Advance Formulation Techniques

By
Muhammad Farhan Sohail

Introduction

Traditional Formulation Approaches

The traditional approach of formulation is
based on trial and error, where the focus is
one individual factor at a time.
Advance Formulation Techniques

Advance
formulation
techniques
are
approaches for formulation development
resulting
in
a
dosage
form
which
demonstrates the optimized properties and
without the drawbacks associated with the
conventional dosage forms.

OFAT Approach: (One Factor At A Time

Approach)
The desired properties of formulation are obtained
by changing one factor and keeping all others fixed.
Some initial experiments with selected levels of the
ingredients are selected based on the experience
are carried out.
The succeeding experiments are based on the
results obtained after each experimentation in the
direction of increase or decrease of the response
(properties).
In this way a maximum or minimum of property is
reached.

OFAT Approach: (One Factor At A Time

Approach)
Since in this approach, the product
properties are optimized one by one, the
approach is also called as the sequential
approach.
After formulating a product, if it is not the
desired one, then the center of attention is
one specified factor.
One by one, by controlling the other factors
at a constant level, effort is made to get the
desired product/formulation.

Limitations Of The Traditional Approaches

The traditional OFAT approach has certain
limitation:
1. Unplanned and based on trial and error.
2. Less effective.
3. Sequential (optimization one one).
4. Unable to obtain the information on factor
interactions.
5. Require more number of experimentation to
obtain information helpful to make formulation
decision.
6. Time consuming, laborious and costly.

Need for advance formulation approaches

Advance formulation approaches are needed
because coping with the following is becoming
increasingly difficult for the pharmaceutical
industries by the traditional approaches:
Increasing pressure for developing new products
quickly to cope with market competition.
Products with more stringent quality standards.
Partial or totally unavailability of historical knowledge
for the new formulations.
The task of formulation is complex because there is
often no model or detailed understanding of how
changes in formulation ingredients affect product
properties.

Need for advance formulation approaches

Data generated during optimization process is
huge and difficult to understand.
Optimization process is multidimensional (some
properties are required to be minimum while
others to be maximum).
Existence of opportunity to improve the
formulation operations and resulting profitability
by streamlining the formulation design tasks.
Formulation requires experimentation which is
expensive in terms of laboratory and staff time
and in terms of opportunities missed through
slow response to new customer requirements.

Need for advance formulation

approaches
New formulation approaches are powerful tools
and are based on the artificial intelligence and
computational approaches.
These are coupled with visualization and statistical
validation and robust optimization methods.
These approaches require desk-top decision
support software. Computational approaches can
reduce the formulators effort by automatically
generating knowledge directly form data which is
obtained from the planned experimentation using
different settings of the factors.

Need for advance formulation

approaches
The newer approaches allow simultaneous
optimization of all properties, thus are also called
as
the
simultaneous
approaches.
Such
approaches plan the complete set of experiments,
called as experimental design beforehand. In this,
the experiments are carried out and the results are
fitted to a mathematical model. The response
values can be predicted by using a range for the
settings of variables (formulative, process and
machine). A wide range of possible choices (factor
settings) is available.

Advantages Of The Advanced

Approaches:
1. Reveals the interaction between different
variables.
2. Enhancement of product quality and
performance at low cost.
3. Shorter time to market.
4. Development of new products.
5. Improved customer response.
6. Improved confidence.
7. Improved competitive edge.

Applications

1. Formulation design.
2. Optimization of formulation.
3. Optimization of process.
4. Process validation.
5. Scale up.
6. Cost reduction.
7. Prediction.

Optimization
The word optimize simply implies to make as
perfect, effective, or functional as possible.
Optimization of a product or process is the
determination of experimental conditions
resulting in optimal performance.

A product that has desired characteristics and meet

all specifications is an optimized formulation

Interaction Of Factors

Cause and Effect Model:

In a cause-and-effect model, the
transformation of a system (ingredients) into
an output (product) depends on the way the
external factors interact with the internal
components of a system.
Four types of interactions between internal
and external factors can be proposed:

Cause and Effect Model

Cause and Effect Model

In case of the active factors, if the system factors are sensitive
to the adjustable external factors, the system can be readily
transformed into a desired output. In case of the partially
desired output, with change of the amount of the factors levels
or modifying the factors themselves may cause favorable
outputs. Cases with no interaction or negative interactions,
warrants search for entirely other active factors which can
cause a favorable output.
Thus, a careful selection of a set of controllable external factors
at appropriate amounts (levels) may cause an interaction which
can manipulate the inaccessible internal factors to yield a
desired output. Advanced formulations pose complex and nonlinear relationships between factors and properties and thus,
require use of computer-aided approaches to understand the
cause and effect relationships.

