PREPARATION, CHARACTE

MACROMOLECULAR COMPLEXES OF EUDRAGIT

AKPA, PAUL ACHILE

PG/PhD/04/39114

PREPARATION, CHARACTERIZATION AND APPLICATIONS OF IONIC LIQUID SOLUBLE

MACROMOLECULAR COMPLEXES OF EUDRAGIT® E100 AND EUDRAGIT®

DEPARTMENT OF PHARMACEUTICS

FACULTY OF PHARMACEUTICAL SCIENCES

Okey ijere

Digitally Signed by: Content m

DN : CN = Webmaster’s name

O= University of Nigeria, Nsukka

OU = Innovation Centre

i

RIZATION AND APPLICATIONS OF IONIC LIQUID SOLUBLE

L100 55 IN DRUG

DEPARTMENT OF PHARMACEUTICS

FACULTY OF PHARMACEUTICAL SCIENCES

: Content manager’s Name

Webmaster’s name

a, Nsukka

ii

PREPARATION, CHARACTERIZATION AND APPLICATIONS OF IONIC

LIQUID SOLUBLE MACROMOLECULAR COMPLEXES OF EUDRAGIT®

E100

AND EUDRAGIT® L100 55 IN DRUG DELIVERY

BY

AKPA, PAUL ACHILE

PG/PhD/04/39114

DEPARTMENT OF PHARMACEUTICS

FACULTY OF PHARMACEUTICAL SCIENCES

UNIVERSITY OF NIGERIA, NSUKKA

iii

APRIL, 2013

CERTIFICATION

Paul Achile Akpa, a postgraduate student in the Department of Pharmaceutics with

Registration Number PG/PhD/04/39114 has satisfactorily completed the requirements for the

degree of Doctor of Philosophy in Pharmaceutics. The work embodied in this Thesis is

original and has not been submitted in part or full for any diploma or degree of this or any

other University.

.

......................................... …………………...................

Professor V. C. Okore (Supervisor) Prof. A. A. Attama (Supervisor)

Date:…………… Date:……………

………………………

Professor A. A Attama Date:……………………

Head of Department

iv

DEDICATION

“Feci quod potui, faciant meliora potentes”

I have done what I could; let those who can do better

To my bosom friend Elechi Maduekwe (Prof). who now contemplates time and history

from the other side in gratitude for all the support that he proffered to me in many of my

projects.

v

ACKNOWLEDGEMENT

Firstly, I would like to express my deep gratitude to my project supervisors Profs. Vincent C.

Okore and Anthony A. Attama for the very fascinating topic of my Ph.D work, for the

fruitful discussions, inspirations and for the wide berth of freedom in research given to me

by them. Furthermore I would like to thank them for their understanding and constant

encouragement in all situations. Thank-you to Professor Marcos Lopes Dias (Instituto de

Macromoleculas Eliosa Mano, Universidad de Rio de Janiero, Brasil) for the very fruitful

cooperation (Execution of the more advanced physico-chemical characterization tests on

polyelectrolytes and polyelectrolyte complexes. I want to thank Dr. Kana of SHESTCO,

Abuja for the electron microscopic studies as well as some of the X-ray diffraction studies.

Dr. Fabian Ezema of the Department of Physics of the University of Nigeria, Nsukka is also

appreciated for introducing me to the stimulating world of Materials Science, Prof. Kenneth

R. Seddon and his post-doctoral associate Dr. Malgorzata S. Kwasny (Gosia) of the Ionic

Liquids Laboratory of the Queen’s University Belfast are warmly acknowledged for all the

studies involving Ionic Liquids. Dr. Brigitte Skalsky and Giuseppe Paschali both of Evonik,

Darmstadt,Germany made Eudragit samples available. Furthermore I am grateful for their

nice company during my stay in Darmstadt in April 2010. Okelu J.V.C is appreciated for

making it possible for me to get stavudine from May and Baker Plc. Lagos. Onyeka Onyeibor

made it possible for me to get artesunate samples from Emzor Pharma Ltd, Lagos. Dr.

