T H EO R I E S AND M EC H A N IS M S O F

DISSOLUTION TESTING

By
D.Narender
M.ph
arma
cy 1
DEPARTMENT Os tF PHARMACEUTICS
UNIVERSITY C O L L E G E O FSeme
PHARMACEUTICAL S C I E N C E S
ster
KAKATIYA UNIVERSITY
 OUT LINE
 Definitions
 Theories of Dissolution
 Mechanisms of drug release
 Wagnertheory
 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 overcome the cohesive forces present in
solid
Drug Dissolution Process
 THEORIES OF DISSOLUTION:
3 Theories
1) Diffusion layer model / Film theory
2) Danckwert’s 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

S 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
C s – C b = 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
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. Du e 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). (ү.D)1/2
m=mass of solid dissolved
Ү = rate of surface renewal.
 3) Interfacial layer model

Film boundary
Cs
S
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

High Solubility Low Solubility

(Dose Vol. NMT (Dose Vol. >250
250 mL) mL)

High Permeability CLASS І CLASS II

(Fract. Abs. NLT
90%) e.g. Propranolol e.g. piroxicam,
metoprolol naproxen

Low Permeability CLASS III CLASS IV

(Fract. Abs.
<90%) e.g. ranitidine e.g. furosemide
cimetidine 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 = S 0 e -ks ( t-to) > 1

Where So is the surface area at time to.

B ut we know that
dW/dt = K . S . C s (2)
Substitution for S from equation (1) ,we get
dW/dt = K.Cs.So.e - k s ( t - t o ) ------------------------
(3)
Integration of above equation gives
w= w 0 +K/ks C s 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

W 0 – W t = K .t ------------------- 1
W 0 = initial amount of drug in the dosage form.
W t = amount of drug in the pharmaceutical dosage form at time t
K = proportionality constant.
Dividing this equation by W0 and
simplifying ft = K 0 .t
where ft = 1-(Wt/W 0 )
F t = 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 Q 0
---------------- 2
The above
Q equation
= Q 0 e - k t is aslo expressed as 3
Because ln=2.3 log, equation (2) becomes
log Q = log Q 0 + kt/2.303 ---------------------(4)
This is the first order equation
A graphic of the logarithm of released amount of drug versus time
will be linear.
 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.
Higuchi’s 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 . C s / 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 , d Q, of the
drug released because of this shift is given by
d Q = A.dh – ½ C s dh -----------------------(2)
Substituting (2) in (1),we get
D . C s / h = (A – ½ 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)
This is known as higuchi equation.
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,

d Q / dt = ½ [ D(2 A – Cs)Cs/t]1/2 ------------------------ (11)

Ordinarily A is m u c h greater that C s 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; C s 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
Hixon Crowell cube root equation for dissolution kinetics is based on assumption that:
a) Dissolution occurs normal to the surface of the solute particles
b) Agitation is uniform all over the exposed surfaces and there is no stagnation.
c) The particle of solute retains its geometric shape
The particle (sphere) has a radius r and surface area 4Π r 2
Through dissolution the radius is reduced by dr and the infinitesimal volume of
section lost is
dV = 4Π r 2 . dr ------------------(1)
For N such particles,the volume loss is
dV = 4N Π r2 dr (2) The surface of N
particles is
S = 4 N Π r2
-(3)
Now ,the infinitesimal weight change as
represented by he noyes –whitney law
,equation is
ρ.dV, can be setequal to dW,
ρ.dV = k . S . C s . d t - (5)
Equations (2) and (3) are substituted into equation (5) , to yield
-4 ρ N Π r 2 . dr = 4 N Π r 2 . K . C s .dt -------------(6)
Equation 6 is divided through by 4 N Π r2 to give
- ρ . Dr = k Cs. dt -(7)
Integration with r = ro at t= 0produces the expression
r = ro – k C s .t/ ρ (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 ρ(Π/6)d 3 -(9)
Taking cube root of the equation (9) yield,
W 1/3 = [ N ρ(Π/6)] 1/3 . d. ----------------------------(10)
The diameter d from equation (10) ,is substituted for 2r into equation 8
to give
 W0 -W =k t ------------------(11)
1/3 1/3

Where k = [ N ρ(Π/6)]1/3.2 k C s / ρ .
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 w0 and simplifying,we get
1/3

( 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
M t / M∞ = k . t n

Mt / M∞ = percent drug released at time t

K= constant incorporating structural and geometrical characteristics of
the sustained release device.
n =exponential which characterizes mechanism of drug release
 Exponent n of the power law and drug release mechanism
from polymeric controlled delivery systems of different geometry

Exponent Cylinder DR
n Sphere mechanism
slab

0.5 0.45 0.43 Fickian

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

1.0 0.89 0.85 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 –T i )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” 21 s t 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 no.15-48.
5)Text book of Dissolution ,Bio availability and Bio equivalence, by
hammed m.abdoue.page no 337-354.
6)Pharmaceutical Dissolution Testing ,by Umesh . V. Banakar, pg.no 1-
100,pg no 200- 350
7) Text book of Martins, physical pharmacy and pharmaceutical
sciences. page no 337-354.
8)Encyclopedia of pharmaceutical technology, by J a m e s Swarbrick,
J a m e s C.Boylan volume 4 page no 121-126
9)European Jou rn al of Pharmaceutical sciences 13 (2001) page no.123 –
133.