Professional Documents
Culture Documents
pharmaceutics , formulation
and processing
ABDUL MUHEEM,
M.Pharma(1st sem)
Deptt. of Pharmaceutics,
Faculty of Pharmacy,
Jamia Hamdard
Email: muheem.abdul985@gmail.com
Optimization makes the perfect formulation &
reduce the cost
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The term Optimize is defined as to make perfect , effective , or
functional as possible.
It is the process of finding the best way of using the existing resources
while taking in to the account of all the factors that influences decisions in
any experiment
Traditionally, optimization in pharmaceuticals refers to changing one
variable at a time, so to obtain solution of a problematic formulation.
In the other word we can say that quantitate a formulation that has
been qualitatively determined.
Its not a screening techniques
Why Optimization is necessary?
Innovat
ion &
efficacy
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TERMS USED
FACTOR: It is an assigned variable such as concentration ,
Temperature etc..,
Quantitative: Numerical factor assigned to it
Ex; Concentration- 1%, 2%,3% etc..
Qualitative: Which are not numerical
Ex; Polymer grade, humidity condition etc
LEVELS: Levels of a factor are the values or designations
assigned to the factor
FACTOR LEVELS
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Concentration 1%, 2%
RESPONSE: It is an outcome of the experiment.
It is the effect to evaluate.
Ex: Disintegration time etc..,
EFFECT: It is the change in response caused by varying the
levels
It gives the relationship between various factors & levels
INTERACTION: It gives the overall effect of two or more
variables
Ex: Combined effect of lubricant and glidant on hardness of the
tablet
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Optimization parameters
Optimization parameters
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Optimization parameters
VARIABLES
Independent Dependent
Formulating Processing
Variables Variables
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Optimization Parameters
1.Problem types:
Constraints
Example-Making hardest tablet but should disintegrate within 20 mins
( Constraint)
Unconstraint
Example: Making hardest tablet ( Unconstraint)
2. Variables:
Independent variable- E.g. - mixing time for a given process step.
granulating time.
Dependent variables, which are the responses or the characteristics
of the in process material Eg. Particle size of vesicles, hardness of the
tablet.
From response surface only, we find the points which will give
desirable value of the response.
Example of dependent & independent variables
Tablet formulation
X3 Disintegrant level Y3 Dissolution
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Classic optimization
It involves application of calculus to basic problem for
maximum/minimum function.
Limited applications
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Response surface representing the relationship between the independent variables
X1 and X2 and the dependent variable Y.
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GRAPH REPRESENTING THE RELATION BETWEEN
THE RESPONSE VARIABLE AND INDEPENDENT
VARIABLE
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We can take derivative ,set it equal to zero & solve for x to obtain the
maximum or minimum
Y = f(X1 , X2)
The above function is represented by contour plots on which the axes
represents the independent variables x 1& x2
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Statistical design
Techniques used divided in to two types.
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TYPES OF EXPERIMENTAL DESIGN
Completely randomized designs
Randomized block designs
Factorial designs
Full
Fractional
Response surface designs
Central composite designs
Box-Behnken designs
Three level full factorial designs
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Completely randomized Designs
These designs compares the values of a response variable
based on different levels of that primary factor.
For example ,if there are 3 levels of the primary factor with
each level to be run 2 times then there are 6 factorial possible
run sequences.
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Homogenous fractional
Useful when large number of factors must be screened
Mixed level fractional
Useful when variety of factors needed to be evaluated for
main effects and higher level interactions can be assumed
to be negligible.
Ex-objective is to generate a design for one variable, A, at 2
levels and another, X, at three levels , mixed &evaluated.
Box-hunter
Fractional designs with factors of more than two levels
can be specified as homogenous fractional or mixed level
fractional
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Plackett-Burman
Latin square
They are special case of fractional factorial design where there is
one treatment factor of interest and two or more blocking factors
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Signal-to-Noiseratios(S/N),whicharelogfunctionsofdesiredoutput,
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WecanusetheLatinsquaretoallocatetreatments.Iftherowsofthesquare
representpatientsandthecolumnsareweeks,thenforexamplethesecond
patient,intheweekofthetrial,willbegivendrugD.Noweachpatientreceives
allvedrugs,andineachweekallvedrugsaretested.