Nicholas Obitte also provided ibuprofen drug samples. Thanks to Giginna Mathias for

assistance in the tabletting studies. Chinwendu Nze, Ijeoma Ibe and Adiele Fortune are

greatly appreciated for their assistance in the basic characterization studies during the course

of this work.

vi

I am grateful to all colleagues in the Department of Pharmaceutics and indeed the Faculty of

Pharmaceutical Sciences, University of Nigeria,Nsukka for the friendly atmosphere in the

faculty. My friends Dr. Kenneth C. Ofokansi, Prof. Charles O. Okoli, Dr. Theophine Okoye,

Dr.Willy Obonga, Dr. Nicholas Obitte, Dr.Edwin Omeje, Dr.M.A Momoh, Mr. David

Chukwunine, My “twin” Dr.Mrs.Petra Nnamani, K.C Franklin, Dike John, Pharm.Nonso

Odimegwu and all our Laboratory staff led by Mr. Otuu and before him Oga Awa are all

acknowledged. My words lack the requisite courage to completely express the profundity of

my appreciation of the contributions of so many to the termination of this project which in

some moments seemed like a journey of 40 years in the wilderness of science. Thanks also to

my colleagues and friends Dr. Michel Tchime at BDCP/INTERCEDD Aku road Nsukka for

providing the atmosphere for the quiet writing of this thesis. Thanks to all at Uhere study

centre for the warm cocoon of charity that enveloped me during the progress of this work.

My doctors Dr. Joe M and others made all this possible.

Many thanks to my friends abroad for all the help in making my foreign trips to learn more a

success. Dominic Obimah, Chibuike Ogbuabo and Modibo Usman are acknowledged.

My gratitude to my family for their positive support. I wish to thank my beloved friend Late

Pharm. Elechi Bon-Louis Maduekwe for appreciating my work, giving me strength and

motivation to get things done. It is to him that this Thesis is dedicated.

Akpa Paul Achile

30th

April, 2013.