Response Surface Methodology(rsm)

This is model independent methodology wherein one or
more selected experimental responses are recorded for
a set of experiments, carried out in a systemic way to
predict the optimum and the interaction effects.
These approaches comprise, the postulation if empirical
mechanical model for each response within zone of
interest.
Rather than estimating the effects of each variable
directly, RSM involves fitting the coefficient into the
model equation of a particular response variable and
mapping the response, i.e., studying the response over
whole of experimental domain in the form of surface.

Response Surface Methodology(rsm)

Experimental Designs Of RSM:
For implementation of RSM one of following
statistical design is adopted;
Factorial design
Central Composite Design
Uniform shell design
Mixture design
Response Surface Analysis:
Usually, the results of RSM are graphically depicted
using one or more of following plots:

Response Surface Methodology(rsm)

RESPONSE SURFACE PLOT is a 3-D graphical
representation of a response plotted between two
independent variables and one response variable.
The use of 3-D response surface plot allows
understanding of the behaviour of the system by
demonstrating the contribution of independent
variables.
CONTOUR PLOT is the geometric illustration of a
response, obtained by plotting independent variable
versus another while holding magnitude of response
level and other variables constants. The contour plot
represents 2-D slices of corresponding 3-D
response surface. The resuling curves are called
contour lines.

Artificial Neural Networks(ANN)

ANN are machine based computational

techniques that attempt to stimulate some of
neurological processing abilities of human brain.
ANN offers unique advantages, as non-linear
processing capacity and the ability to model
poorly understood system. When compared with
RSM, the results are comparable with beter
prognostic abilities. However they are difficult to
implement particularly at higher number of
factors and/or levels, and no statistical criterion is
revealed to declare degree of aptness of model.

Artificial Neural Networks(ANN)

Architect and work pattern of ANN:
Pattern of connectivity among the ANN units is
equivalent to a mammalian neural architect as
shown below.
A typical ANN forms input and output layers and at
least one or more hidden layers and works by
reducing the error between observed and predicted
outcomes by adjusting the weight.
Mathematically, it detects the underlying patterns in
data that recognizes the functional relationships
between factors and responses and predicts
optimum levels of factors from a limited input data.

Artificial Neural Networks(ANN)

ANNs thus, are particularly suitable for complex and
non-linear systems for which the conventional
approaches more exhausting.
The neural network makes no assumptions about the
functional form of the relationships; it simply generates
and assesses a range of models to determine one that
best fits the experimental data provided to it.
As such, increasingly, (ANNs) are used to model a
complex behavior in problems like pharmaceuticals
formulation and processing. The models generated by
neural networks allow what if possibilities to be
investigated easily.

Artificial Neural
Networks(ANN)

Statistical Optimization Approach

Design of experiment (DoE), a statistics-based
approach carried out systematically, identifies
the critical variables, reveals their interactions
and helps obtain combinations of variables to
accomplish optimum response with lesser
number of experiments.
DoE algorithms are based on the principle
component analysis, polynomial regression,
analysis of variance (ANOVA) and mathematical
optimization algorithms.

References
N K Jain, Progress in controlled and Novel Drug Delievry
systems, CBS Publishers, New Dehli, 2004.
Class lecture by Dr. Nadeem Irfan Bukhari
Colbourn E. Spotlight on Intelligensys. Controlled
release society Newsletter. Vol 21 (3): Ibric, S, Djuric, Z.,
Parojcic J., Petrovic, U.
Artificial intelligence in pharmaceutical product
formulation: Neural computing. Chemical Industry &
Chemical Engineering Quarterly 15 (4) 227236 (2009)
Rowe, R. C. Roberts, R. J. Intelligent software for
product formulation, Taylor and Francis, London, 1998.

Thank You