Computer Aided Pharmaceutics and Drug Delivery An

Application Guide for Students and Researchers of

Pharmaceutical Sciences

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Dedicated to
my Mother Mrs. Chanderpati
&
my Father Mr. Dayanand Saharan
Foreword

I remember starting to use a computer in the early 1990s. PCs were chunky and very
costly and it was a matter of pride to have a PC on the desk at that time. The initial
scientific uses were centered on the preparation of scientific reports and publications.
Computational chemists and scientists working on molecule modeling had sophisti-
cated workstations which catered to the requirements of in silico drug discovery.
Computers on the desk of formulation scientists reached in 1992. Later in the 2000s,
it almost became a routine to start the work of the day by checking and responding to
emails. The internet fired the popularity of PC as scientists and they started commu-
nicating through emails which were easier, cheaper, and faster than any other mode.
Further, gradually with better functionality of search engines, the task of retrieving
information became easier. Journals started appearing online and this transition
gradually reduced the visits of researchers and students to libraries. Hand searching
of journals gradually shifted to proprietary database searching (SciFinder, Interna-
tional Pharmaceutical Abstracts, etc.) and online searching on platforms like
PubMed. The internet was being considered as a host of libraries with subscription
services from publishers for either individual journal or online libraries of
publishers, like ScienceDirect, Ingenta, etc. My first software purchase in the area
of pharmaceutics was Design Expert in 2002.
Life is very different now; I am dependent on various apps on mobile phone,
tablet, and PCs.
I know Prof. Vikas Anand since his master’s program at NIPER, India. During his
studies, I observed him developing a keen interest in computers. He used to spend
most of his time either in the Library or Computer Centre of NIPER. In those days,
he was pretty good at scholarly information retrieval, e.g., patent searching and data
analysis on computers relevant to pharmaceutical sciences. Since then, he continued
to develop his interest. I am happy to see that his and his team’s efforts have resulted
in a great compilation of the most interesting topics on computer applications in
pharmaceutics.
There are not many books written on computer applications in the area of
pharmaceutics or focusing on in silico developments in drug delivery. The title
Computer Aided Pharmaceutics and Drug Delivery fascinated me. I am sure that
everyone in the area of Pharmaceutics would love to read it and recommend it. A lot
has been written on Computer-Aided Drug Design (CADD), but this is a unique

vii
viii Foreword

attempt at combining computers with pharmaceutics. I would like to see more

volumes in future with the rising role of molecular pharmaceutics, DoE, prediction
of physicochemical properties and ADMET predictions, robotics and automation,
and in silico analysis of pharmaceutical formulations. The idea of authors to con-
ceive the term “Computer-Aided Pharmaceutics” will flourish with advancements in
AI, data science, and quantum computing.
I would like to recommend this book to all graduate and postgraduate students of
pharmacy as the chapters are good at conceptual understanding and updated with
recent knowledge in the field. Scientists working in industries and other research
institutions will also find it attractive with applications of commercial software/
expert systems/AI packages through the most recent publications.
I wish to congratulate the team of authors and Springer publisher for excellent
work and contribution to the pharmaceutical sciences. It is especially pleasing to
note that Vikas’s contributions in the field, keep it up.

