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optimization of formulation & process

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Research Process:

Require intelligence planning and approach.

Time

Traditional Trend

Randomized fashion of research Required More number of trials.., Take more time Cant predict the extension i.e. cant say what happen if such change are made within that particular system.

Wastage of

Man Money Material Time And still for output ??? We are not sure !!

Optimization

Designing experiments to yield the most information from the fewest runs Reduce the number of trial to minimum but in logical manner Carry out research in systematic way

OPTIMIZATION

The design of experiments is a structured , organised method used to determine the relationship between the factors affecting a process and the output of that process

The term Optimize is defined as to make perfect. It is used in pharmacy relative to formulation and processing Involved in formulating drug products in various forms

It is the process of finding the best way of using the existing resources while taking in to the account of

Basic Terminology

Independent variables

Conc. Of Polymer, Agitation Speed

Dependent variables

Friability, hardness

Pharmacological activity

Variables

Independent variables or primary variables : Formulations and process variables directly under control of the formulator. These includes ingredients Dependent or secondary variables : These are the responses of the in progress material or the resulting drug delivery system It is the result of independent variables

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Independent variable:

Significant variable

More important.. Go on changing level.. E.g. Polymer Conc, Granulation time

Insignificant variable

Not that much importance you can keep it at constant level also.. E.g. Effect of lubricant on floating tablet

Dependent variable

Also Known as Response variable. Its output of our experiment. No limit for dependent variable.

Keep as many as you wish.

Friability, Hardness.

Contour Plot:

Its a graphical representation of results. From the Full model equation, eliminate insignificant terms gives refined equation or

reduced equation.

This refined equation or Full equation is

transferred in form of graphs. That is known as contour plot or response surface methodology plot.

Basic Terminology

FACTOR : It is an assigned variable such as concentration , Temperature etc.., Quantitative : Numerical factor assigned to it Ex; Concentration1%, 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

Basic Terminology

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

I.INTRODUCTION

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OPTIMIZATION

I.INTRODUCTION

It is defined as choosing the best element from some set of available alternatives to make a formulation & prcess as perfect, effective & functional as possible.

In Pharmacy word optimization is found in the literature referring to any study of formula. In development projects pharmacist generally experiments by a series of logical steps, carefully controlling the variables and changing one at a time until satisfactory results are obtained. This is how the optimization done in pharmaceutical industry. Best one is the last one or optimum how do you evaluate?

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II. OPTIMIZATION PARAMETERS There are two optimization parameters 1.Problem Types 2.Variables PROBLEM TYPES -There are two general types of optimization problems:

1. Unconstrained

2. Constrained In unconstrained optimization problems there are no restrictions. For a given pharmaceutical system one might wish to make the hardest tablet possible. This making of the hardest tablet is the unconstrained optimization problem. The constrained problem involved in it is to make the hardest tablet possible, but it must disintegrate in less than 15 minutes.

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PROBLEM TYPES

Multi component formulation and complex processes with multiple interactions therein !

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VARIABLES -

several variables. Mathematically these variables are divided into two groups. 1.Independent variables 2.Dependent variables

The independent variables are under the control of the formulator. These might include

the compression force or the die cavity filling or the mixing time.

The dependent variables are the responses or the characteristics that are developed due

to the independent variables.

The more the variables that are present in the system the more the complications that

are involved in the optimization.

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known, it gives the response surface as represented in the Fig. 1. Surface is to be evaluated to get the independent variables, X1 and X2, which gave the response, Y. Any number of variables can be considered, it is impossible to represent graphically, but

mathematically

evaluated.

it

can

be

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Classical optimization is done by using the calculus to basic problem to find the maximum

and the minimum of a function mainly for unconstrained problems. The curve in the Fig. 2. represents the relationship between the response Y and the single

independent variable X and we can obtain the maximum and the minimum. By using the

calculus the graphical represented can be avoided. If the relationship, the equation for Y as a function of X, is available [Eq. (1)]:

Figure 2. Graphic location of optimum (maximum or minimum)

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When the relationship for the response Y is given as the function of two independent variables, X1 and X2 ,

Y = f(X1, X2)

Graphically, there are contour plots (Fig. 3.) on which the axes represents the two

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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

One of the most widely used methods of experimental optimization in fields

other than pharmaceutical technology is the evolutionary operation (EVOP). This technique is especially well suited to a production situation. The basic philosophy is that the production procedure (formulation and process) repetition. The process is run in a way such that it both produces a product that meets all specifications and (at the same time) generates information on product improvement. is allowed to evolve to the optimum by careful planning and constant

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EVOLUTIONARY OPERATIONS

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THE SIMPLEX METHOD The simplex approach to the optimum is also an experimental method and has

been applied more widely to pharmaceutical systems. A simplex is a geometric figure that has one more point than the number of factors. So, for two factors or independent variables, the simplex is represented by a triangle. Once the shape of a simplex has been determined, the method can employ a simplex of fixed size or of variable sizes that are determined by comparing the magnitudes of the responses after each successive calculation. The initial simplex is represented by the lowest triangle; the vertices represent the spectrophotometric response. The strategy is to move toward a better

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0.25, conditions are

is obtained. One can

.

