AMITY INSTITUTE

OF PHARMACY

Optimization
Techniques In
Pharmaceutical
Formulation &
Processing
Anirban Saha,
Navneet Kumar Giri
M.Pharm (Pharmaceutics)
Year- 2nd , Semester- 3
Amity University, Noida
 8/20/2017

Outline
Introduction
Why Necessary
Terms Used
Advantages
Optimization parameters
Problem type
Variables
Applied optimisation methods
Other Applications
Factorial Design
Conclusion
8/20/2017

Introduction
The term Optimize is defined as to make perfect , effective , or as 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 refer 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 . Its not a screening technique.
 8/20/2017

Why is Optimization necessary?

Primary objective may not be optimize absolutely but to compromise
effectively & thereby produce the best formulation under a given set of
restrictions .

Reducing
cost

Safety &
Save OPTIMIZATION
Time Reducing
error

Reproducib
ility
8/20/2017

Terms Used
o 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.
o LEVELS: Levels of a factor are the values or designations assigned to
the factor.
o RESPONSE: It is an outcome of the experiment.
It is the effect to evaluate.
Ex- Disintegration time.
8/20/2017

Terms Used
o EFFECT: It is the change in response caused by varying the
levels
It gives the relationship between various factors & levels.

o INTERACTION: It gives the overall effect of two or more

variables
Ex- Combined effect of lubricant and glidant on hardness of
the tablet LEVELS
FACTOR

Temperature 300 , 500

Concentration 1%, 2%
 8/20/2017

Advantages
o Yield the Best Solution within the domain of study.

o Require fewer experiments to achieve an optimum

formulation.

o Can trace and rectify problem in a remarkably easier

manner.
8/20/2017

Optimization Parameters

CONSTRAINED

PROBLEM TYPE

UNCONSTRAINED
PARAMETERS

VARIABLES DEPENDENT

INDEPENDENT
 8/20/2017

Problem Types
Unconstrained
In unconstrained optimization problems there are no restrictions.

For a given pharmaceutical system one might wish to make the hardest tablet

possible.

The making of the hardest tablet is the unconstrained optimization problem.

Constrained
The constrained problem involved in it, is to make the hardest tablet possible,

but it must disintegrate in less than 15 minutes.

 8/20/2017

Variables
Independent 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.

Dependent variables : 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.

8/20/2017

Example of Variables
 8/20/2017

Classical Optimization
Classical optimization is done by using the calculus to basic problem to find
the maximum and the minimum of a function.

The curve in the fig 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.

Y = f(X)
 8/20/2017

Drawbacks

Limited applications
Problems that are too complex.
They do not involve more than two variables.

For more than two variables graphical representation is

impossible.
8/20/2017

Applied Optimization Methods

Lagrangian
Method

EVOP Applied Search

METHOD Method
optimization

Simplex
Lattice
Method
 8/20/2017

EVOP Method (Evolutionary Operation)

Make very small changes in formulation repeatedly.
The result of changes are statistically analyzed.
If there is improvement, the same step is repeated until further
change doesnt improve the product.

Where we have to select this technique?

This technique is especially well suited to a production situation.
The process is run in a way that is both produce a product that
meets all specifications and (at the same time) generates
information on product improvement.
8/20/2017

Advantages:
generates information on product development.
predict the direction of improvement.
Help formulator to decide optimum conditions for the formulation
and process.

Limitations:
More repetition is required
Time consuming
Not efficient to finding true optimum
Expensive to use.
 8/20/2017

Example: In this example, A formulator can change the concentration

of binder and get the desired hardness.
8/20/2017

SIMPLEX Method
A simplex is a geometric figure, defined by no. of points or
vertices equal to one more than no. of factors examined.
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
It is of two types:
A. Basic Simplex Method
B. Modified Simplex Method.
 8/20/2017

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.
 8/20/2017

The simplex method is especially appropriate when:

Process performance is changing over time.
More than three control variables are to be changed.
The process requires a fresh optimization with each new lot of
material.
The simplex method is based on an initial design of k+1, where k is
the number of variables. A k+1 geometric figure in a k-dimensional
space is called a simplex. The corners of this figure are called vertices.
 8/20/2017

In simplex lattice, the response may be plotted as 2D (contour plotted) or 3D plots (response
surface methodology)
 8/20/2017

Advantage
This method will find the true optimum of a response with
fewer trials than the non-systematic approaches or the one-
variable-at-a-time method.

Limitations :
There are sets of rules for the selection of the sequential
vertices in the procedure.
Requires mathematical knowledge.
 8/20/2017

LAGRANGIAN Method
o It represents mathematical techniques.

o It is an extension of classic method.

o applied to a pharmaceutical formulation and processing.

o This technique follows the second type of statistical design

o This technique require that the experimentation be completed before

optimization so that the mathematical models can be generates
 8/20/2017

Steps involved
Determine constraints.
Determine objective formulation.
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.
 8/20/2017

SEARCH Method
o Unlike the Lagrangian method, do not require differentiability of
the objective function.
o It is defined by appropriate equations.
o Used for more than two independent variables.
o The response surface is searched by various methods to find the
combination of independent variables yielding an optimum.
o It take five independent variables into account and is computer
assisted.
o Persons unfamiliar with mathematics of optimization & with no
previous computer experience could carryout an optimization
study.
 8/20/2017

Advantages:
o Takes five independent variables in to account
o Person unfamiliar with the mathematics of optimization and with no
previous computer experience could carry out an optimization study.
o It do not require continuity and differentiability of function
Disadvantage:
o One possible disadvantage of the procedure as it is set up is that not
all pharmaceutical responses will fit a second-order regression
model.
8/20/2017

New Network for Optimization

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.
8/20/2017

APPLICATIONS
Formulation and Processing

Clinical Chemistry

Medicinal Chemistry

High Performance Liquid Chromatographic

Analysis

Formulation of Culture Medium in Virological

Studies.

Study of Pharmacokinetic Parameters.

8/20/2017

Uses

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.
 8/20/2017

Conclusion
o Optimization techniques are a part of development process.

o The levels of variables for getting optimum response is evaluated.

o Different optimization methods are used for different optimization

problems.

o Optimization helps in getting optimum product with desired

bioavailability criteria as well as mass production.

o More optimum the product = More the company earns in profits !!!
 8/20/2017

References
Jain N. K., Pharmaceutical product development, CBS publishers and distributors, 1st
edition,297-302, 2006.
Cooper L. and Steinberg D., Introduction to methods of optimization, W.B.Saunders,
Philadelphia, 1970, 1st Edition, 301-305.
Bolton. S., Stastical applications in the pharmaceutical science, Varghese publishing
house,3rd edition, 223.
Deming S.N. and King P. G., Computers and experimental optimization,
Research/Development, vol-25 (5),22-26, may 1974.
Rubinstein M. H., Manuf. Chem. Aerosol News,30, Aug 1974.
Digaetano T.N., Bull.Parenter.Drug Assoc., vol-29,183, 1975.
Spendley, W., Sequential application of simplex designs in optimization and
evolutionary operation, Technometrics, Vol- 4 441461, 1962.
Forner D.E., Mathematical optimization techniques in drug product design and
process analysis, Journal of pharmaceutical sciences. , vol-59 (11),1587-1195,
November 1970.
8/20/2017