University of South Australia Sanjay Garg

Adelaide, SA, Australia
12 May 2021
Preface

I got an opportunity to learn computer applications for the very first time in my
school days, in the 1980s, when I had learnt a little bit of programming in DOS and
the thing I remember most is playing Pac-Man when our teacher was not around us. I
had no course on computers in our Bachelor of Pharmacy program. In 1999–2001, I,
as a student of Master’s Program in Pharmaceutics, had a full course on computers at
NIPER (Mohali). We, the students of the postgraduate program, had received long
hand practical trainings from teachers of not only the computer department but also
from other departments like pharmaceutics, pharmaceutical analysis, pharmaceutical
chemistry, and pharmacology. We were taught and trained for various applications
of computers like chemical structure drawing, molecular modeling, information
retrieval, reference managing, applications of Excel in data handling and visualiza-
tion, communication tools, and many others. At that time, we were curious to find
whether all that training will ever be of any use in formulation development. But
now after about 20 years of experience in the field, I can say with confidence that our
dependency on computers has increased tremendously for designing quality in
formulations, in silico ADMET (Absorption, Distribution, Metabolism, Excretion,
and Toxicity) predictions, and automation of manufacturing, laboratory, and analyt-
ical procedures.
Advancements in Computer-Aided Drug Design (CADD) and the availability of
three-dimensional structures of polymers, receptors, and other macromolecules have
allowed formulation scientists to explore in silico drug-polymer interactions for drug
targeting, controlling drug release, and other applications. The rise of animal and
human ethical concerns has also propagated in silico characterization of ADMET
eliminating/reducing the use of animals/humans. Computer simulations have
provided new avenues to discover pharmacokinetics/pharmacodynamics of new
molecules on whole organisms, isolated tissues, cells, proteins, and genes. Data
collection and maintenance is now very easy through electronic notebooks and
numerous data storage options like cloud storage, thanks to the ultra-high internet
speed, search engines, and databases which have eased the process of scholarly
literature retrieval. Artificial intelligence, robotics, big data (omics, chemical and
clinical), IoT, and health devices/apps are accelerating innovative computer
applications in drug formulation design, manufacturing, and delivery of drugs.
Computational approaches, statistical and molecular modeling have radically

ix
x Preface

transformed dosage form development and drug delivery programs of pharmaceuti-

cal industries through experimental design and quality predictions via Artificial
Intelligence (AI) based software. The concept of QbD (Quality by Design) has
emerged as an interesting application of computers for formulation development.
DoE (Design of Experiments) and optimization of process/formulation have been
made a lot easier with the help of software and expert systems.
This book Computer Aided Pharmaceutics and Drug Delivery (CAPDD)
explores the role of computers, software, databases, artificial neural networks, expert
systems, and information technologies in the fields of pharmaceutical formulation
development, manufacturing, drug delivery, biopharmaceutical and pharmacoki-
netic characterization, and pharmaceutical analysis. This book aims to fulfill the
curricular requirements of graduate and postgraduate students of pharmacy. Formu-
lation scientists and research scholars find few resources on computer applications
outside the primary literature. Scientists at midcareer found it most difficult to deal
with the issue of scarcity of books on this topic. This book also caters to the
requirements of scientists and research scholars to present most updated computer
applications in a very lucid manner to make the learning curve somewhat shallow.
Abundant applications of computers in formulation designing and characterization
are provided as examples, case studies, and illustrations. Short reviews of software,
databases, and expert systems have been added to culminate the interest of readers
and inspire them to apply these tools for developing novel formulations for effective
drug delivery.
I do hope that the vision of this book will be realized with the rise in computer-
based formulation development, characterization, and manufacturing in pharmaceu-
tical industries to speed up the delivery of drug products to patient’s bedside. I
sincerely believe that you will enjoy reading and learning from history the present
and future applications of computers as I have enjoyed while editing this book.

Dehradun, Uttarakhand, India Vikas Anand Saharan

Acknowledgments

First and foremost, I would like to thank God, the almighty, for all the graces,
blessings, health, knowledge, and opportunity to me so that I can accomplish this
book project in time.
I am extremely grateful to the management and administration of Sardar
Bhagwan Singh University, especially Dr. Gaurav Deep Singh (Hon’able Chancel-
lor), Sh. S. P. Singh (Chairman, Gaurav Bharti Shiksha Sansthan), Prof. Veerma
Ram (Hon’able Vice Chancellor), and Sh. KBS Rawat (The Registrar) for all-round
support during my entire tenure at the University. I am highly privileged to have
some of my great teachers, like Dr. Luvkush, Prof. Veerma Ram and Ms. Urmi
Chaurasia, Prof. Sanjay Garg, and Prof. P. K. Choudhury, as a constant and
continuous source of inspiration and motivation.
I appreciate the support received from Prof. R. J. Krupadam (CSIR-NEERI),
Prof. Hemant Jadhav (BITS, Pilani), Prof. Sokindra Kumar (Subharthi Univer-
sity), Prof. Alka Chaudhary (SGRR University), Prof. Ganesh Bhatt (Shivalik
College of Pharmacy), Prof. Mamta F. Singh (Sardar Bhagwan Singh University),
Dr. Seema Sadrai (Tehran University of Medical Sciences), Dr. Anand Sharma
(NIPER Mohali), Dr. Hitesh Kulhari (Central University of Gujarat), Dr. Mahesh
K. Kataria (Seth GL Bihani SD College of Technical Education), Dr. Bhavna
(DIT University), Dr. Ujwal Kolhe (NIPER, Reabareli), Dr. Supriyo Saha (Sardar
Bhagwan Singh University), and Mr. Prashant Beniwal (Seth GL Bihani SD
College of Technical Education) for reviewing book chapters and providing
their critical comments for improving the quality of book chapters.
I would like to thank all the chapter authors for their hard work, valuable
contributions, and their patience in various phases of publication of this book. I
am extremely thankful to Dr. Gaurav Singh (Editor, Springer Nature), Mr. Ejaz
Ahmad (Project Coordinator, Springer Nature), Ms. Raman Shukla (Associate
Editor, Springer Nature), and Ms. ArulVani Parttibane (Project Manager, Straive)
for their continuous support in providing necessary guidance throughout this project.
I thank Springer for providing a platform from where this book can reach to its
readers.

