COMPUTER SIMULATION: CONCEPT AND

APPLICATION IN FORMULATION AND

DEVELOPMENT
Subject: Computer Aided Drug Development (MPH 203T)

Presented By: Under the Guidance of:

Sharanya v. Paramshetti Dr. D. V. Gowda
Roll No- 21P08008 professor and Head,
I M.Pharm department of pharmaceutics.
Department of pharmaceutics. JSS college of pharmacy, Mysore
JSS College of Pharmacy, Mysore
 INTRODUCTION

Before a new drug can be released on the market, it must be formulated to produce
a quality product that is acceptable to both regulatory bodies and patients and can
be manufactured on a large scale.

There are many formulation types depending on the route of administration of the
active drug.

The process of formulation for any of the Pharmaceutical product is generically the
same, beginning with some form of product specification and ending with one or
more formulations that meet the requirements.
Correct choice of additives or excipients is paramount in the provision of efficacy,
stability, and safety.

For instance, the excipients may be chemically or physically incompatible with the
drug or they may exhibit batchwise variability to such an extent that at the
extremes of their specification they may cause failure in achieving the desired drug
release profile.

In addition, some excipients, especially those that are hydroscopic, may be

contraindicated if the formulation is to be manufactured in tropical countries.

Hence formulators must work in a design space that is multidimensional in nature

and virtually impossible to conceptualize.
Over the past decade a small number of visionary scientists have been
experimenting with and developing advanced computing techniques.

These include expert and knowledge-based systems for the generation of initial
formulations and processing conditions ab initio; neural computing for modeling
formulation and process data to explore relationships within the data set and
optimize the formulation; and computer simulation for the development of
mathematical models of the interaction between the formulation and the
manufacturing process to predict outcomes.

The idea behind this work is to assist the formulation of products with the added
benefits of consistent decision making, decreased timelines, and cost savings.
EXPERT AND KNOWLEDGE-BASED SYSTEMS

“An expert system is a computer program that draws upon the

knowledge of human experts captured in a knowledge base to solve
problems that normally require human expertise.”
 Expert systems comprise an interface allowing a two- way communication between
the user and the system: a knowledge base where all the knowledge pertaining to the
domain is stored and an inference engine where the knowledge is extracted and
manipulated to solve the problem in hand.

Inferencing strategies may be either-

• Forward chaining, which involves the system reasoning from the data and
information gained by consultation with the user to form a hypothesis

• Backward chaining, which involves the system starting with a hypothesis and then
attempting to find data and information to prove or disprove the hypothesis.

Both strategies are used in formulation expert systems.

 NEURAL COMPUTING

The properties of a formulation are determined not only by the ratios in which the
ingredients are combined but also by the processing conditions.

Although relationships between ingredient levels, processing conditions, and

product performance may be known anecdotally, rarely can they be quantified.

Traditionally, formulators have tended to use statistical techniques such as a

response surface methodology to investigate the design space, but optimization by
such a method can be misleading, especially if the formulation is complex.
 Recent advances in mathematics and computer science have resulted in the
development of three techniques that can be used to remedy the situation—

1. neural networks (an attempt to mimic the processing of the human brain);

2. genetic algorithms (an attempt to mimic the evolutionary process by which

biological systems self-organize and adapt),

3. fuzzy logic (an attempt to mimic the ability of the human brain to draw
conclusions and generate responses based on incomplete or imprecise
information).
 Like humans, neural networks learn directly from input data.

The learning algorithms take two main forms-

1. Unsupervised learning, where the network is presented with input data and learns
to recognize patterns in the data, is useful for organizing amounts of data into a
smaller number of clusters.

2. Supervised learning, which is analogous to “teaching” the network, the network is

presented with a series of matching input and output examples, and it learns the
relationships connecting the inputs to the outputs. Supervised learning has proved
most useful for formulation, where the goal is to determine cause-and-effect links
between inputs (ingredients and processing conditions) and outputs (measured
properties).
Diagram of a multilayer perceptron with one hidden layer
 COMPUTER SIMULATION

A computer simulation or a computer model is a computer programme that attempts to

simulate an abstract model of a particular system.

Simulation of a system is represented as the running of the system’s model.

Simulation is best described as the process of translating a real system into a working
model in order to run experiments.