vii

TABLE OF CONTENTS

Page

Title page

i

Certification

ii

Dedication

iii

Acknowledgement

iv

Table of contents

vi

List of figures

xv

List of tables

xvii

Abstract xix

viii

CHAPTER ONE: GENERAL INTRODUCTION

1

1.0 Introduction 1

1.1 Polyelectrolytes 8

1.2 Classification of polyelectrolyte complexes 13

1.3 Characterization of polyelectrolyte complexes

15

1.4 Excipients used to prepare polyelectrolyte complexes of the present study

18

1.4.1 Eudragits ®

; Polymethacrylates

18

1.4.1.1 Eudragit®

E100 19

1.4.1.2 Eudragit®

L100-55

21

ix

1.5 Combination of polyelectrolytes to produce polyelectrolyte complexes

24

1.6 Self-assembly

24

1.7 Solubility of polymers

24

1.8. Solubility profile of polyelectrolyte complexes

25

1.8.1 Solubility in water 26

1.8.2 Solubility in organic solvents 26

1.8.3 Solubility in ionic liquids 27

1.9 Tablets-Definition and types 28

1.9.1 Methods of tablet production 29

1.9.1.1 Direct compression 29

x

1.9.1.2 Dry granulation 30

1.9.1.3 Melt extrusion 30

1.9.1.4 Wet granulation 30

1.9.2 Orally disintegrating tablets (ODTs) 31

1.9.2.1 Dissolution testing of ODTs 32

1.10 Model drugs 32

1.10.1 Stavudine 32

1.10.2 Artesunate 34

1.10.3 Ibuprofen 36

1.10.4 Aspirin 38

xi

1.11 Rationale for the study

40

1.12 Objectives of study 41

CHAPTER TWO MATERIALS AND METHODS

42

2.1 Materials

42

2.2 Methods 42

2.2.1 Preparation of polyelectrolyte complexes by solution blending. 42

2.2.2 Determination of the stoichiometry of the prepared polyelectrolyte complex 43

2.2.3 Evaluation of solubility of complex in different solvents 43

2.2.3.1 Solubility of PEC in ionic liquids 44

2.2.3.2 Retrievability of polyelectrolyte complex from ionic liquids 46

xii

2.2.4 Morphologies of the complexes using scanning electron microscopy (SEM) 46

2.2.5 Thermal analysis of starting polymers and the formed complex 47

2.2.6 Fourier transform infrared (FTIR) studies on starting polymeric materials

formed polyelectrolyte complex

47

2.2.7 Wide angle X-ray diffraction studies 47

2.2.8 Raman spectrophotometric studies 47

2.2.9 Tablet pre-formulation evaluation 47

2.2.9.1 Flowability 47

2.2.9.2 Bulk density 48

2.2.9.3 Tapped density 48

2.2 .9.4 Carr’s index 49

xiii

2.2.10.1 Formulation of studies 49

2.2.10.6 Tablet compression 54

2.2. 10.7. Tablet evaluation tests 54

2.2.10.8 Crushing strength determination 54

2.2.10.9 Friability test 55

2.2.10.10 Weight uniformity 55

2.2.10.11 Disintegration time test 55

CHAPTER THREE RESULTS AND DISCUSSION 56

3.1 Yield of polyelectrolyte complex 56

xiv

3.2 Stoichiometry of polyelectrolyte complex 56

3.3 Solubility of polyelectrolyte complex in common solvents 58

3.4 Solubility of polyelectrolyte complex in ionic liquids 58

3.5 Retrievability of polyelectrolye complex from ionic liquids 58

3.6 Morphology of polyelectrolyte complex using scanning electron microscopy

(SEM)

59

3.7 Thermal analysis of sample polymers and polyelectrolyte complexes 64

3.7.1 Thermogravimetric analysis (TGA) 66

3.7.2 Differential scanning calorimetry (DSC) 69

3.8 Fourier transform infrared spectroscopy (FTIR) 74

3.9 Wide angle x-ray diffraction studies (WAXD) 79

xv

3.10 Raman spectra 85

3.11 Pre-formulation studies 92

3.12 Formulation studies 97

CHAPTER FOUR SUMMARY AND CONCLUSION

103

4.1 Summary 103

4.2 Conclusions

104

4.3 Recommendations 104

REFERENCES 106

xvi

LIST OF FIGURES

Fig. 1 Pharmaceutical materials science panorama 3

Fig. 2 Some examples of polyelectrolyte complexes commonly

employed in the preparation of polyelectrolyte complexes

or macromolecular complexes

9

Fig. 3 Eudragit®

E100 21

Fig. 4 Eudragit®

L100-55 23

Fig. 5 Structure of stavudine 34

Fig .6 Structure of artesunate 35

Fig. 7 Structure of ibuprofen 31

Fig. 8 Structure of aspirin 36

Fig.9 Result of stoichiometric analysis 57

xvii

Fig. 10 Plates of scanning electron microscope (SEM) pictures 60

Fig. 11 Result of DSC studies 67

Fig. 12 Results of FTIR analysis 75

Fig. 13 Results of WAXD studies 81

Fig. 14 Raman spectra 86

xviii

LIST OF TABLES

Table 1: Some common polycations and polyanions used for

the preparation of polyelectrolyte complexes

14

Table 2 : Physicochemical properties of pharmaceutical grade

methacrylate polymers

24

Table 3 : Ionic liquids tested for solubility of polymer complex 45

Table 4 : Composition of stavudine tablets

50

Table 5 : Composition of aspirin tablets 51

Table 6 : Composition of ibuprofen tablets 52

Table 7: Composition of artesunate tablets 53

Table 8: Flow properties of stavudine 93

Table 9: Flow properties of aspirin 94

xix

Table 10: Flow properties of ibuprofen 95

Table 11: Flow properties of artesunate 96

Table 12: Physicochemical characterization of stavudine tablets 98

Table 13: Physicochemical characterization of aspirin tablets 99

Table 14: Physicochemical characterization of ibuprofen tablets 100

Table 15: Physicochemical characterization of artesunate

tablets

101

xx

ABSTRACT

The present study focused on the preparation, characterization and drug delivery evaluation

of a novel polyelectrolyte complex formed from the combination of a pair of oppositely

charged polymethacrylates dissolved in methanol. The polyelectrolyte complex obtained at

the end of the interaction of the two polymer solutions was collected, washed, dried and

ground to fine particulate structure. The resulting powder was subjected to a series of

physicochemical tests with a view to ascertaining the nature of the formed complex.