xi
xii Acknowledgments

Without the support of my mother, father, and wife, it was really impossible to
complete this arduous task. They have sacrificed a lot of my personal time while I
was working on this book. I also missed my sons, Inesh and Krit, when I was
working on this book and they were not beside me.

18th May 2022 Vikas Anand Saharan

Sardar Bhagwan Singh University
Dehradun, Uttarakhand, India
Contents

1 History and Present Scenario of Computers in Pharmaceutical

Research and Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Vikas Anand Saharan, Surojit Banerjee, Swati Penuli,
and Swati Dobhal
2 Historical Developments on Computer Applications in
Pharmaceutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Nidhi Nainwal, Richa Bahuguna, Surojit Banerjee,
and Vikas Anand Saharan
3 Computer-Aided Formulation Development . . . . . . . . . . . . . . . . . . 73
Rania M. Hathout and Vikas Anand Saharan
4 Quality by Design in Pharmaceutical Development . . . . . . . . . . . . . 99
Rajesh Kumar, Amit Mittal, and Mangesh Pradeep Kulkarni
5 Teaching Principles of DoE as an Element of QbD for Pharmacy
Students . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Rania M. Hathout
6 Computer-Assisted Manufacturing of Medicines . . . . . . . . . . . . . . . 153
Lalji Baldaniya and Bhumika Patel
7 Computer-Aided Biopharmaceutical Characterization:
Gastrointestinal Absorption Simulation and In Silico
Computational Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Daisy Arora and Bharat Khurana
8 Computer Simulation and Modeling in Pharmacokinetics
and Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Ruchi Chawla, Varsha Rani, Mohini Mishra, and Krishan Kumar
9 Physiologically Based Pharmacokinetic (PBPK) Modelling . . . . . . . 255
Ankit Balhara, Sumeet Kale, and Saranjit Singh

xiii
xiv Contents

10 Computers in Clinical Development . . . . . . . . . . . . . . . . . . . . . . . . 285

Swati Changdeo Jagdale and Asawaree Anand Hable
11 Artificial Intelligence and Its Applications in Drug Discovery,
Formulation Development, and Healthcare . . . . . . . . . . . . . . . . . . . 309
Debadri Banerjee, Deepti Rajput, Surojit Banerjee,
and Vikas Anand Saharan
12 Robotic Automation of Pharmaceutical and Life Science
Industries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Vikas Anand Saharan
13 Soft Robots for the Delivery of Drugs . . . . . . . . . . . . . . . . . . . . . . . 415
Surojit Banerjee and Vikas Anand Saharan
14 Online Literature Searching for Research Projects
in Pharmaceutical Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Vikas Anand Saharan, Surojit Banerjee, Swati Dobhal,
Manoj Kumar Sarangi, and Anupama Singh
15 Patent Searching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Brahmeshwar Mishra and Gunjan Vasant Bonde
16 Computer Aided Drug Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Bhupinder Kumar, Pooja A. Chawla, and Viney Chawla
17 Quantitative Structure-Property Relationship (QSPR) Modeling
Applications in Formulation Development . . . . . . . . . . . . . . . . . . . . 543
Pankaj Wadhwa and Amit Mittal
18 Modelling Approaches for Studies of Drug-Polymer Interactions
in Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Mire Zloh and Nuno Martinho
19 Computers in Pharmaceutical Analysis . . . . . . . . . . . . . . . . . . . . . . 593
Mukesh Maithani, Viney Chawla, and Pooja A. Chawla
20 Telemedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
Mehdi Chamani, Parsa Khoshkhat, and Farid Abedin Dorkoosh
21 Bioinformatics in Drug Design and Delivery . . . . . . . . . . . . . . . . . . 641
Rishav Kumar, Meenakshi Gupta, and Maryam Sarwat
22 Statistical Modeling Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Pooja Arora and Ambulge Sheetal
23 Molecular Modeling of Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . 681
Bilge Bicak, Bahar Gok, Serda Kecel-Gunduz,
and Yasemin Budama-Kilinc
Contents xv

