Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

JCPR 2011;7 (1): 21-28

2010 Medipoeia
Received 14-9-2011
Revised: 15-9-2011
Accepted: 17-9-2011











Ritesh N. Sharma*
S. K. Patel College of Pharmaceutical
Education and Research, Ganpat
University, Mahesana-Gozaria
Highway, Kherva Dist. Mahesana-
382711, Gujarat, India

Shyam Sunder Pancholi
Babria Institute of Pharmacy,
Varnama, Vadodara-391240, Gujarat,
India
























Correspondence:
Ritesh N. Sharma*
S. K. Patel College of Pharmaceutical
Education and Research, Ganpat
University, Mahesana-Gozaria
Highway, Kherva Dist. Mahesana-
382711, Gujarat, India
E-mail:- riteshin001@yahoo.co.in



Optimization techniques in pharmaceutical industry:
A Review

Ritesh N. Sharma*

Shyam Sunder Pancholi


ABSTRACT
Optimization techniques are abundant in pharmaceutical industry. In general, all the required
information should be obtained from as few experiments as possible. Conventional techniques
such as response surface models or simplex optimization are often used. With the advent of the
computer in the laboratory, a new class of optimization problems arose which could not be
tackled with the standard methodologies. For these search type problems, new strategies such as
simulated annealing (SA), genetic algorithms (GA) and artificial neural network are applied.
Although these are not guaranteed to give the optimal result, in almost all cases they are able to
find very good solutions where other techniques fail completely. These methods find themselves
in an intermediate position between the strong methods, and weak methods. This article provides
an overview of conventional and recent optimization techniques.
Keywords: simulated annealing and artificial neural network.
1. INTRODUCTION
In order to design the best formulation it is of course possible to use a trial and error
approach but this is not an effective way. Systematic optimization techniques are always preferable.
These methods can be divided into sequential methods, simultaneous methods or combinations of both

(De Boer et.al. 1988). Optimization refers to the art and science of allocating available resources to
the best possible effect. Optimization techniques are used in industrial planning, allocation,
scheduling, decision-making, etc. New optimization techniques are arriving daily, often stimulated by
fascinating insights from other fields. Genetic algorithms, for example, use an anology to chromosome
encoding and natural selection to evolve a good optimized solution. Certain characteristics of their
architecture and the way they process information makes them superior to conventional techniques on
certain class of optimization techniques. Many different optimization methods exist and they can be
classified in a number of ways. The optimization techniques thus formulated can be classified as
conventional and recent based on the type of objective and constraints (De Boer et.al. 1991). In
pharmaceutical technology, one is often engaged with the design and analysis of formulations. A
formulation of a solid dosage form consists normally of the medicinal-substance and a number of
excipients (Dick et.al. 1988). In many cases, the physical properties of the formulation are determined
by the physico-chemical properties of these excipients and the process of manufacturing In order to
design the best formulation it is of course possible to use a trial and error approach but this is not an
effective way. In the modern laboratory, the advent of complicated instruments controlled by
computers has changed the nature of the problems faced by the chemist. Whereas the actual doing of
the experiment used to be a major limiting factor in obtaining relevant information, and therefore
warranted a large investment in time and energy to be designed and executed, in the modern
laboratory experiments can be performed in a fast, reproducible way. Optimization is the search for a
maximum or minimum in the value of a certain response function. For example, the yield of a
chemical reaction is a function of several variables, such as concentrations of components in the
mixture and physical characteristics such as temperature and pressure (Doornbos et.al. 1981).

2. MATERIALS AND METHODS
Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

Such optimizations are typically performed in an
iterative fashion (Figure 1). The search is started either from one or
more random positions or from a set of points, picked according to
some criterion.