A simulation does not duplicate a system; rather it is an abstraction of reality using

mathematics to express cause-and-effect relationships that determine the behavior of
the system.
Hence the representation displayed on a computer may not always be pictorially
similar to the real system, and, if it is, then it must be regarded as an added bonus.

Computational resources available today, large scale models of the body can be
used to produce realistic simulations.

It involves the use of computer simulations of biological systems, including cellular

subsystems (such as the networks of metabolites and enzymes which comprise
metabolism, signal transduction, pathways and gene regulatory networks), to both
analyze and visualize the complex connections of these cellular processes.
A computer model is the algorithms and equations used to capture the behaviour of the
system being modulated.

Computer simulation is the actual running of the program that contains these equations
or algorithms.

Computer Simulation In-silico- “performed on computer or via computer simulation”

Software- BIOSPHERA

IVALA

Software for computer simulation is often customized and based on that developed in
academia. There are not many commercial packages available for pharmaceutical
formulation.
In the current situation, the rapid development of technologies and computer
simulation is an integral part in the field of Pharmacokinetic and Pharmacodynamics
studies.

Computer simulation methods are depending on the availability of literature and

studies regarding pharmacokinetic and pharmacodynamic parameters of the
selected drugs.

The success of computer simulation methods depends on the quality of data inputs
available.

The main reason behind the less development of the simulation technique in the field
of medical is that critical part in understanding the aim and objective of the study,
which is the essential part for all experts.
 Make a Model
Real System
Model System

Construct
Perform Perform
approximate
Experiments Simulations
theories

Experimental Simulation Theoretical

Results Results Prediction

Compare & Compare &

improve model improve theory
 WHOLE ORGANISM

The essential goal of biocomputing is that computer simulation is able to model the
whole organism.

In drug development, it provides an obligatory handle to lead to a response from

exposure.

The intact organism can be mathematically represented; a whole series of

possibilities can be brought into practice, such as the simulation of clinical trails
and of the prospective behaviour of entire populations.
 EXPOSURE KINETICS RESPONSE
DYNAMICS
• Dosage • Route & • Continuous/
• Effect &
regimen absorption Discrete
• Chronic
toxicity
• Demographic • Receptor
• Clinical
exposure s Endpoints
interaction
• Environmenta • Serum • Surrogate
• Biomarkers
l factors concentration Endpoints
 In whole organism simulation, whole body systems are
usually repesented in one of the two ways:

A.Lumped- parameter PK-PD Model

B. Physiological modeling

• Isolated tissue and organs

• Cell, Proteins and Genes

LUMPED-PARAMETER PK-PD MODEL

The lumped element model (also called lumped parameter model, or component
model), is a simplified description of the behaviour of spatially distributed physical
systems into a topology consisting of discrete entities that approximate the behaviour of
the distributed system under certain assumptions.

The purpose of this study is to characterize the Pharmacokinetics (PK) and

Pharmacodynamics (PD) of population by modeling analysis and to predict proper
dosage regimens.

Plasma concentration over time was best described by a two-compartment linear model
and body weight was associated with central volume of distribution.
To predict the system’s behaviour over time, use a relatively small number of
differential equations, between one and ten.

Some variation of population PK-PD predicated on non-linear regression and

nonlinear mixed-effects models are used frequently but not always.

It is also used to estimate both the population parameter values and their statistical
distribution.

The same approach can be taken in reverse by using models to generate synthetic
data, ultimately performing a full clinical trial simulation from fist principles.
 PHYSIOLOGICAL MODELING

Physiologically based Pharmacokinetic (PBPK) models.

The model is still based on ordinary equations, but they strive to describe in more
detail about organism and especially the interacting organs.

Organism being studied by increasing the number of differential equations (from

10 to perhaps 30) and establishing appropriate interactions between the organs that
resemble their physical arrangement.
Model selection is driven by some kind of closeness criteria on that balances model
complexity with the actual information content provided by the measurements.

A consensus workshop developed some time ago, a set of “good practices” that can
serve as guidance to model development, selection and application.

PBPK models come at the problem from a different angle.

PBPK models can suffer greatly in their predictive power if their parameterization
is inaccurate, poorly specified, or not well tailored to the particular drug.

It is intresting to note that the foremost challenges for the detailed modelling of the
intact organism ( computing time, complexity of interactions, model selection).
 ISOLATED TISSUE AND ORGANS

Historically, the organs that are most extensively investigated include Heart and the Liver.

Even though the Kideny and Brain have also been the subjects of mathematical modeling
research.