Evaluation of the formed complex in a wide range of solvents was carried out with a view to

assessing the range of solvents that could be used to solubilize the complex prior to distinct

applications in pharmacy. WAXD as well as other relevant studies were carried out,

Morphological studies using scanning electron microscopy (SEM) were conducted.

Additionally, fourier transform infra red (FTIR), Raman spectroscopy (RM) and (DSC)

studies were done. Results obtained indicate that the starting polymers interact

stoichiometrically at a ratio of 1:1. Morphological studies reveal a well rounded smooth

surface for the final complex material while the aspect of the individual polymers viewed

appear to be highly convoluted and irregular. DSC studies did not reveal any major

transitions. Complexes were then employed in formulation of rapidly disintegrating tablets

and drug release studies were conducted in simulated intestinal fluid and simulated gastric

fluid. Results obtained indicated that the polyelectrolyte complex obtained is suitable for the

formulation of rapidly disintegrating tablets especially those containing crystalline active

pharmaceutical ingredients such as aspirin. Overall, findings obtained in this investigation

appear to suggest that the combination of the pair of oppositely charged polymethacrylates

Eudragit®

E100 and Eudragit®

L100 -55 results in the formation of a polyelectrolyte complex

with unique properties which makes it suitable for the formulation of rapidly disintegration

xxi

tablets. Tablets containing the pre-selected drugs namely artesunate, aspirin, ibuprofen and

stavudine disintegrated rapidly in a matter of seconds following contact with the aqueous

medium.

CHAPTER ONE

GENERAL INTRODUCTION

1.0 Introduction

The objective of pharmaceutical research and development is to develop drug products for

the treatment of diseases in man or animals. Pharmaceutical research and development is thus

situated in the realm of materials science and engineering. Consequently, pharmaceutical

scientists engaged in developing safe, efficacious, and economic drug products for the well-

being of the general public are specialized materials scientists. Recently, it was noted that in

many parts of the world especially the underdeveloped countries, the addition of value to

traditional mineral resources will translate to the overall enhancement of the quality of life in

such countries. Materials are the substance of which something is made. Since the dawn of

civilization, materials along with energy have been used by people to enhance their quality

of life (1, 2). Materials can be found everywhere around us since all the substances used by

man in the various types of products are made of materials. Some of the more commonly

encountered materials include wood (timber), concrete, brick, steel, plastic, glass, rubber,

aluminum, copper, etc. Traditionally, the discipline of materials science is engaged most

commonly with the study of structural or functional materials for engineering applications.

The subject matter of materials science includes the assessment of the internal structure,

properties, processing and applications of materials. Commonly studied materials include

metallic, polymeric (plastic) and ceramic materials. Today, a lot of attention is also turned to

evaluation of the so-called soft matter such as polymers, powders and biomaterials (2-4). It is

xxii

pertinent to highlight the fact that in the broad field of Pharmaceutics, which constantly

borrows heavily from the basic sciences such as Physics, Chemistry and Biology, there is the

tendency to grow in symphony with the degree of progress made in these basic fundamental

disciplines. In recent times, there has been an upsurge of research interest in the

physicochemical characterization of the many materials that are handled in the course of

pharmaceutical research leading to effective finished products employed in human and

animal health. Experts now even speak of the emerging field of Pharmaceutical Materials