Fig. 1. The basic iterative optimization cycle.
The field of optimization is broad and has applications in all areas
of chemistry and pharmacy. Naturally, many different methods
have been used and in some cases even developed by chemists. In
this article, an overview is how to apply optimization techniques in
pharmaceuticals formulation.
2. CONVENTIONAL OPTIMIZATION METHODS
Hybrid Methods
Hybrid methods combine the characteristics of
different optimization methods. hybrid methods are most useful
when they combine the best features of their components. One
approach which has been in practice is a hybrid form of a GA and
SA. The GA is used to maintain a pool of trial solutions and to
generate offspring; the SA governs the selection part by accepting
all improving (Mackay et.al. 1998).
The advantages of the GA are that inadmissible regions
of the search space are handled gracefully and do not constitute a
barrier that a vintage SA may find difficult to cross. The advantage
of the SA is the added control that the user may exert through the
cooling scheme. For the selection and generation stages, typical
strategies are summarized in Table 1. Other possible hybrids are
GA/TS . The main strengths of all these methods their versatility
and their ability to adapt to all kinds of problems are also their
weakness (Cornell J.A. 1990).
Monte Carlo Simulated Annealing
MCSA, also known as the Metropolis algorithm, is probably the
most used optimization method in chemistry today. Although the
principle of the method was used in 1953 by Metropolis it only
became popular after 1983 when Kirkpatrick described its use as a
general optimization scheme. The method is implemented in a
large number of software packages and is the de facto standard in
structure optimization problems (Hobbs et.al. 1998).

Table 1. Selection and generation characteristics for SA, TS, and
GA
The principle of the method is very simple indeed. A
random walk is performed in the search space (Papahadjopoulos
et.al. 1995), accepting all moves that lead to a better solution, and
accepting moves that lead to a worse solution with a probability
e_1E=T. This is analogous to the well-known Boltzmann
distribution.
The only part that must be provided by the user are an
evaluation function, a procedure to generate a new trial state and a
cooling scheme. The algorithm is stopped when the optimal
solution has been found, a predefined number of evaluations is
reached, or no improvement has been obtained for a specified
number of evaluations (Tricot et.al. 1984).
Random Search
Random search is not a strategy many people would
use, unless there is no other alternative. Yet in some molecular
mechanics software packages it is implemented to serve as a
reference point for other optimization procedures (Press et.al.
1988). The strategy is simple: just keep on trying new candidate
solutions and keep the best one(s) until the time is up. A typical
example is molecular recognition seemingly small changes to an
active molecule can lead to a drastic decrease in activity. It is
therefore not surprising that, especially in combinatorial chemistry,
the random search strategy has led to the discovery of several
interesting and completely new drug leads, although also in this
field more sophisticated techniques are being investigated (Barron,
A. R. 1993).
Method Characteristic
Selection
SA Accept new solution if better, else accept with
probability e
-E/T

TS Accept best of all admissible new solutions, even
if it is worse than the previous solution
GA Accept solutions according to their relative quality
in the population
Generation
SA Randomly pick one solution out of the
neighborhood
TS Generate all solutions in neighborhood
GA Use random based procedures such as cross-over
and mutation to generate new solutions
Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

Multivariate methods
The development of modern analytical equipment provides
the researcher with larg quantities of data. Extracting useful
information from the collected data becomes a new challenge for
the researcher. Just looking at data tables or examining one
variable at a time is not enough in most cases (Schmidt et.al.
1993).
PCA (Schmidt A.H. 1993 & Wolcott et.al. 2000)
The objective of PCA is to describe the variation in data
with a minimum of variables. Variables are often dependent on
each other, PCA shows the underlying structure n the data. The
principle of PCA are illustrated in two dimensions in equation1
gives the mathematical expression for the PCA model.
X= 1 .x + T.P+ E (1)
A data matrix X consists of N object described by K
variables. The parameter consist x determines the center of the
data set, T is the score vector matrix, P is the loading matrix and
the matrix E contains the residuals, the part of data matrix
explained by PC model.
The score values for two principle components, e.g. t
1

and t
2
together span a mathematical plane to form a two
dimensional model of the data. One could say the t
1
/t
2
score plot
constitute a window through which data can be viewed. Grouping
and trends in data are more easily discovered in this way, outliers
can be detected (Markowski W. 1996).
PLS (Markowski W. 1993)
PLS takes PCA one step further, as it deals with both X
and Y data. X data could be variables such as reaction temperature
and pH, and Y data could be responses in the form of yield. The
underlying structures in X and Y data set are related to each other.
Each object is represented in both X-space and Y-space. The first
step is same for PLS and PCA.
X = 1.x+T.P+E (2)
Y = 1.y+U.C+F (3)
Using PLS, it is possible to male predictions in Y and X
data. The matrix is described by equation 2 and the Y matrix is
described by equation 3. The inner relation then gives equation 4.
SIMCA (Markowski W. 1993 & Wrisley L. 1993)
SIMCA is a method used to classify objects. Provided the most of
the variables express a real similarity, a class can be well
approximated by a PC model with few components. From this
model, which is the basis of the SIMCA method, a tolerance
interval (usually 95%) can be constructed around the PC hyper
planes, new objects are assigned to different classes depending on
which tolerance cylinder they fit inside. All objects outside the
tolerance interval are classified as outliers,

