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# Optimization techniques in 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

Primary objective may not be optimize absolutely but to compromise effectively &thereby produce the best formulation under a given set of restrictions 2
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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. Modern pharmaceutical optimization involves systematic design of experiments (DoE) to improve formulation irregularities. In the other word we can say that quantitate a formulation that has been qualitatively determined.

Reduce

the cost

optimization

reproduci bility

## 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 Temperature
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## LEVELS 300 , 500 1%, 2%

Concentration

RESPONSE: It is an outcome of the experiment. It is the effect to evaluate. Ex: Disintegration time etc..,

## 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

Optimization parameters
Optimization parameters

Problem types

Variable

Constrained
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## Unconstrained Dependnt Independent

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Optimization parameters
VARIABLES

Independent

Dependent

Formulating Variables
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Processing 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. Higher the number of variables, optimization process.

more complicated

will be the

There should be a relationship between the given response and the independent variable, and once this relationship is established , a response surface is generated. From response surface only, we find the points which will give desirable value of the response.

## Example of dependent & independent variables

Independent variables Dependent variables

X1 Diluent ratio

Y1 Disintegration time

X2 compressional force

Y2 Hardness

Tablet formulation
X3 Disintegrant level Y3 Dissolution

X4 Binder level

Y4 Friability

X5 Lubricant level 11

Y5 weight uniformity

Classic optimization
It involves application of calculus to basic problem for maximum/minimum function. Limited applications i. Problems that are not too complex ii. They do not involve more than two variables For more than two variables graphical representation is impossible It is possible mathematically , but very involved ,making use of partial derivatives , matrics ,determinants & so on.
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Response surface representing the relationship between the independent variables X1 and X2 and the dependent variable Y. 13

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

## Using calculus the graph obtained can be

Y = f (x) When the relation for the response y is given as the function of two independent variables,x1 &X2 Y = f(X1 , X2) The above function is represented by contour plots on which the axes represents the independent variables x1& x2

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Statistical design
Techniques used divided in to two types. Experimentation continues as optimization proceeds It is represented by evolutionary operations(EVOP), simplex methods. Experimentation is completed before optimization takes place. It is represented by classic mathematical & search methods.
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In later one it is necessary that the relation between any dependent variable and one or more independent variable is known.

## There are two possible approaches for this

Theoretical approach- If theoretical equation is known , no experimentation is necessary. Empirical or experimental approach With single independent variable formulator experiments at several levels.
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## Optimization may be helpful in shortening the experimenting time.

The design of experiments is determined the relationship between the factors affecting a process and the output of that process. Statistical DOE refers to the process of planning the experiment in such a way that appropriate data can be collected and analyzed statistically.
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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.

Randomized block designs For this there is one factor or variable that is of primary interest. To control non-significant factors, an important technique called blocking can be used to reduce or eliminate the contribution of these factors to experimental error.
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Factorial Design These are the designs of choice for simultaneous determination of the effects of several factors & their interactions. Symbols to denote levels are: (1)- when both the variables are in low concentration.

## a- one low variable and second high variable.

b- one high variable and second low variable ab- both variables are high. Factorial designs are optimal to determined the effect of pressure & lubricant on the hardness of a tablet Effect of disintegrant & lubricant conc . on tablet dissolution . It is based on theory of probability and test of significance.

It identifies the chance variation ( present in the process due to accident) and the assignable variations ( which are due to specific cause.)

## Factorial design are helpful to deduce IVIVC.

IVIVC are helpful to serve a surrogate measure of rate and extent of oral absorption. BCS classification is based on solubility and permeability issue of drugs, which are predictive of IVIVC.

Sound IVIVC omits the need of bioequivalence study. IVIVC is predicted at three levels: Level A- point to point relationship of in vitro dissolution and in vivo performance. Level B- mean in vitro and mean in vivo dissolution is compared and co related. Level C- correlation between amount of drug dissolved at one time and one pharmacokinetic parameter is deduced.