Science (3). This new field is very much linked with advances in nanotechnology and related

sub-fields of study. The major feature of this emerging area is the utilization of a broad array

of characterization techniques developed by the physical sciences for the evaluation of the

common materials which are employed in the pharmaceutical industry both as active

pharmaceutical ingredients (APIs) or inert excipients. Normally, the first decision is to apply

fundamental concepts in the physical sciences to the challenge of understanding the

behaviour of soft, mostly organic , crystalline and amorphous materials. Conventionally,

materials science has been concerned with the six major classes of materials which include

ceramics, metals, polymers, wood and composites and semi-conductors but today the horizon

of materials science has broadened to include the novel materials that are now in existence as

a result of cutting edge research in new frontiers of materials science especially

nanotechnology. The remit of Pharmaceutical Materials Science ranges from events

intercalated at the molecular scale such as crystallization, polymorphism, etc. to the metrics

of macroscopic performance including hydration rate, mechanical strength and their

possible effects on planned industrial processes such as powder flow and compaction.

Additionally, the relationships between the various aspects of the broad field of

pharmaceutical materials science is illustrated in Figure 1. Briefly, detailed studies that

xxiii

fall within the realm of pharmaceutical materials science could be reflected in Fig.1

include the following:

Figure 1. Pharmaceutical materials science panorama.

xxiv

The figure indicates the progression from crystal engineering of active pharmaceutical

ingredients through processing and manufacturing of particles and powders into dosage forms

such as tablets, culminating with therapeutic action in the patient.

I. Crystal engineering of active pharmaceutical ingredients (API).

II. Manufacture of particles and powders into dosage forms such as tablets and capsules

culminating in the evaluation of the therapeutic action of the drug in the patient.

III. Design of custom materials with specific physical and chemical properties

IV. Use of theoretical models to predict material performance in biological environments.

V. The development of more up to date novel characterization techniques for nanoscopic

and micron-sized particles.

It is important to mention that although research in pharmaceutical materials science is

traceable historically to departments of physical pharmacy, the noted rapid pace and the

concomitant development of this intrinsically multidisciplinary field today owes much to the

active engagement of professionals from various fields. Moreover, the field is increasingly

becoming delineated as a subject matter in its own right with materials scientists playing

a key role in effecting the daily transformations of this fascinating field of study.

By way of a brief historical excursus, the following eminent milestones may be

recognized.

� First documented use of the term “Pharmaceutical Materials Science in

an article published by Frank and his co-workers (5). In the work, they

describe the application of the principles of materials science to the

production of freeze dried biological molecules for therapeutic uses.

xxv

� Craig (6) in an article posed the question whether the field of

Pharmaceutical Materials Science is either a new field or is the re-

incarnation of an old field of study.

� Scientific articles describing the study of pharmaceutical materials

and their unique range of applications and properties have

consistently appeared in journals dedicated to Chemistry, Physics and

in the Pharmaceutical literature. One of the first patents on a method

for forming tablets by uniaxial die compaction which is still very much

in use, was granted to William Brockedon in 1843.

� Additionally, it is adjudged that the Monsanto Chemical Company in

the USA was dabbling with pharmaceutical materials science when its

workers described the design, fabrication and evaluation of a an

apparatus for testing the hardness and mechanical modulus of

pharmaceutical tablets in 1956.

� The 1940s are described as the cellulose decade with the appearance of

many semi-synthetic cellulosic polymers for use in diverse

applications.

� By the 1950s, many pharmaceutical industries commenced the

adoption of principles gleaned from the metallurgical sector especially

for the study of properties of powders employed in pharmaceutical

applications.

� Physical concepts culled from the physical sciences which are used

today in the study of tablets include:

o Plastic flow

o Brittle fracture

xxvi

� The emergence of physical pharmaceutics in 1953 helped to centre

research efforts in the field. An unequalled innovator in this field is

Takeru Higuchi at the University of Wisconsin in the United States of

America (7).

Contemporary pharmaceutical materials science is much influenced by the quest for

discovering custom materials with drug delivery applications. Innovators include:

� Robert Langer of the Massachusetts Institute of Technology (MIT) (8), credited with

the establishment of the modern fields of controlled drug delivery and tissue

engineering.