Many of the computer simulations for Heart and Liver were carried out with Distributed
Blood Tissue Exchange (BTEX) Models.

The model BTEX is used because of the increased level of detail and temporal resolution
certainly makes the good mixing and uniformity hypotheses at the basis of lumped
parameter models less reasonable.
It can be hypothesized that the integration of organ-specific modeling with the
whole organism models would result in improvements for the PBPK approach
through “better” (i.e. more ohysiologically sensible and plausible) models of
individual organs.

The main challenge in doing so is the required shift from lumped to distributed
parameter models.

The development and integration of in vivo, organ specific mathematical models is

the mission of National Institute for General Medical Sciences at the NIH, the
Center for Modelling Integrated Metablic Systmes (MIMS) that can successfully
predict behaviours for a range of parameters, including rest and exercise and
various pathophysiological conditions.
Microcirculation Physiome and the Cardiome are other multicenter projects
focused on particular aspects of the Physiome undertaking.

There is an enormous variety of software for pharmacokinetic and

pharmacodynamic simulations.

The physiome of an individual’s or species’ physiological state is the description of

its functional behaviour.

The physiome describes the physiological dynamics of the normal intact organism
and is built upon information and structure (genome, proteome, and morphome).
CELL, PROTEIN AND GENES
 BENEFITS
Many simulations performed with minimum effort.

Allows investigation of the sensitivity of the system to small changes in parameters.

Assists in determining the accuracy to which the input parameters need to be controlled.

Allows the testing of the system in operating conditions that would be costly, dangerous, or time
consuming to perform.

Computer simulation methods helps in rapid development of dosage forms with cheaper price and
by using less manpower.

Excellent training tool.

 APPLICATIONS

The mechanical modeling of the tablet compaction process with finite elements was first
attempted in 1987 and has been refined since.

However, this methodology is based on the assumption that a tablet is a continuum, the
properties of which can be defined by constitutive equations.

It works well for tablet formulations comprising one ingredient but has little relevance
to multicomponent formulations.

Recently a combined finite-discrete element method for simulating multicomponent

pharmaceutical powder tabletting has been proposed
In this the irregular particle shapes and random sizes of powders are represented
as a pseudoparticle assembly having a scaled-up geometry but based on the
variations of real powder particles.

The method is currently being evaluated and validated against experimental data,
but initial results indicate that it does capture the characteristics of the
pharmaceutical tableting process.
A prerequisite of tablet compaction is the initial filling of the tablet die with
powder.

Powder packing is one process that has received a great deal of attention, and
commercial software for simulating this process is available (Macro Pac,
Intelligensys Ltd., UK).

This software is able to simulate the packing of multicomponent formulations of

particles of any shape and size with a Monte Carlo technique.

It is ideal for the simulation of the packing of pharmaceutical formulations into

both tablet dies and hard gelatin capsule shells.
A computer simulation of a size 0 capsule filled with pellets with
a size distribution of 0.8 and 1.2mm.
Solid inclusions in the form of pigments are often added to tablet film coatings to
improve their color and/or their opacity.

A potential problem is that of localized cracking around the individual particles or

aggregates compromising the release control of the active drug.

A simulation of crack propagation in such systems has been developed, allowing

the investigation of such effects of the addition of a second population of pigments,
pigment particle size and size distribution, polymer molecular weight, addition of
plasticizers, and many other factors affecting the film coating formulation.

Recently this simulation has been made available as MacroCrack from Intelligensys
Ltd., UK.
 A computer simulation of crack propagation in a
tablet film coating containing one population of an
inclusion
 CONCLUSION

The next generation of formulators in the pharmaceutical industry are likely to find
themselves using all of the above techniques routinely and to an increasing extent.

Several pharmaceutical companies have already implemented some of them and made
them available to formulators either as stand-alone programs or linked via an intranet.

However, the largest benefit in the future will undoubtedly arise from the seamless
integration of all of the techniques into a common decision support system allowing the
in silico generation of formulated products ab initio with the added benefits of
consistency, decreased timelines, and cost savings.
 REFERENCES

Computer Applications in Pharmaceutical Research and Development; Sean Ekins,

2006, John Wiley & Sons.

A Textbook of Computer Aided Drug Development; Karri V V S Narayana Reddy.

Computer Aided Drug Development; Dr Md Rageeb Md Usman.

THANK YOU