release profile differences
among these matrix formulations ,the percent
drug released time versus time were fitted using
this equation
Mt / M = k. tn
Mt / M = percent drug released at time t
K= constant incorporating structural and
geometrical characteristics of the sustained

Exponent n of the power law and drug release mechanism

from polymeric controlled delivery systems of different geometry

Exponent n Cylinder
slab

Sphere

DR
mechanis
m

0.5

0.45

0.43

0.5 < n <

1.0

0.45 < n
< 0.89

0.43 < n
< 0.85

Fickian
diffusion
Anomalou
s
transport

0.89

0.85

1.0

Case-II
transport

Applications:
1. This equation can be applied to any kind of delivery
system
2. This model is generally used to analyze the release
of pharmaceutical dosage forms, when the release
mechanisms is not well known or when more than
one type of release phenomena could be involved.

Weibull Model

It expresses the accumulated fraction of the drug in solution

at time by following equation:
m = 1- exp [-(t Ti )b /a ]
m = accumulated fraction of the drug at time t
a = scale parameter
Ti = location parameter ( represents lag time before the onset
of dissolution or
release process and in most cases will be
zero )
b = shape parameter.

The equation may be rearranged into:

log[ -ln(1-m)]= b log ( t-Ti )- log a
graph: -ln(1-m) vs t gives linear relation and the slope is equal to
shape parameter

CONCLUSION
The Quantitative interpretation of the values obtained in
dissolution assays is easier using mathematical equations which
describe the release profile in function of some parameters related
with the pharmaceutical dosage forms.
The release models with the major appliance and the best
describing drug release phenomena are in general ,the Higuchi
model, Zero order model and Korsmeyer- Peppas model. the
Higuchi and Zero order models represent two limit cases in the
transport and drug release phenomena and the Korsmeyer-Peppas
model can be a decision parameter between these two models
while the Higuchi model has a larger application in polymeric
systems, the zero order model becomes ideal to describe coated
dosage forms or membrane controlled dosage forms.

References
1) Remington's The science and
practice of pharmacy 21st edition page
no 672-685.
2) A Text book of Applied Bio
pharmaceutics and pharmacokinetics,
by Leon Shargel,andrew , 4 th edition
,page no 131-195.
3) Text book of Bio pharmaceutics and
pharmacokinetics ,by V.Venkateshwarlu
page no.32-55.
4) Text book of Bio pharmaceutics and
pharmacokinetics, by Brahmankar.page