� Nicholas Peppas of Purdue University (9) widely regarded as the key innovator

especially in the application of various theoretical models to the study of drug release

from polymeric matrices many of which have found application in controlled drug

release.

Developments in the course of the past half a century in the area of pharmaceutical materials

science have culminated in a transformation in the way materials for pharmaceutical

applications are handled. It is commonplace today to encounter studies which include the

characterization of pharmaceutical materials using state of the art analytical tools, which

originated in mainsteam physical sciences. The new frontiers of continuing research in

pharmaceutical materials science include:

� Modification of the structures of active pharmaceutical ingredients (APIs) involving the

use of wide ranging techniques for solubility enhancement.

� Some modern techniques employed in the study of pharmaceutical raw materials include

:

xxvii

o Vibrational spectroscopy

o Thermal analytical methods

o Particle scattering techniques

The ultimate objective of using all these probes is to gain a deeper insight into the chemical

structure of these materials with an emphasis on ascertaining their true nature. Degree of

crystallinity, molecular interactions and the impact of co-processing on these materials are

consistently evaluated.

Also, it is becoming a common practice especially on the large scale for the use of certain

advanced methodologies to investigate the properties of pharmaceutical materials. These

methodologies include the following:

� Fracture mechanics

� Rheological tools

� Tomography imaging

� Continuum and discrete element modeling approaches

The import of all these studies is that they provide “parts” of the “whole” picture of the

properties under evaluation. The understanding of how these materials perform during

manufacturing and in normal use has been advanced in a considerable manner. Common

engineering and biochemical approaches have achieved widespread acceptance for the study

of relevant pharmaceutical materials (3). Despite the advances already experienced in the

field up till today, experts are of the view that what is in the future far outweighs what has

come up till now. Today it is envisaged that new approaches for designing and fabricating

biocompatible materials will be developed. Significant advances in the realm of

experimental and computational chemistry, physics and biology will concatenate to usher in

xxviii

new opportunities for focusing on materials of relevance to the pharmaceutical industry at

the molecular and supramolecular levels. These are exciting times to be engaged in this

field. Novel pharmaceutical applications are been found on a daily basis for existing

materials and characterization techniques. Also, whole classes of new therapeutic materials

with unique properties are being created each year. Novel materials under investigation today

include polymeric materials like the polyelectrolytes and polyelectrolyte complexes.

1.1 Polyelectrolytes

Polyelectrolytes (PE) are a group of macromolecules with many interesting and practically

useful properties. They have the twinned distinction of being both polymers and electrolytes

hence they exhibit properties of a macromolecule and the charge possibilities of an

electrolyte. Polyelectrolytes are also commonly referred to as macromolecular complexes and

are regarded as naturally occurring machines inside cells. Normally, they comprise of a

handful to several thousand individual components which include proteins, DNA,

carbohydrates and lipids. These supramolecular entities perform many vital tasks in the living

organelle such as translating the genetic code, converting energy or assisting

intercommunications between nerve cells. Some examples of polyelectrolytes are shown in

Fig. 2.

Figure 2: Some examples of polyelectrolytes commonly employed in the prepa

polyelectrolyte complexes or macromolecular complexes.

DNA

: Some examples of polyelectrolytes commonly employed in the preparation of

polyelectrolyte complexes or macromolecular complexes.