A B C D E
B A D E C
C E A B D
D C E A B
E D B C A
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Response surface designs
This model has quadratic form
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Two most common designs generally used in this
response surface modeling are
Central composite designs
Box-Behnken designs
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o
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Box-Behnken design
Box-Behnken designs use just three levels of each factor.
In this design the treatment combinations are at the midpoints of edges of
the process space and at the center. These designs are rotatable (or near
rotatable) and require 3 levels of each factor
These designs for three factors with circled point appearing at the origin and
possibly repeated for several runs.
Its alternative to CCD.
The design should be sufficient to fit a quadratic model , that justify equations
based on square term & products of factors.
Y= b0+b1x1+b2x2+b3x3+b4x1x2+b5x1x3+b6X2X3+b7X12 +b8X22+b9X32
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A Box-Behnken Design
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Three-level full factorial designs
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V. APPLIED OPTIMIZATION METHODS
Thereareseveralmethodsusedforoptimization.Theyare
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Evolutionary operations:
Widely used method(mostly for tablets)
Technique is well suited to production situations(formulation & process)
Small changes in the formulation or process are made (i.e., repeats the
experiment so many times) & statistically analyzed whether it is
improved.
Simplex is a geometric figure that has one more point than the number of
factors.
The strategy is to move towards a better response by moving away from worst
response.
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5
7
2
Lactose 3 Stearic acid
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A simplex lattice of four component is shown by 15 formulation
4 formulations of each component A,B,C&D
4 formulation of 1/3 mixtures of three components ABC, ABD, ACD, & BCD.
(ABCD)
100% pure component is not taken as un acceptable
formulation is obtained, thus vertices does not represent
the pure single substance , therefore a transformation is
required.
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Example
Optimization of a tablet.
phenyl propranolol(active ingredient)-kept constant
X1 disintegrate (corn starch)
X2 lubricant (stearic acid)
X1 & X2 are independent variables.
Dependent variables include tablet hardness,
friability ,volume, in vitro release rate e.t.c..,
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Polynomial models relating the response variables to
independents were generated by a backward stepwise
regression analysis program.
+ B7X12+B8X12X22
Y Response
Bi Regression coefficient for various terms containing
the levels of the independent variables.
X Independent variables
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EXAMPLE OF FACTORS IN THIS FACTORIAL
DESIGN
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EXAMPLE OF FULL FACTORIAL EXPERIMENT
Factor Stearate Drug Starch Response
combination Thickness
Cm*103
(1) _ _ _ 475
a + _ _ 487
b _ + _ 421
ab + + _ 426
c _ _ + 525
ac + _ + 546
bc _ + + 472
abc + + + 522
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Constrained optimization problem is to locate the levels of
stearic acid(x1) and starch(x2).
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GRAPH OBTAINED BY SUPER IMPOSITION OF TABLET
HARDNESS & DISSOLUTION
Contour plots for the Lagrangian method: feasible solution space indicated by
crosshatched area
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Optimizing values of stearic acid and strach as a function of restrictions on
tablet friability: (A) percent starch; (B) percent stearic acid
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Search methods (RSM) :
It takes five independent variables into account and is
computer-assisted.
It is defined by appropriate equations.
Response surface methodology is used to determine the
connection between different explanatory variables
(independent variables) and one or more of the response
variables.
Persons unfamiliar with mathematics of optimization & with
no previous computer experience could carryout an
optimization study.
THE SEARCH METHODS
1. Select a system
2. Select variables:
a. Independent
b. Dependent
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.Incanonicalanalysisorcanonical
reduction,second-orderregression
equationsarereducedtoasimpler
formbyarigidrotationandtranslation
oftheresponsesurfaceaxesin
multidimensionalspace,as
foratwodimensionsystem.
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Forms of Optimization techniques:
3. Combination of both.
Sequential Methods:
Also referred as the "Hill climbing method".
Initially small number of experiments are done, then research is done using the
increase or decrease of response.
Thus, maximum or minimum will be reached i.e. an optimum solution.
Simultaneous Methods:
Involves the use of full range of experiments by an experimental design.
Results are then used to fit in the mathematical model.
Maximum or minimum response will then be found through this fitted model.
Example:- Designing controlled drug delivery
system for prolonged retention in stomach required
optimization of variables like
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ArtificialNeuralNetworks
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APPLICATIONS
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REFERENCE
Modern pharmaceutics- vol 121
Pharmaceutical statistics
www.google.com
Formulation optimization of nifedipine containing microspheres using factorial
design by Solmaz Dehghan
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