BCS classification and its expected outcome on IVIVC for Immediate release formulation

BCS Class I

Solubility High

Permeability High

IVIVC Correlation( if dissolution is rate limiting) IVIVC is expected Little or no IVIVC Little or no IVIVC

II III IV

## High Low Low

Factorial design
Full Used for small set of factors Fractional It is used to examine multiple factors efficiently with fewer runs than corresponding full factorial design

## Types of fractional factorial designs

Homogenous fractional Mixed level fractional Box-Hunter Plackett - Burman Taguchi Latin square

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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 It is a popular class of screening design. These designs are very efficient screening designs when only the main effects are of interest. These are useful for detecting large main effects economically ,assuming all interactions are negligible when compared with important main effects

Used to investigate n-1 variables in n experiments proposing experimental designs for more than seven factors.
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Taguchi It is similar to PBDs. It allows estimation of main effects while minimizing variance.
Taguchi Method treats optimization problems in two categories, [A] STATIC PROBLEMS :Generally, a process to be optimized has several control factors which directly decide the target or desired value of the output.
[B] DYNAMIC PROBLEMS :If the product to be optimized has a signal input that directly decides the output,

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-Noise ratios (S/N), which are log functions of desired output,

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We can use the Latin square to allocate treatments. If the rows of the square represent patients and the columns are weeks, then for example the second patient,in the week of the trial, will be given drug D. Now each patient receives all ve drugs, and in each week all ve drugs are tested.

A B C D E

B A E C D

C D A E B

D E B A C

E C D B A

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## Response surface designs

This model has quadratic form
=0 + 1X1 + 2X2 +.11X12 + 22X22

Designs for fitting these types of models are known as response surface designs. If defects and yield are the outputs and the goal is to minimize defects and maximize yield
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Two most common designs generally used in this response surface modeling are Central composite designs Box-Behnken designs Box-Wilson central composite Design This type contains an embedded factorial or fractional factorial design with centre points that is augmented with the group of star points. These always contains twice as many star points as there are factors in the design
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The star points represent new extreme value (low & high) for each factor in the design
To picture central composite design, it must imagined that there are several factors that can vary between low and high values. Central composite designs are of three types Circumscribed(CCC) designs-Cube points at the corners of the unit cube ,star points along the axes at or outside the cube and centre point at origin Inscribed (CCI) designs-Star points take the value of +1 & -1 and cube points lie in the interior of the cube Faced(CCI) star points on the faces of the cube.
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## Generation of a Central Composite Design for Factors

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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

It is written as 3k factorial design. It means that k factors are considered each at 3 levels. These are usually referred to as low, intermediate & high values. These values are usually expressed as 0, 1 & 2 The third level for a continuous factor facilitates investigation of a quadratic relationship between the response and each of the factors
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V. APPLIED OPTIMIZATION METHODS There are several methods used for optimization. They are

Evolutionary Operations The Simplex Method The Lagrangian Method Search Method Canonical Analysis

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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. It continues until no further changes takes place i.e., it has reached optimum-the peak. EVOP is not a substitute for good laboratory scale investigation , because of the necessarily small in the EVOP. It is not suitable for lab , therefore its impractical & expensive.

## Simplex Method(Simplex Lattice)

It is an experimental techniques & mostly used in analytical rather than
formulation & processing. Simplex is a geometric figure that has one more point than the number of factors. e.g-If 2 independent variables then simplex is represented as triangle. The strategy is to move towards a better response by moving away from worst response. Applied to optimize CAPSULES, DIRECT COMPRESSION TABLET), liquid systems (physical stability). It is also called as Downhill Simplex / Nelder-Mead Method.

In simplex lattice, the response may be plotted as 2D (contour plotted) or 3D plots (response surface methodology)

The worst response is 0.25, conditions are selected at the vortex, 0.6, and, indeed, improvement is obtained. One can follow the experimental path to the optimum, 0.721

Figure 5 The simplex approach to optimization. Response is spectorphotometric reading at a given wavelength

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solvent

system

## Includes observing responses( solubility) at three point i.e.

100% A, 100% B and 50 50 mixtures of A and B

## Eg: Preparation of tablet components) gives 7 runs.

with

excipients

(three

A regular simplex lattice for a three component mixture consist of seven formulations 4 7

1 Starch

Lactose

2 6

Stearic acid

## A simplex lattice of four component is shown by 15 formulation

4 formulations of each component A,B,C&D 6 formulation of 50-50 mixture of AB, AC, AD, BC, BD&CD. 4 formulation of 1/3 mixtures of three components ABC, ABD, ACD, & BCD. 1 formulation of 25% of each of four (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.