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The simplex method of optimization was applied to a capsule formulation using the dissolution rate and compaction rate as the desired responses to be optimized. The formulation parameters investigated included the levels of drug, disintegrant, lubricant, and fill weight

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Keep track of n+1 points in n dimensions

Vertices of a simplex (triangle in 2D

tetrahedron in 3D, etc.)

Sometimes known as amoeba method:

simplex oozes along the function

Basic operation: reflection

If reflection resulted in best (lowest) value so far, try an expansion

If reflection didnt help (reflected point still worst) try a contraction

If all else fails shrink the simplex around the best point

Method fairly efficient at each iteration (typically 1-2 function evaluations) Can take lots of iterations

Somewhat flakey sometimes needs restart after simplex collapses on itself, etc.

Benefits: simple to implement, doesnt need derivative, doesnt care about function smoothness, etc.

The several steps in the Lagrangian method can be summarized as follows: 1 .Determine objective function 2 .Determine constraints 3. Change inequality constraints to equality constraints. 4. Form the Lagrange function, F: a. One Lagrange multiplier for each constraint b. One slack variable q for each inequality constraint 5. Partially differentiate the Lagrange function for each variable and Set

6. Solve the set of simultaneous equations. 7. Substitute the resulting values into the objective functions.

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In mathematical optimization, the method of Lagrange multipliers provides a strategy for finding the maxima and minima of a function subject to constraints. For instance (see Figure 1), consider the optimization problem maximize subject to constraints. For instance (see Figure 1), consider the optimization problem maximize subject to One of the most common problems in calculus is that of finding maxima or minima (in general, "extrema") of a function, but it is often difficult to find a closed form for the function being extremized. Such difficulties often arise when one wishes to maximize or minimize a function subject to fixed outside conditions or constraints. The method of Lagrange multipliers is a powerful tool for solving this class of problems without the need to explicitly solve the conditions and use them to eliminate extra variables. Consider the two-dimensional problem introduced above: maximize subject to We can visualize contours of f given by for various values of , and the contour of given by . Suppose we walk along the contour line with . In general the contour lines of and may be distinct, so following the contour line for one could intersect with or cross the contour lines of . This is equivalent to saying that while37

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Forms of Optimization techniques: There are three forms of systematic optimization techniques: 1. Sequential Optimization techniques. 2. Simultanuous Optimization techniques. 3. Combination of both.

1. Sequential Methods: This method is alos referred to as the "Hill climbing method". As first of all a small

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2. Simultanuous Methods: This method involves the use of full range of experiments by an experimental design and the results are than used to fit in the mathematical model. And maximum or minimum response will then be found through this fitted model.

Artificial Neural Network (ANN) and Optimization of Pharmaceutical formulations: ANN has been entered in pharmaceutical studies to

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Lagrangian method is one of the optimization methods and is an extened form of Classic method of simplifying the formulae and methods. This method helps in finding the maxima i.e. greatest possible amount, and minima i.e. minimum possible degree, of a function depending on the constraints.

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1. Objective function is determined: Objective function is a function in optimization theory. This function is to be maximized or minimized i.e. to be optimized. Here function is a quantity depending on another quantity and it can be changed by changing the values of the other quantity. We can express objective funcion with expression like "Z(X')" Where X' is the decision variable representing

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2. Constraints are determined Constraints are the factors that causes limitations to the freedom of something. Problems related to pharmaceutical product and process design are considered as constrained optimization problems. 3. Inequality constraints are converted into equality constraints 4. From the lagrange function, assign a. One lagrange multiplier i.e. lambda for each

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5. The lagrange function for each variable, is differentiated partially, and setting the derivative equal to zero. 6. The set of simultaneous equations are solved 7. Resulting values are substituted into the objective functions Provision for this method is the completion of the experiment before the optimization so that the 45 mathematical models can be generated. Moreover,

optimization so that mathematical models can be generated. The experimental design here was full 3 square factorial, and , as shown in Table- 1 nine formulations were prepared.

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variable were generated by a backward stepwise regression analysis program. The analyses were performed on a polynomial of the form and the terms were

y = B0+B1X1+B2X2+B3X12+B4X22+B5X1X2 +B6X1X22+B7X12X2+B8X12X22

In Eq. (3), y represents any given response and Bi represents the regression coefficient for the various terms containing levels of the independent variable. One equation is generated for each response or dependent variable.