24 Pharmaceutics Informatics: Bio/Chemoinformatics in Drug

Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
Rania M. Hathout and Abdelkader A. Metwally
25 Computer-Aided Development and Testing of Human
Extra-Thoracic Airway Models for Inhalation Drug Delivery . . . . . 725
Xiuhua April Si and Jinxiang Xi
About the Editor

Vikas Anand Saharan had obtained his B.Pharm from SBSPGI Dehradun, mas-
ter’s from NIPER Mohali, and PhD from Mohanlal Sukhadia University Udaipur.
He has 20 years of teaching and research experience in pharmacy, published 60+
papers in journals, presented 75+ papers in conferences, and supervised 39+
M.Pharm and 2 PhD thesis. He has authored 3 books and 19 book chapters. He
has received an award for GATE guidance and appreciation awards for teaching and
research. He is a reviewer and editorial board member of various national and
international journals. He is a recipient of grant-in-aid under the AICTE-
MODROBS project. Presently he is also entrusted with the responsibilities of chief
program coordinator for PhD and nodal officer for AISHE at Sardar Bhagwan Singh
University.

xvii
History and Present Scenario of Computers
in Pharmaceutical Research 1
and Development

Vikas Anand Saharan, Surojit Banerjee, Swati Penuli,

and Swati Dobhal

Contents
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2 The Birth of Computational Chemistry: The 1960s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Evolving Collaboration of Computational Chemists with Other Chemists: The 1970s . . . 7
1.4 Multifaceted Acceptance of Computational Chemistry and the Birth of CADD:
The 1980s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.5 CADD Regaining Momentum and Entry of ML: The 1990s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.6 CADD and Big Data: The 2000s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.7 AI Integration with CADD: The 2010s to Present . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.8 Computer-Aided Pharmaceutics and Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
1.9 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Abstract

Twentieth and early twenty-first centuries have observed a lot of fascinating

developments in pharmaceutical research and development with the rising role
of computers. Computers have transformed drug discovery form hit-and-trial
approach to rational drug design. Initial quantitative structure-activity relation-
ship (QSAR) studies led to the foundation of computer-aided drug design
(CADD), which subsequently evolved to structure-based drug design (SBDD),
ligand-based drug design (LBDD), and fragment-based drug design (FBDD). The
successes of computational chemistry and CADD have brought many interesting

V. A. Saharan (*) · S. Banerjee · S. Penuli

Department of Pharmaceutics, School of Pharmaceutical Sciences and Technology, Sardar
Bhagwan Singh University, Dehradun, Uttarakhand, India
S. Dobhal
Department of Pharmacology, School of Pharmaceutical Sciences and Technology, Sardar
Bhagwan Singh University, Dehradun, Uttarakhand, India

# Springer Nature Singapore Pte Ltd. 2022 1

V. A. Saharan (ed.), Computer Aided Pharmaceutics and Drug Delivery,
https://doi.org/10.1007/978-981-16-5180-9_1
2 V. A. Saharan et al.

drug molecules from bench to the patient’s bedside. Drug discovery, being a
multidisciplinary field, has been benefited with the advancements from the field
of not only computers but also from associated technologies like softwares,
Internet, big data, omics, internet of things, and artificial intelligence (AI). This
chapter is the author’s attempt to explore history from 1960 to the present time for
finding key developments that have played a larger role in evolving drug discov-
ery and development.