## Transformed % = ( Actual %- Minimum %)

(Maximum %-Minimum %)

Lagrangian method It represents mathematical techniques & it is applied to a pharmaceutical formulation and processing. This technique follows the design second type of statistical

Disadvantage-Limited to 2 variables .
Helps in finding the maxima (greatest possible amount) and minima (lowest possible concentration) depending on the constraints.. A techniques called sensitivity analysis can provide information so that the formulator can further trade off one property for another . Analysis for solves the constrained optimization problems.

Steps involved
.Determine objective formulation

Determine constraints. Change inequality constraints to equality constraints. Form the Lagrange function F:

Partially differentiate the lagrange function for each variable & set derivatives equal to zero.
Solve the set of simultaneous equations. Substitute the resulting values in objective functions
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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. Y= B0+B1X1+B2X2+B3 X12 +B4 X22 +B+5 X1 X2 +B6 X1X2 + B7X12+B8X12X22 Y Response Bi Regression coefficient for various terms containing the levels of the independent variables. X Independent variables
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FACTOR

LOWLEVEL(mg)

120.0 50.0
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A:stearate
B:Drug C:starch
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0.5
60.0 30.0

## EXAMPLE OF FULL FACTORIAL EXPERIMENT

Factor combination (1) a Stearate Drug Starch Response Thickness Cm*103 475 487

_ +

_ _

_ _

b
ab c ac bc

_
+ _ + _

+
+ _ _ +

_
_ + + +

421
426 525 546 472

abc
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522

Constrained optimization problem is to locate the levels of stearic acid(x1) and starch(x2). This minimize the time of in vitro release(y2),average tablet volume(y4), average friability(y3) To apply the lagrangian method, problem must be expressed mathematically as follows Y2 = f2(X1,X2)-in vitro release Y3 = f3(X1,X2)<2.72-Friability Y4 = f4(x1,x2) <0.422-avg tab.vol
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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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## 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 3. Perform experimens and test product. 4. Submit data for statistical and regression analysis 5. Set specifications for feasibility program

## 6. Select constraints for grid search

7. Evaluate grid search printout 8. Request and evaluate:. a. Partial derivative plots, single or composite b. Contour plots

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Canonical analysis
It is a technique used to reduce a second order regression equation. This allows immediate interpretation of the regression equation by including the linear and interaction terms in constant term.

It is used to reduce second order regression equation to an equation consisting of a constant and squared terms as followsY = Y0 +1W12 + 2W22 +..

## 2variables=first order regression equation.

3variables/3level design=second order regression equation.

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. In canonical analysis or canonical reduction, second-order regression equations are reduced to a simpler form by a rigid rotation and translation of the response surface axes in

multidimensional space, as
for a two dimension system.

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Forms of Optimization techniques: 1. Sequential optimization techniques. 2. Simultaneous 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

## presence/ absence / concentration of stomach

enzyme pH, fluid volume and contents of guts Gastric motility and gastric emptying.

## When given as single oral tablet

(A).
Same drug when given in

release

## NEW NETWORK FOR OPTIMIZATION

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Artificial Neural Network & optimization of pharmaceutical formulation ANN has been entered in pharmaceutical studies to forecast the relationship b/w the response variables &casual factors . This is relationship is nonlinear relationship.

## ANN is most successfully used in multi objective simultaneous optimization problem.

Radial basis functional network (RBFN) is proposed simultaneous optimization problems.

## RBFN is an ANN which activate functions are RBF.

RBF is a function whose value depends on the distance from the Centre or origin.
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APPLICATIONS

## Formulation and Processing

Clinical Chemistry

Medicinal Chemistry High Performance Liquid Chromatographic Analysis Formulation of Culture Medium in Virological Studies. Study of Pharmacokinetic Parameters.

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## Provide solution to large scale manufacturing problems

Provides string assurances to regulatory agencies superior drug product quality In microencapsulation process
Improvement of physical &biological properties by modification

REFERENCE
Modern pharmaceutics- vol 121 Textbook of industrial pharmacy by sobha rani R.Hiremath. Pharmaceutical statistics

## Pharmaceutical characteristics Practical and clinical applications

www.google.com Formulation optimization of nifedipine containing microspheres using factorial design by Solmaz Dehghan

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