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Drug Delivery & Formulations

Formulating Knowledge
Large amounts of data are currently being generated in an attempt
to understand and improve formulation and manufacturing efficiency;
this requires novel data mining technologies tailored specifically for the
formulator/process engineer.
By Ray Rowe and Elizabeth Colbourn at Intelligensys
Ray Rowe is Chief Scientist at Intelligensys; he is also Professor of Industrial Pharmaceutics at the University of
Bradford (UK). He was formerly a Senior Principal Scientist at AstraZeneca where he advised senior management
on the implementation of new science and technology for product development. Dr Rowe was awarded a BPharm
from the University of Nottingham (UK) in 1969, and a PhD and DSc from the University of Manchester (UK) in
1973 and 1993 respectively. He has contributed to over 350 publications in the pharmaceutical sciences, including
a book and eight patents.
Elizabeth Colbourn is Product Director at Intelligensys. A Canadian by birth, she has written over 50 refereed
publications covering many aspects of materials and molecular modelling. She has a BSc in Chemistry from
Queens University, Canada, and a D Phil in Theoretical Chemistry from the University of Oxford. For several
years, Dr Colbourn was based at ICIs Wilton Research Centre where she established and led the materials
modelling team, and was also appointed to ICIs prestigious Scientific Ladder, one of the first two women
to attain this position.

The pharmaceutical industry is currently undergoing a

radical change in its ways of working. Directives from
the FDA have raised questions about understanding the
relationships between formulation and manufacturing
that result in controlled product performance.
However, these relationships can rarely be precisely
quantified, and the formulation and manufacturing
have to be carried out in a design space that is multidimensional in nature and difficult to conceptualise.
Attempts to investigate these problems through the use

of experimental design have resulted in the generation

of large amounts of data, but processing the data
remains a challenge. This article introduces two new
implementations of data mining (the software packages
INForm and FormRules) that are specifically tailored
for the pharmaceutical formulator/process engineer in
order to generate understandable rules, and to model
and optimise the formulation/process.
ADVANCED TECHNOLOGIES
Both INForm and FormRules rely on advanced
computing techniques such as neural networks, fuzzy logic
and genetic algorithms. Neural networks are mathematical
constructs that are capable of learning, for themselves,
relationships within data. No assumptions need be made
about the functional form of these relationships, since the
neural network simply tries out a range of models to
determine one that best fits the known data. In
recent years, artificial neural networks (often
referred to as ANNs) have increasingly and
successfully been used to model complex
behaviour in problems like pharmaceutical
formulation and processing (1).

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Fuzzy logic can be implemented to allow the formulators

objectives to be described in a linguistically intuitive way.
Traditional crisp logic means that values must be either
true (1) or false (0). Fuzzy logic, based on the theory of
fuzzy sets, allows the membership in each set to take
a value between 0 and 1. For example, if a tablet
disintegration time of less than 300 seconds is desired,
then a value above 300 seconds will have a desirability of
less than 100%, with the desirability decreasing as the
disintegration time increases. This gives the formulator
considerable control over the optimisation process.
As the name implies, genetic algorithms use an
evolutionary approach to finding the best solutions. To
do this, a measure of fitness is set up, using the desired
values for each property, together with its importance
relative to other properties. The optimisation starts with
a random trial population, and the fitness of each
member in the population is assessed. New solutions are
generated from the fittest members, using mathematical
operations that are analogous to reproduction and
mutation, and their fitness is assessed. In this way the
population evolves so that ultimately the fittest solution
is the one that best meets the formulators specified
needs. If there are constraints on the ingredients or
processing conditions for example, if a particular
combination of ingredients must sum to 100% these
can be implemented easily by penalising the fitness of
non-conforming solutions.
Combining these technologies enables the development
of useful and powerful methodologies. For example,
using neural networks for modelling together with
genetic algorithms for optimisation (as is done within
INForm) allows the user to develop a formulation or
process to meet stringent, often conflicting, objectives.
More recently, new methodologies like neurofuzzy logic
(implemented in FormRules) have evolved; this
combines the ability of neural networks to learn from
data with fuzzy logics capacity to express complex
concepts simply, allowing the formulator and process
engineer to gain an understanding of the underlying
rules governing the formulation and process.
DATA MINING FOR CONTROLLED RELEASE
Several examples illustrate this point. The first refers to a
controlled release tablet (2), in which two polymers are
mixed in varying amounts, together with a lubricant and
other excipients. The tablet hardness, the percentage of
moisture, and the particle size are also used as input
Innovations in Pharmaceutical Technology

