Modeling of dissolution

Presented by: NAKAT ANUP RAMESH 1st semester,

data

Guided By: [Link] Department Of Pharmaceutics, AISSMS COLLEGE OF PHARMACY, PUNE

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Contents

Introduction. Zero Order Drug release. First Order Drug release. Weibull model Higuchi model. Hixon - Crowell Cube Root model. Korsemeyer - Peppas equation. Baker - lonsdale model Hopfenberg model Similarity factor. Conclusion. References.
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Dissolution
Definition It is a process in which a solid substance solubilizes in a

given solvent i.e. Mass transfer from the solid surface to the liquid phase.
Drug dissolution in an aqueous medium is an important

condition of systemic absorption.

Dissolution is the rate controlling step in the absorption of

drug with low solubility.

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Zero Order release kinetics

Same amount of drug is released per unit time.

Drug dissolution from pharmaceutical dosage form that do

not 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 .
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Zero Order Drug Release

Topical drug delivery system. Transdermal drug delivery system. Implantable depot system. Oral control release systems.

Oral osmotic tablets.

Matrix tablet with low solubility drug.
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Zero Order release kinetics

As initial amount of drug

in solution is usually zero,

So equation becomes,
Zero order drug release

Q= Kot Hence to represent zero order drug release, Plot of % Cumulative drug Release Vs time is plotted.

% cumulative drug release

5 4 3 2 1 0 0 0.2 0.4 tim e 0.6 in hr 0.8 1 1.2

time in hr Linear (time in hr)

To obtain good correlation between in vitro- in vivo dissolution rate, In vitro is always carried out under sink condition.

This can be achieved by:

Bathing the dissolving solid by fresh solvent from time to time. Increasing the volume of dissolution fluid. Adding a Water miscible solvent such as alcohol to the dissolution fluid. By adding selected adsorbents to remove the dissolved drug.
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First Order Drug Release

Sustained release dosage form. Release rate depends on concentration of

drug. Dissolution is said to be under nonsink condition. Release rate equation for first order kinetics can be given by,
Qt=Q0e Or In(Qt/Q0)=kt
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-Kt

First Order Release Kinetics

Hence to illustrate

log of %drug remaining

relationship between drug release & time, plot of log of % drug remaining Vs time is plotted.

First order drug release

2 1.98 1.96 1.94 1.92 1.9 1.88 1.86 1.84 1.82 0 1 2 3 4 5 time in hr

log of %drug remaining

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concentration of dissolved drug

If we plot a graph between conc. Of dissolved drug Vs. time is plotted.

Fist order dissolution and Zero order dissolution under sink and nonsink condition are compared

Dissolution rate under sink and nonsink condition

60 50 40 30 20 10 0 0 2 4 6 time in hr Zero order dissolution under sink condition First order dissolution under non-sink condition

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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 curve exponential (b=1) sigmoid, s-shape (b>1) parabolic with higher initial slope (b<1)
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 Hence plot of, logarithm

log of dissolved amount of drug

Weibull model
6 5 4 3 2 1 0 0 5 log of time 10 Dissovled amount of drug

of the dissolved amount of drug Vs logarithm of time.

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Disadvantage: It does not characterize the dissolution kinetic properties of the drug. Not any single parameter related with dissolution rate of drug

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Higuchi Equation
Explained release of water soluble & poorly water soluble

drug from variety of matrixes including semisolid & solid. of drug depend upon its diffusion.

Higuchi equation is mainly followed, when release

Equation can be given by,

Mt / M0 = kt

1/2

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

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Higuchi Equation
Hence plot of %

cumulative drug released Vs square root of time is plotted.

% cumulative drug release
100 80 60 40 20 0 0

Higuchi Equation

% cumulative drug release

1 SQRT

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Hixon Crowell cube root law

The geometric shape of the dosage form stays constant as

dissolution is occurring then the dissolution occurs in plane 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.
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Hixon Crowell cube root law

Hence plot of cube root

cube root of mass of drug dissolved

of mass of drug dissolved Vs time is plotted.

Hixson-Crowel cube root law

5 4 3 2 1 0 0 2 4 time in hr 6 8 cube root of mass of drug dissolved

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Korsemeyer-Peppas equation
Model for understanding release behavior of

drug from hydrophilic matrix.