Keywords
Computational chemistry · CADD · Artificial intelligence · Drug discovery ·
Hardware · Software · Database · Program · Molecular modeling · SAR

Chapter Objectives
Upon reading of this chapter, it is expected that reader will be able to understand:

• History of use of computers in pharmaceutical companies

• The history of advancements in computers, computer languages, and softwares
for drug discovery and development
• Key developments in the fields of computational chemistry, computer-aided drug
design (CADD), and artificial intelligence (AI)
• The advancements of drug discovery programs vis a vis to advancements in
science with the rising role of computers and softwares
• Some significant discoveries and developments, which have a long-term impact
on pharmaceutical industries, either in research and development or in
manufacturing of drug products
• Marketed drugs whose discovery was assisted by computers and softwares

1.1 Introduction

Development of the human race has brought about revolutionary changes in several
aspects of life, be it lifestyle or technology. Computers, in terms of technology, have
been a boon for the society owing to the ease of some high-end tasks it provided.
Charles Babbage conceived the idea of computer with his “Analytical Engine” and
“Difference Engine” designs in the nineteenth century and passed on plans for its
completion [1]. Babbage could not construct any of his designs but later the designs
of Babbage laid foundations of modern computing. Alan M. Turing conceived the
idea of a universal machine (Universal Turing Machine) in 1936 [2]. Universal
Turing machine laid foundations for the successful construction of initial computers
like Turing’s Automatic Computing Engine (ACE), and John von Neumann’s
Electronic Numerical Integrator and Computer (ENIC) and Electronic Discrete
Variable Computer (EDVAC) [3]. Universal Automatic Computer (UNIVAC) was
the first commercial computer developed by J. Presper Eckert and John Mauchly and
delivered by Remington Rand, an office equipment company in 1951 [4]. IBM701,
of pioneer IBM700 series, was the first commercially available scientific computer,
1 History and Present Scenario of Computers in Pharmaceutical Research and. . . 3

which came in the 1950s [5]. IBM 704, IBM 709, IBM 650, and IBM 610 were some
computers which were purchased for their use in finance and business operations of
industries or business firms [6]. In science, initially, use of computers was restricted
to solving mathematical problems but later the use of computers grew in the fields of
chemistry and biology albeit through more involvement of mathematics in science.
With the development of dispersive computer technologies and widespread use of
softwares and the Internet, drug discovery in pharmaceutical industries has gradually
become a multidisciplinary field.
Programming languages are the languages used by the programmers to commu-
nicate with the computers, that is, it is the language of the computers, for example,
DOS, C, C++, JAVA, SQL, etc. Programming languages allow humans to give
instructions to a computer in a language the computer understands. These program-
ming languages form the framework for the development of the various softwares
and applications that are run on computers [7]. Software is an array of instructions or
programs that are defined to perform a specific function. ChemDraw, AutoDock,
DesignExpert, and GraphPad Prism are some softwares used in pharmaceuticals and
other research fields [8]. Hardware are the physical parts of the computers like the
central processing unit (CPU), monitor/screen, mouse, keyboard, graphics card, etc.
that are involved in storage and execution of the software. The programming
language, software and hardware together, end up in the efficient working of the
computer system.
The initial computer language used was the Regional Assembly Language that
required a great deal of efforts by programmers. With the development of high-level
programming languages, several new languages came into existence that eased the
work of the programmers and resulted in development of various application
softwares that can be employed for scientific purposes in pharmaceutical industries
and other institutions. The efforts and exertion of performing data analysis, statistical
computations, and data compilation was eased as all of this is now just a click away
with the help of softwares like SPSS, XLSTAT, Stata, etc. The experiments that
were hard to perform or used animal models can now be easily performed using
simulation softwares in computers, for example, Ex-Pharm. The softwares are also
being employed in the process of drug discovery like docking models of drugs, that
is, if the structure of protein to which the drug will bind is available from a database,
the structure of potential biologically active molecule can be easily elucidated using
software, for example, AutoDock, etc. [9]. Software packages have been advanced
with computing speed of computers and the use of integrated AI technologies for
accurate predictions of biological activity, physicochemical property, toxicity, and
pharmacokinetics.
This chapter is an attempt of authors to look back into the history to find some
remarkable developments of hardware, programming languages, and softwares for
their specific applications in the field of drug discovery and development. Emphasis
has been laid down to track key developments of computational chemistry,
computer-aided drug discovery (CADD), and AI. In addition to this, significant
developments of early twenty-first century are also presented.