Figure 1: The set-up for a controlled release tablet,

showing inputs and outputs

Figure 2: Results of data mining for controlled release tablet, showing

dependence of release at 8 hours on different input variables

variables, as illustrated in the screenshot in Figure 1. The

properties, as shown in Figure 1, are the amount of drug
released at various time intervals from 1 to 24 hours.
Using FormRules for data mining, the key relationships
within the data can be extracted readily. The results show
that the short-term release (up to about 4 hours) is
dominated by Polymer A, and that as the amount of
Polymer A increases, the amount of drug released
decreases approximately exponentially. At long times
(greater than 16 hours), the release profile is dominated
by the amount of Polymer B, with the amount of drug
released decreasingly linearly as the amount of Polymer B
is increased. At intermediate times, both Polymer A and
Polymer B affect the release profile. As shown in
Figure 2, for the 8-hour release, in addition to the two
polymers, the amount of lubricant and the percentage of
moisture also play a role.

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Figure 3: Optimisation set-up for immediate release tablet,

requesting rapid disintegration time and high tablet hardness
The 3D graph shows that low disintegration times occur
at low concentrations of PVP.

ingredients and processing conditions affect each of the

properties, and the nature of the functional form
describing the interaction.
OPTIMISING IMMEDIATE RELEASE TABLETS

The purple colour used to display the relevant submodel

indicates that the most important relationship in
determining the 8-hour release involves an interaction
between Polymer A and the amount of lubricant. The
amount of Polymer B and the percentage of moisture also
play a role. Neither of these inputs has an interaction with
any other variable, as is clear from the fact that they
contribute to different submodels. (The total model is the
sum of all the submodels.) The neurofuzzy approach also
allows rules to be extracted directly from the data. A
typical rule is: if Polymer A is LOW and lubricant is LOW,
then 8-hour release is HIGH, with 100% confidence.
As this example illustrates, models and rules obtained
using the neurofuzzy approach highlight directly which

Another example illustrating the power of neural

computing techniques is shown by an optimisation of
immediate release tablets. Here, data published by
Kesavan and Peck (3) have been analysed using socalled multi-layer perceptron neural networks (1) as
implemented in INForm. The inputs to the model are the
type of diluent (either lactose or dicalcium phosphate
dihydrate), the amount of diluent, the PVP concentration,
the granulation equipment used (either fluidised bed or
high shear mixing) and whether the binder was added dry
or in solution. The properties measured by Kesavan and
Peck include tablet hardness, friability, thickness and
disintegration time; using INForm, a separate model has
been developed for each property. ANOVA statistics show
that good models (with R2 values in excess of 0.8) can be
found for each of the properties.
One of the challenges in developing an immediate release
tablet is to create a hard tablet that also disintegrates
quickly. Such conflicting objectives pose a challenge to
the formulator, and within the measured data, the
disintegration time ranges from 161 to 1,520 seconds
while hardness is between 3.84 and 12.44. The models
allow what if trials to be carried out to see what would
happen if various changes were made to the ingredients
and processing conditions but optimising in this trialand-error fashion can be laborious. The task of finding an
optimum is made significantly easier when optimisation
algorithms, like the genetic algorithms described above,
are integrated with the neural network models. This allows
the formulator to specify the properties that the
formulation should have, and the software then searches
for a formulation that best meets these requirements.
A screenshot illustrating one possible set of requirements is
shown in Figure 3; here, disintegration time must be
less than 240 seconds, and hardness must be
greater than 10kPa. Using INForms models
and genetic algorithms, the optimisation
shows that the most rapid disintegration times
are achieved when the diluent is lactose (in

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line with the expectations of experienced formulators).