xxix

ration of

xxx

Polyelectrolytes are a cluster of macromolecules with many interesting and practically useful

properties (10). The term polyelectrolyte has been coined to describe substances of high

molecular weight which are simultaneously electrolytes. Within the compass of this

definition are a number of subclasses. According to source, we have, on the one hand,

naturally occurring polyelectrolytes such as proteins and polysaccharides and on the other

hand, synthetic materials such as polyacrylic acid and polyvinyl alcohol. From the point of

view of electrolytic behaviour, polyelectrolytes, just like the simple electrolytes of low

molecular weight, may be either weak or strong. A weak electrolyte is one for which there

exists a neutral molecule, held together by electronic bonds, and which can dissociate into

ions; a strong electrolyte is one for which only ions exist. Acetic acid and sodium chloride are

familiar examples of the two classes.The former is present in liquid acetic acid mostly as the

electrically neutral CH3OCO2H molecule, which in water or other basic solvents can

dissociate into a negative acetate ion and a positive hydrogen ion; this dissociation involves

an electron rearrangement. The latter, however, exists as a lattice of positive sodium ions and

negative chloride ions in the crystal; in solution, these ions become solvated and separate,

retaining the charges which characterize them. No dissociation, in the sense of the breakage

of electronic bonds occurs. Only electrostatic Coulombic forces need to be considered.

Polyelectrolytes being both polymers and electrolytes, exhibit both the properties of a

macromolecule and the charge possibilities of an electrolyte. The investigation of the

physico-chemical behaviour of polyelectrolytes including those of natural origin like

proteins, glycoproteins and polynucleotides were commenced by Fuoss and his co-worker in

1949 (11). They worked with a dilute solution of sodium polyacrylate which was added to a

solution of poly-4-vinyl-n-N-butylpyridonium bromide. Polycations and polyanions can

interact to form precipitates (i.e., polyelectrolyte complexes – PECs). The resulting

aggregate is a compact insoluble cluster, cross-linked by electrostatic forces. Particles are

xxxi

thought to vary in size between 20-40 nm. In three fields- hydrodynamics, electrodynamics,

and thermodynamics the properties of these compounds could be described. Various

combinations of polyelectrolytes for example,cationic starches and carboxymethylcellulose

,are today used to enhance paper properties such as dry or wet strength. These polymer

complexes are insoluble, macromolecular structures formed by the non-covalent association

of polymers with an affinity for each other. These complexes are formed by the ionic

association of repeating units on the polymer chain. Association of repeating units could lead

to two different outcomes. In cases were association occurs between the repeating units of

different polymers, an interpolymer complex results while in cases where the interaction is

between separate regions of the same chain, an intra-polyelectrolyte complex results.

Further investigations were not carried out until Michaels and Miekka (12), made a similar

discovery producing spherical complexes of between 20 and 40 nm in size, using different

conditions such as various types of polyelectrolytes, salt concentrations, and charge ratios.

Many macromolecular complexes occur naturally inside the interior of the cell where they

function as molecular machines. Some well known complexes facilitate the regulation of

gene expression via effects on RNA and DNA. For example, the spliceosome removes non-

protein coding snippets from newly formed RNA and then goes on to form functional

messenger RNA (mRNA) which can later be converted into protein. Additionally, the

nuclear-pore complex (one of the largest known molecular machines) straddles the nuclear

membrane, thereby controlling the passage of nutritional and other types of materials through

the membrane. Additionally, there has been a tremendous amount of evaluation of both

stoichiometric and non-stoichiometric attributes of interpolyelectrolyte complexation

reactions. Tsuchida and his co-worker (13) devoted a lot of attention to the study of

polyelectrolyte complexes. He instituted the series of biennial international symposia on

polyelectrolyte complexes. Beginning from the early 1990s, the technique of forming layered

xxxii

structures of polyelectrolytes was established by Gero Desher and co-workers (14, 15). These

polyelectrolyte multilayers (PEMs) have been thoroughly investigated in various model

systems (15-20). Polyelectrolyte multilayers are currently employed in a wide array of

applications owing to their versatility embracing organic, polymeric, inorganic and biological

materials as well as the simplicity of the nanofabrication process. These devices are utilized

in domains such as tissue engineering, functionalisation of implants, gene delivery and

transfection, biosensing, biocatalysis, electroluminescent devices, lithium-ion-batteries, non-

linear optics, anti-reflective coatings, corrosion protection, photocatalysis, microreactors, gas

and liquid separation, functionalisation of nanoparticles, controlled drug release and some