Equation can be given by,

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 for elucidation of drug release mechanism.
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Korsemeyer-Peppas equation
Hence plot of log

cumulative % release Vs log time is plotted.

Korsmeyer-Peppas equation
log of % cumulative drug release
2.5 2 1.5 1 0.5 0 0 0.2 0.4 log of tim e 0.6 0.8 log of % cumulative drug release Linear (log of % cumulative drug release) y = 1.176x + 1.1264 R2 = 0.9729

This plot explains the

diffusion mechanism by which drug diffuses from dosage form.

n value indicates the

release mechanism.
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Korsemeyer-Peppas equation
n value
<0.5 0.5 0.5<n<1 1 n>1

Diffusion mechanism
Quasi fickian Fickian Anomalous Non fickian case 2 Non fickian super case 2
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Baker-Lonsdale Model
Developed from the Higuchi model. Describes the Drug controlled released from Spherical

matrix. Equation can be given by,

If matrix is heterogeneous

Matrix porosity can be describe by:

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Baker-Lonsdale model
5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0 1 2 3 tim e in hr 4 5 6

equation Vs. time is plotted.

left side of equation

Hence plot of left side of

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Hopfenberg Model
The release of drug from surface-eroding devise with

several geometries was analysed by Hopfenberg.

He describes the drug released from slabs, spheres, infinite

cylinders 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.
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 Modified form of this model is developed in that the lag

time (l)is placed in the beginning of the drug release from pharmaceutical dosage form.

In the rate limiting step of drug release the matrix erosion

is done. So this equation does not influence the matrix erosion.

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 Of all these above mentioned models, the kinetic model

that best fits the dissolution data was evaluated by comparing the correlation coefficient ( r ) values obtained in various models, the model that gave higher r value is considered as best fit model.

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Other release parameter

tx%, Sampling time and Dissolution efficiency are the

parameter used to characterise drug release and gives information of drug release.
tx%-time necessary to the release of a determined

percentage of drug. Sampling time-amount of drug dissolved in that time. Dissolution efficiency-

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Release profile comparision

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.

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1)Statistical method.

The method is based on in the analysis of variance can be distinguished in one-way analysis of variance (ANOVA) and multivariate analysis of variance (MANOVA).

It is the difference between the means of two drug release data set in single time point dissolution or in multiple time point dissolution.

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2) Model independent method. a) Ratio test procedureIt is the relation between parameters obtain from release assay of test of the reference formulation and the release assay of test product at same time. b) Pair wise procedureThis includes: 1)Difference Factor. 2) Similarity factor.

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1)Difference factor. It is the percent error between two curves all time points, denoted by f1.

over

n-sampling number. Rj-% dissolved of the reference product. Tj-% dissolved of the test product.
The percent error is zero when test and reference profile are

identical.
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2)Similarity factor

It is logarithmic transformation of the sum- squared error difference between the test and reference product over all time points.

It is used to denote similarity between two profile, denoted

by f2. It is fits results between 0-100

This method is more adequate to dissolution profile

comparisons when more than 3 or 4 dissolution time points are available.

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 FDA has set a standard of f1 value between 0 to 15 & f2 value

between 50 to 100 shows similarity of the dissolution profile.

To compare dissolution treatment effect the 12 individual

dosage units should take.

Model independent method are very easy to apply.

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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 patterns from the dosage form.
The graphs obtained from kinetic data states

the efficiency of drug release from the dosage form.

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References
Martins physical pharmacy &pharmaceutical sciences,

fifth edition, Patrick J. sinko,lippincott Williams & Wilkins publication,337-349.

Kinetic analysis of dissolution data of ambroxol

hydrochloride sustained release matrix tablet,IJPS,septoct 2006,594-598.

Modeling and comparison of dissolution profiles European

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

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References
Evaluation of mathematical models describing drug

release from lipophilic matrices , journal of controlled release, august 2006,224-228.

movement studies from matrices combining mixtures of swellable and inert polymers, International Journal of Pharmaceutics, September 2007, 6173.

Compaction properties, drug release kinetics and fronts

[Link]/DTresour/899art/dis

[Link]

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References
Mathematical evaluation of in vitro release profiles

of hydroxypropylmethylcellulose matrix tablet containing carbamazepine associated to b-cyclodextrin, European Journal of Pharmaceutics and Biopharmaceutics ,May 2004, 177179.

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Thank you !!!

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