However, it is impossible to obtain a disintegration time of
less than 240 seconds and a hardness greater than 10 within
the design range of the data used to train the models.
The optimisation highlights an important finding: the
design space used for the initial experimentation may not
contain the optimum. The optimisation has suggested
that 47.5% lactose and 2% PVP gives the best
formulation, but these are on the upper and lower limits,
respectively, of the values used in obtaining the data.
Therefore the optimisation exercise suggests that
carrying out further experiments with increased amounts
of diluent could be useful. It is also significant that the
software can be used to suggest the optimum process
conditions, as well as the ingredient amounts.
SUSPENSION FORMULATION
INForm and FormRules work with the data that they are
given and can therefore be applied to all other types of
formulation too as long as data are available. To
illustrate, data from Elkheshen, Badawi and Badawi (4),
for a suspension formulation, have been mined using
FormRules. For this data set, rifampicin, sodium citrate,
citric acid, sodium benzoate and flavour were mixed in
fixed amounts, while the amounts of Avicel, sucrose,
Aerosol and Aerosil were varied. These last four were
therefore taken as inputs to the model. The measured
properties were the bulk density of the powder, its
flowability, the viscosity of the suspension after 24 hours,
the sedimentation volume as a percentage of the original
volume, and the ease of redispersion.
Data mining shows that the bulk density is controlled
primarily by the amounts of sucrose and Aerosil, with
some contribution from the amount of Aerosol.
Flowability depends mainly on the amount of Aerosil,
with some contribution from the sucrose. Redispersibility,
on the other hand, is mainly affected by the amounts of
Aerosil and Aerosol, with some contribution from the
amount of Avicel. The key rules for redispersibility are:

These rules show that the amount of Aerosil has

the main effect on redispersibility, although the
methodology has discovered a small effect from Aerosol
as well. Therefore, a formulator particularly concerned
with improving redispersibility would be guided to focus
attention on the quantity of Aerosil in the formulation.
BENEFITS IN PRODUCT DEVELOPMENT:
BETTER PRODUCTS FASTER
Neural computing and advanced computing technologies
have a proven track record in pharmaceutical formulation
(1). Their implementation in INForm and FormRules
allows formulators and process engineers to extract
maximum value from their formulation and processing
data, improving both the efficiency and the effectiveness
of their product development cycle. Using these
approaches, key relationships can be discovered rapidly,
expressed succinctly and communicated clearly. Because
the methods are entirely data-driven, they can be applied
to many different formulation and processing problems;
the only requirement is the availability of data of
reasonable quality and quantity.
Forward-thinking pharmaceutical companies are already
adopting these technologies as part of decision support
toolkits for their product formulators and process
engineers and all the indications are that such advanced
computing techniques will be used routinely in the
future. New technologies like genetic programming are
under active investigation, and will be integrated into the
toolkits once their utility has been completely proven.
The authors can be contacted at
postmaster@intelligensys.co.uk
References
1.

of Pharmaceutical Technology, 2005.

2.

If Aerosil % is LOW and Aerosol % is LOW,

then Redispersibility % is LOW,
If Aerosil % is LOW and Aerosol % is HIGH,
then Redispersibility % is LOW,
If Aerosil % is HIGH and Aerosol % is LOW,
then Redispersibility % is HIGH, and
If Aerosil % is HIGH and Aerosol % is HIGH,
then Redispersibility % is HIGH.

74

Colbourn EA and Rowe RC. Neural Computing

and Formulation Optimization, in Encyclopedia

Chen Y, McCall TW, Baichwal AR, Meyer MC (1999).

J. Controlled Release, 29, 33-41.

3.

Kesavan JG and Peck GE (1996). Pharm

Dev Technol, 1, 391-404.

4.

Elkeshen SA, Badawi SS and Badawi AA (1996).

Drug Development and Industrial Pharmacy, 22,

623-630.

Innovations in Pharmaceutical Technology