28977662 Modeling of Dissolution Data

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Modeling of dissolution data

Presented by:

NAKAT ANUP RAMESH

1st semester,

Guided By: Dr.A.R.MadgulakarDepartment Of Pharmaceutics,

AISSMS COLLEGE OF PHARMACY, PUNE

1



Contents

y Introduction.

y Zero Order Drug release.

y First Order Drug release.

y Weibull model

y Higuchi model.y Hixon - Crowell Cube Root model.

y Korsemeyer - Peppas equation.

y Baker - lonsdale model

y

Hopfenberg modely Similarity factor.

y Conclusion.

y References.

2



Dissolution

y Definition-

y It is a process in which a solid substance solubilizes in agiven solvent i.e. Mass transfer from the solid surface to theliquid phase.

y Drug dissolution in an aqueous medium is an important

condition of systemic absorption.

y Dissolution is the rate controlling step in the absorption of drug with low solubility.

3



4



5

Zero Order release kinetics

y Same amount of drug is released per unit time.

y Drug dissolution from pharmaceutical dosage form that donot disaggregate and release the drug slowly,

Can be given by following equation,

Q= Qo + Kot

Where,

Q =amount of drug released or dissolved.

Qo=initial amount of drug in solution.

Ko=zero order drug release constant .



Zero Order Drug Release

y Topical drug delivery system.

y Transdermal drug delivery system.

y Implantable depot system.

y Oral control release systems.

y Oral osmotic tablets.

y Matrix tablet with low solubility drug.

6



Zero Order release kinetics

y As initial amount of drugin solution is usually zero,

y So equation becomes,

Q= Kot

Hence to represent zeroorder drug release, Plot of % Cumulative drugRelease Vs time isplotted.

Zero order drug release

0

1

2

3

4

5

6

0 0.2 0.4 0.6 0.8 1 1.2t ime in hr

% c

u m u l a t i v e d r u g r e l e a s e

time in hr

Linear (time in hr)

7



To obtain good correlation between in vitro- in vivodissolution rate, In vitro is always carried out under sinkcondition.

This can be achieved by:

Bathing the dissolving solid by fresh solvent from time totime.

Increasing the volume of dissolution fluid.

Adding a Water miscible solvent such as alcohol to thedissolution fluid.

By adding selected adsorbents to remove the dissolveddrug.

8



First Order Drug Release

y Sustained release dosage form.y Release rate depends on concentration of

drug.

y Dissolution is said to be under nonsink condition.

yRelease rate equation for first order kineticscan be given by,

Qt=Q0e-Kt

Or

In(Qt/Q0)=kt

9



First Order Release Kinetics

y Hence to illustraterelationship betweendrug release & time, plotof log of % drug

remaining Vs time isplotted.

First order dr ug release

1.82

1.84

1.86

1.88

1.9

1.92

1.94

1.96

1.98

2

0 1 2 3 4 5

time in hr

l o g o f % d r u g r e m a i n

i n g

log of %drug

remaining

10



If we plot a graph betweenconc. Of dissolved drug

Vs. time is plotted.

Fist order dissolution andZero order dissolutionunder sink and nonsinkcondition are compared

Dissolution rate under sink and nonsink

condition

0

10

20

30

40

50

60

0 2 4 6

time in hr

c o n c e n t r a t i o n

o f

d i s s o l v e d

d r u g

Zero order

dissolution

under sink

condition

Fir st order

dissolution

under non-sink

condition

11



Weibull Model

This model can successfully applied to all kinds of dissolution

curve. This model express the accumulated fraction of the drug m,

in solution at time t,

` Equation can be given by ,

a- Scale parameter define as time scale of process.Ti-location parameter-lag time before the onset o the

dissolution process.

b- shape parameter-characterize the curveexponential (b=1)sigmoid, s-shape (b>1)parabolic with higher initial slope (b<1)

12



y Hence plot of, logarithmof the dissolved amountof drug Vs logarithm of time.

Weibu odel

0

1

2

3

4

5

6

0 5 10

log of time

l o g

o f d i s s o l v e d

m o u n t o f

d r u g

Di ovl

amou of dr ug

13



Disadvantage:

It does not characterize the dissolution kineticproperties of the drug.

Not any single parameter related with dissolution rate of drug

14



Higuchi Equation

Explained release of water soluble & poorly water solubledrug from variety of matrixes including semisolid & solid.

Higuchi equation is mainly followed, when releaseof drug depend upon its diffusion.

Equation can be given by,

Mt / M0 = kt1/2

Mt = amount of drug release in time t.

M0 =Initial amount of drug release.t= time required.

15



16



y Hence plot of % cumulative drugreleased Vs square rootof time is plotted. Hi

uc ¡ i Equ ¢

£

i ¤ n

0

20

40

60

80

100

0 1 2 3

SQRT

¥

c u m u l

¦

§

i v e

¨

r u

©

r e l e a s e

% cumul

d ug

l

17

Hi uc i Equati n



Hixon Crowell cube root law

The geometric shape of the dosage form stays constant asdissolution is occurring then the dissolution occurs inplane that are parallel to the dosage form surface.

The rate of dissolution is based on the cube root of the weight of the particle.

` Equation can be given by,

M01/3-M1/3= kt

Where,M0=original mass of drug particles.M =mass of particle undissolved.t =time required.

18



y Hence plot of cube rootof mass of drugdissolved Vs time isplotted.

Hixs n-C wel cube t law

0

1

2

3

4

5

0 2 4 6 8

time in

c u b e

t

f m a s s f

u

i s s

l v e

c

be r

t

ass

!

r

"

! #

ss

l$

e!

19

Hi n ±Cr well cube r t law



Korsemeyer-Peppas equation

y Model for understanding release behavior of drug from hydrophilic matrix.