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The active ingredient, phenyl-propanolamine HCl, was kept at a constant level,and the levels of disintegrant (corn starch) and lubricant (stearic acid) were

include tablet hardness, friability, volume, in vitro release rate, and urinary excretion rate in human subject.

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Figure 6. Contour plots for the Lagrangian method: (a) tablet hardness;

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Figure 6. Contour plots for the Lagrangian method: (b) dissolution (t50%)

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If the requirements on the final tablet are that hardness be 8-10 kg and

t50%

This has been obtained by superimposing Fig. 6a and b, and several different combinations of X1 and X2 will suffice.

Figure 6. Contour plots for the Lagrangian method: c) feasible solution space indicated by crosshatched area

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A technique called sensitivity analysis can provide information so that the formulator can further trade off one property for another. For sensitivity analysis the formulator solves the constrained optimization problem for systematic changes

in the secondary objectives. For example, the foregoing problem restricted tablet

friability, y3, to a maximum of 2.72%.

relaxed and demonstrates that substantial improvement in the t50% can be obtained up to about 1-2%.

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tightened

relaxed and demonstrates that substantial improvement n the t50% can be obtained up to

about 1-2%.

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The plots of the independent variables, X1 and X2, can be obtained as shown in Fig.8. Thus the formulator is

changed restriction.

friability

Figure 8. 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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the efficient and effective procedures that might be

applied.

such

Representation of

analysis and the

available solution space is shown for the suspension in Figs. 9 and 10.

Figure 9. Response surface concept and results of the second case study

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Figure 10. Secondary properties of various suspensions yielding zero dose variation.

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Although the Lagrangian method was able to handle several responses or dependent variable, it was generally limited to two independent variables. A search method of optimization was also applied to a

computer-assisted. It was proposed that the procedure described could be set up such that persons unfamiliar with the mathematics of optimization and with

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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

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

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The five independent variables or formulation factors selected for this study are shown in Table 2.

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The experimental design used was a modified factorial and is shown in Table4. The fact that there are five independent variable dictates that a total of 27 experiments or formulations be prepared. This design is known as a five-factor, orthogonal, central, composite, second-order design . The firs 16 formulations represent a half-factorial design for five factors at two levels, resulting in X 25 =16 trials. The two levels are represented by +1 and -1, analogous to the high and low values in any two level factorial design. For the remaining trials, three additional levels were selected: zero represents a base level midway between the a fore mentioned levels, and the levels noted as 1.547 represent extreme (or axial) values.

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The translation of the statistical design into physical units is shown in Table 5.

Again the formulations were prepared and the responses measured. The data were subject to statistical analysis, followed by multiple regression analysis. This is an important step. One is not looking for the best of the 27 formulations, but the global best.

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The type of predictor equation usd with this type of design is a second-order polynomial of the following form:

Y = a 0+a1X1+..+a5X5+a11X12++a55X52 +a12X1X2+a13X1X3++a45X4X5

Where Y is the level of a given response, the regression coefficients for second-order polynomial, and X1 the level of the independent variable. The full equation has 21 terms, and one such equation is generated for each response variable .

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1. The feasibility search 2. The grid search. The feasibility program is used to locate a set of response constraints that are just at the limit of possibility.

. For example, the constraints in Table 6 were fed into the computer and were relaxed one at a time until a solution was found.

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This program is designed so that it stops after the first possibility, it is not a full search. The formulation obtained may be one of many possibilities satisfying the constraints.

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The grid search or exhaustive grid search, is essentially a brute force method in

which the experimental range is divided into a grid of specific size and methodically searched.

From an input of the desired criteria, the program prints out all points (formulations) that satisfy the constraints.

plotter from computer tapes.

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The output includes plots of a given responses as a function of a single variable (fig.11).

The abscissa for both types is produced in experimental units, rather than physical units, so that it extends from -1.547 to + 1.547.

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The output includes plots of a given responses as a function of all five variable

(Fig 12).

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Contour plots (Fig.13) are also generated in the same manner. The specific response is noted on the graph, and again, the three fixed variables must be held at some desired level. For the contour plots shown, both axes are in experimental unit (eu) .

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CANONICAL ANALYSIS Canonical analysis, or canonical reduction, is a technique used to reduce a second-order regression equation, to an equation consisting of a constant Y = Y0+1W12+2W22+. and squared terms, as follows:

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reduction, regression

second-order

equations are reduced to a simpler form by a rigid rotation and translation of the response surface axes in

multidimensional shown in

space,

as

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Formulation and Processing

Clinical Chemistry

Medicinal Chemistry

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. The graphs in Fig.15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be controlled by the formulation and processing variables involved.

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