Fig. 2. Illustration of the SIMCA method. Around one or more
classes a tolerance interval is constructed (a). New objects that fit
inside the interval are said to belong to the class (b) (Chloupek
et.al. 1992)
Multivariate Design (Baba et.al. 1991)
Multivariate design, or experimental design in
principle properties as it is often referred to, is a combination of
experimental design and PCA. Instead of variables, principle
properties are used in design. This makes it possible to reduce the
design considerably and still obtain relevant information, eg. which
variables influence tablet quality.
3. RECENT OPTIMIZATION METHODS
Factorial Design and Optimization
Traditionally pharmaceutical formulations are
developed by changing one variable at a time. The method is time
consuming and it is difficult to evolve an ideal formulation using
this classical technique since the combined effects of the
independent variables are not considered (Baba et.al. 1989). It is
therefore important to understand the complexity of pharmaceutical
formulations by using established statistical tools such as factorial
design. The number of experiments required for these studies is
dependent on the number of independent variables selected (Dzido
et.al. 1991). The response is measured for each trial and then either
simple linear equation (4), or interactive equation (5) or quadratic
(6) model is
(Y = b0 + b1X1 + b2X2 + b3X3 ) (4)
Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

(Y = b0 + b1X1 + b2X2 + b3X3 + X1X2 + X1X3 + X2X3
+X1X2X3) (5)
(Y = b0 + b1X1 + b2X2 + b3X3 + b1
2
X11 + b2
2
X22
+ b3
2
X33 + X1X2 + X2X3 + X1X3 + X1X2X3 ) (6)
fitted by carrying out multiple regression analysis and F-statistic to
identify statistically significant term. A prior knowledge and
understanding of the process and the process variables under
investigation are necessary for achieving a more realistic model
(Schoenmakers et.al. 1991). Putting these equations an example it
is tried to explain that with the help of these kinds of equations in
factorial design methods the optimization can be achieved
systemically (Jandera et.al. 1991).
Global Optimization
Global optimization is a branch of applied mathematics
and numerical analysis that deals with the optimization of a function
or a set of functions In real-life problems, functions of many
variables have a large number of local minima and maxima
(Adinarayana et.al. 2002). Finding an arbitrary local optimum is
relatively straightforward by using local optimization methods.
Finding the global maximum or minimum of a function is a lot more
challenging and has been impossible for many problems so far
(Akhnazarova et.al. 1982).
Approaches (Allen et.al. 1992 & Anthony et.al. 1997)
Deterministic
The most successful are:
Branch and bound methods
Methods based on real algebraic geometry
Stochastic, thermodynamics
Several Monte-Carlo-based algorithms
Simulated annealing
Monte-Carlo with minimization
Continuation Methods
Related methods
Tabu search
Stochastic hill climbing
Genetic algorithms
Ant colony optimization
The cross-entropy method
Applications of Global Optimization (Bolton et.al. 1997)
Typical examples of global optimization applications include:
Protein structure prediction (minimize the energy/free energy
function)
Traveling salesman problem and circuit design (minimize the
path length)
Chemical engineering (e.g., analyzing the Gibbs free energy)
Safety verification, safety engineering (e.g., of mechanical
structures, buildings)
Worst case analysis
Mathematical problems (e.g., the Kepler conjecture)
The starting point of several molecular dynamics simulations
consists of an initial optimization of the energy of the system to
be simulated.
Spin glasses
The Simplex Optimization Methods
The simplex methods are based on an initial design of
k+1 trials, 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 (Spendley et.al. 1962).
A simplex defined by three different trial conditions for
two control variables. With two variables the first simplex design
is based on three trials, for three variables it is four trials, etc
(Nelder et.al. 1965). This number of trials is also the minimum for
defining a direction of improvement. Therefore, it is a timesaving
and economical way to start an optimization project (Walter et.al.
1991).
After the initial trials the simplex process is sequential,
with the addition and evaluation of one new trial at a time. The
simplex searches systematically for the best levels of the control
variables. The optimization process ends when the optimization
objective is reached or when the responses cannot be improved
further (Spendley et.al. 1962).