Mt/M = Ktn

Mt = amount of drug release in time t.

M= amount of drug release in time .k = constant related to structural & geometrical factors.

n = release exponent related to release mechanism used forelucidation of drug release mechanism.

20




y Hence plot of logcumulative% release Vslog time is plotted.

y This plot explains thediffusion mechanism by which drug diffuses fromdosage form.

y n value indicates therelease mechanism.

Korsmeyer-Peppas equation

y =% .

% 7

&

x +% .

%

' & (

R

)

=

0

.

1

7

' 1

0

0

.2

%

% .

2

'

'

.

2

0 0

.' 0

.( 0

.& 0

.3

log of time

l o g o f

4

5 u m u l a t i v e

6

r u g

r e l e a s e

l7 8

7

f 9

c@ A @

lB

C

D

E F

G

H @

8

H

F

lF B I F

P D Q

F B

H (l

7 8

7

f 9

c@ A @

lB

C

D

E F

G

H @

8

H

F

lF B I F

R

21




n lu Di usion c nis

<0.5 Qu si icki n

0.5 Ficki n

0.5<n<1 Ano lous

1 Non icki n c s 2

n>1 Non icki n sup r c s 2

22



Baker-Lonsdale Model

y Developed from the Higuchi model.

y Describes the Drug controlled released from Sphericalmatrix.


y If matrix is heterogeneous

y Matrix porosity can be describe by:

23



y Hence plot of left side of

equation Vs. time is plotted.

Bake r-Lonsdale model

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0 1 2 3 4 5 6

time in S

r

l e f t s i d e o f e q u a t i o n

24



Hopfenberg Model

y The release of drug from surface-eroding devise with

several geometries was analysed by Hopfenberg.

y He describes the drug released from slabs, spheres, infinitecylinders showing heterogeneous erosion.

Mt-amount of drug dissolved in time t

Ko-erosion rate constant.

Co-initial conc. Of drug in matrix.

ao-initial radius of sphere or cylinder.The value of n is 1,2,3 for slab , cylinder and and sphere

respectively.

25



Modified form of this model is developed in that the lagtime (l)is placed in the beginning of the drug release frompharmaceutical dosage form.

In the rate limiting step of drug release the matrix erosionis done. So this equation does not influence the matrix

erosion.

26



y Of all these above mentioned models, the kinetic modelthat best fits the dissolution data was evaluated by comparing the correlation coefficient ( r ) values obtainedin various models, the model that gave higher r value isconsidered as best fit model.

27



Other release parameter

y tx%, Sampling time and Dissolution efficiency are theparameter used to characterise drug release and givesinformation of drug release.

y tx%-time necessary to the release of a determined

percentage of drug.y Sampling time-amount of drug dissolved in that time.

y Dissolution efficiency-

28



Release prof ile comparision

y Method that compare the drug release

1)Statistical method.a) Single time point dissolution.

b) Multiple time point dissolution.

2)Model Independent method.a) Ratio test procedure.b) Pair wise procedure.

3)Model dependent method.

29



1)Statistical method.

` The method is based on in the analysis of variance canbe distinguished in one-way analysis of variance(ANOVA) and multivariate analysis of variance

(MANOVA).

` It is the difference between the means of two drugrelease data set in single time point dissolution or inmultiple time point dissolution.

30



2) Model independent method.a) Ratio test procedure-

It is the relation between parameters obtain from releaseassay of test of the reference formulation and the release

assay of test product at same time.

b) Pair wise procedure-

This includes:

1)Difference Factor.2) Similarity factor.

31



1)Difference factor.

It is the percent error between two curves overall time points, denoted by f1.

n-sampling number.

Rj-% dissolved of the reference product.

Tj-% dissolved of the test product.

y The percent error is zero when test and reference profile areidentical.

32



2)Similarity factor-

y I

t is logarithmic transformation of the sum- squared errordifference between the test and reference product over alltime points.

y It is used to denote similarity between two profile, denotedby f2.

y It is fits results between 0-100

` This method is more adequate to dissolution profilecomparisons when more than 3 or 4 dissolution timepoints are available.

33



` FDA has set a standard of f1 value between 0 to 15 & f2 valuebetween 50 to 100 shows similarity of the dissolutionprofile.

` To compare dissolution treatment effect the 12 individualdosage units should take.

` Model independent method are very easy to apply.

34



Conclusion

Hence this conclusion can be drawn that the in

vitro drug release kinetics is necessary step to

be done to study the drug release patternsfrom the dosage form.

The graphs obtained from kinetic data states

the efficiency of drug release from the dosage form.

35



y Martins physical pharmacy &pharmaceutical sciences,fifth edition, Patrick J. sinko,lippincott Williams & Wilkinspublication,337-349.

y

Kinetic analysis of dissolution data of ambroxolhydrochloride sustained release matrix tablet,IJPS,sept -oct 2006,594-598.

y Modeling and comparison of dissolution profiles European

Journal of Pharmaceutical Sciences 13 (2001) ,123-133

36

Ref er ences



efere ces

` Evaluation of mathematical models describing drugrelease from lipophilic matrices , journal of controlledrelease, august 2006,224-228.

y

Compaction properties, drug release kinetics and frontsmovement studies from matrices combining mixtures of swellable and inert polymers, International Journal of Pharmaceutics, September 2007, 6173.

y www.dissolutiontech.com/DTresour/899art/dis

sprofile.html

37



References

y Mathematical evaluation of in vitro release profiles

of hydroxypropylmethylcellulose matrix tablet containingcarbamazepine associated to b-cyclodextrin, EuropeanJournal of Pharmaceutics and Biopharmaceutics ,May2004, 177179.

38



Thank you !!!

39

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28977662 Modeling of Dissolution Data

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