Fig. 3. Control variable
1. The Basic Simplex Method
2. The Modified Simplex Method
3. Evolutionary Operation
4. Mixture Optimization
Artificial Neural Network
An artificial neural network (ANN) or commonly
just neural network (NN) is an interconnected group of artificial
neurons that uses a mathematical model or computational model
for information processing based on a connectionist approach to
computation (Maass et.al. 1997). In most cases an ANN is an
adaptive system that changes its structure based on external or
Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

internal information that flows through the network. The term
"neural network" can also mean biological-type systems. In more
practical terms neural networks are non-linear statistical data
modeling tools (Gurney et.al. 1997). They can be used to model
complex relationships between inputs and outputs or to find
patterns in data (Haykin et.al. 1999).


Fig. 4. Artificial neural network
A neural network is an interconnected group of nodes,
akin to the vast network of neurons in the human brain. More
complex neural networks are often used in Parallel Distributed
Processing.
Background of Artificial Neural Network
There is no precise agreed definition among
researchers as to what a neural network is, but most would agree
that it involves a network of simple processing elements (neurons)
which can exhibit complex global behavior, determined by the
connections between the processing elements and element
parameters (Hertz et.al. 1990). The original inspiration for the
technique was from examination of the central nervous system and
the neurons which constitute one of its most significant
information processing elements (Lawrence, J. 1994). In a neural
network model, simple nodes are connected together to form a
network of nodes hence the term "neural network" (Masters et.al.
1994).
These networks are also similar to the biological
neural networks in the sense that functions are performed
collectively and in parallel by the units (Smith, M. 1994).
Currently, the term ANN tends to refer mostly to neural network
models employed in statistics and artificial intelligence. Neural
network models designed with emulation of the central nervous
system (CNS) in mind are a subject of theoretical neuroscience
(Wasserman et.al. 1993).
In modern software implementations of artificial neural
networks the approach inspired by biology has more or less been
abandoned for a more practical approach based on statistics and
signal processing (Masters et.al. 1994). In some of these systems
neural networks, or parts of neural networks are used as
components in larger systems that combine both adaptive and non-
adaptive elements (Smith, M. 1993). What they do however have
in common is the principle of non-linear, distributed, parallel and
local processing and adaptation.
Employing artificial neural networks
Perhaps the greatest advantage of ANNs is their
ability to be used as an arbitrary function approximation
mechanism which 'learns' from observed data (Wasserman, P.
1993). However, using them is not so straightforward and a
relatively good understanding of the underlying theory is essential
(Hertz et.al. 1990).
Choice of model
Learning algorithm.
Robustness
With the correct implementation ANNs can be used naturally in
online learning and large dataset applications (Lawrence et. al.
1994). Their simple implementation and the existence of mostly
local dependencies exhibited in the structure allows for fast,
parallel implementations in hardware.
Neural network software (Masters et.al. 1994 & Smith et.al.
1993)
Neural network software is used to simulate, research,
develop and apply artificial neural networks, biological neural
networks and in some cases a wider array of adaptive systems.
Simulators
o Research simulators
o Data analysis simulators
Development Environments
o Component based
Criticism
Custom neural networks
Types of neural networks (Kesavan et.al. 1996, Wu T. et.al. 2000
& Chen et.al. 1999)
1. Feed forward neural network
Single-layer perceptron
Multi-layer perceptron
2. Recurrent network
Simple recurrent network
Hopfield network
3. Stochastic neural networks
4. Modular neural networks
Committee of machines
5. Holographic associative memory
Instantaneously trained networks
Cascading neural networks
Neuro-fuzzy networks

Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28


Fig.5. A two-layer neural network capable of calculating XOR.
Applications

The utility of artificial neural network models lies in
the fact that they can be used to infer a function from observations.
This is particularly useful in applications where the complexity of
the data or task makes the design of such a function by hand
impractical (Khuri et. al. 1981).
Real life applications (Barron A.R. 1993)
The tasks to which artificial neural networks are
applied tend to fall within the following broad categories:
Function approximation, or regression analysis, including time
series prediction and modelling.
Classification, including pattern and sequence recognition,
novelty detection and sequential decision making.
Data processing, including filtering, clustering, blind source
separation and compression.
Application areas (Bishop CM. 1995)
system identification and control
game-playing and decision making
pattern recognition
sequence recognition
medical diagnosis
financial applications
data mining
visualization and e-mail spam filtering
Examples
The fallowing example can illustrate importance of
optimization techniques in pharmaceutical formulation



A) Application of a Mixed Optimization Strategy in the Design
of a Pharmaceutical Solid Formulation at Laboratory Scale
The mixed strategy was used to optimize a dry
powder blend containing 500 mg of alpha methyl dopa to be filled
into hard gelatin capsules. The experimental plan consisted of
assessing blend flow and dissolution rate using formulations
manufactured at small laboratory scale, selecting the optimum
formulation, and confirming the data. Two optimization techniques
were used in the solid pharmaceutical product design: a genetic
algorithm (GA) and a downhill simplex technique.
B) Multivariate spline interpolation as a novel method to
optimize pharmaceutical formulations
The generation of response surfaces using multivariate
spline interpolation (MSI) has provided rapid and detailed
information. Nevertheless, no application of MSI in the
pharmaceutical field has been reported to date, even though it
promises potential applications. To overcome the shortcomings of
the classical response surface method, newly a multi-objective
simultaneous optimization method was developed, in which MSI
had been incorporated. The method was applied to the optimization
problem of a transdermal hydrogel formulation for ketoprofen
containing several chemical enhancers. Results suggested a
superior function of the MSI approach.
C) Formulation Optimization of Paclitaxel Carried by
PEGylated Emulsions Based on Artificial Neural Network
(Patterson D. 1996 & Baba Y et. al. 1999)
An artificial neural network (ANN) was used to
optimize the formulation of paclitaxel carried by injectable
PEGylated emulsions; which has a small particle size, high
entrapment efficiency and good stability. A computer optimization
technique based on a spherical experimental design for three-level,
three factors [soybean oil (X1), PEG-DSPE (X2) and polysorbate
80 (X3)] were used to optimize the formulation. Novel formulation
for paclitaxel emulsions was optimized with ANN and prepared.
The contribution indices of each component suggested that PEG-
DSPE mainly contributes to the entrapment efficiency and particle
size of paclitaxel emulsions, while polysorbate 80 contributes to
stability.
3. FUTURE PROSPECTIVES
The scope of optimization technique is intended to
support innovation and efficiency in pharmaceutical industry. The
framework is founded on understanding to facilitate innovation and
production. Pharmaceutical companies need to adopt new
technologies, processes and collaborations (Baba Y et. al. 1989).



Journal of Current Pharmaceutical Research 2011; 7 (1): 21-28

Software and data analysis tools
Networks of research alliances to ensure access to new genetic
technologies and research
Research scientists working in collaboration as virtual drug
discovery teams
Standardized tools and processes delivered through drug
discovery portals e.g. gene mapping.
4. CONCLUSION
The field of optimization is broad and has applications
in all areas of pharmaceutical science. Naturally, many different
methods have been used and in some cases even developed by
chemists. In this article, an overview is given where the methods
have been classified as conventional and recent methods.
The former category comprises methods that are very good in
dealing with low-dimensional problems. An example is the
optimization of a chromatographic experiment, where optimal
separation conditions should be found in as few experiments as
possible. These methods are said to be strong because they
incorporate much knowledge from the user about the problem at
hand. The conventional category also includes weak methods
where knowledge is not a prerequisite. As the efficiency of these
methods is in many cases very low, they are not often used in
industry.
The recent optimization techniques described in this
article have been specifically developed for those cases where the
conventional techniques were not suitable. Because the number of
evaluations may be quite high they usually are applied in
connection with computer experiments rather than with laboratory
experiments.
The conventional and recent methods have
complementary roles in pharmaceutical industry. With the
increasing role of computational techniques, the recent methods
will continue to flourish. Many standard computer software
packages are available for experimental design, and are sometimes
even included in laboratory instruments. Although the user should
still understand the principles of the methods, no programming is
required, thereby significantly lowering the threshold for their use.
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