others (21-30). Research into PEMs has rekindled interest in PECs (31-37). Today, PECs are

produced for industrial applications ranging from coatings, binders, and flocculants for water

purifications to advanced drug delivery platforms. Modern applications in medicine and

biotechnology include, protein immobilization, and employment as carriers in gene therapy

or as biosensors (38-45). In the production process, PECs are formed spontaneously at room

temperature when solutions of a pair of oppositely charged polyelectrolytes are brought into

contact in a suitable vessel. The formation of PECs is governed by the strength and location

of ionic sites, polymer chain rigidity, precursor chemistries, pH, temperature, ionic strength,

mixing intensity, and other controllable factors which will affect the polyelectrolyte product

(45-60).

xxxiii

1.2 Classification of polyelectrolyte complexes

Polyelectrolyte complexes or polymer complexes are classified on the basis of the

type of association among the component monomers (61). The major types of complexes

include

• Stereo-complexes (62,63)

• Interpolyelectrolyte complexes or polyelectrolyte complexes (64-67).

• Hydrogen bonded complexes (61).

Normally, these complexes form readily between most polyanions and polycations.

These complexes are formed by the ionic association of the repeating units on the

polymer chain. The complexes are normally insoluble in aqueous media. Table 1

indicates a summary of some common polycations and polyanions which have been

used to produce polyelectrolyte complexes.

xxxiv

Table 1: Some common polycations and polyanions used for preparation of

polyelectrolyte complexes.

S/No Natural polycations Natural polyanions Reference

1 Chitosan Carboxymethylcellulose,

alginic acid, dextran sulphate

47

2 Poly-L-lysine Pectin 52

3 DEAE-dextran Carrageenan 53

4 Amino-

poly(oxyethylene)

Collagen 54

5 Proteins such as

gelatin,

Sodium alginate 46

6 Arabic gum 55

7 Xanthan gum 56

8 Nucleic acid 50

xxxv

1.3. Characterization of polyelectrolyte complexes

A good drug delivery system ought to facilitate the placement of the candidate drug in the

right quantity and in the right place and at the right time in the right place in the body.

Hence, the bioavailability of the drug is thus the parameter of interest in dosage form

research and development. For a drug delivery system to be regarded as useful, it has to

possess certain desirable attributes such as:

• Physical and chemical stability

• Production at reasonable costs in a technically feasible and reliable

manner.

In order to achieve all this, it is paramount that there exists the possibility of characterizing

these drug delivery systems as best as possible so as to facilitate the understanding of their

inherent nature.

A thorough characterization needs to take place at all stages, from the drug discovery stage

preformulation to the final formulation studies. Increasingly, characterization is not restricted

to the drug and dosage form itself but extends to the formulation and production process as

emphasized recently by the US Food and Drug Administration (US FDA) (73).

Moreover, many modern dosage forms undergo post-administration changes. For example, it

has been established that lipid formulations undergo digestion after oral administration. Use

of high energy solids such as metastable polymorphs or amorphous forms of drugs in many

drug delivery systems are somewhat limited as these are known to undergo crystallization

or polymorphic conversion following administration. The possible list of types of products

may be extended ad infinitum and this highlights the necessity of characterizing the drug

delivery system after administration.

xxxvi

There exists an authentic plethora of techniques, which are used to probe the nature of

the drug and delivery systems at all levels albeit,

• Molecular

• Colloidal

• Particulate

• Bulk level

In recent times many new techniques have been developed to probe the test materials in

order to generate relevant data critical to the evaluation of these substances. Other

techniques that have been around for a longer time have now been greatly improved. In

addition, improved analytical methods now frequently include multivariate data analysis.

The objective for employing a wide array of characterization techniques is to aid the

pharmaceutical scientist to understand the complex mixtures both qualitatively and

quantitatively. Characterization techniques include spectroscopic techniques which probe the

nature of drugs and delivery systems at the molecular level. These methods also allow the

examination of drug-excipient interactions during drug distribution. Additionally, physical

and chemical stability can be monitored and controlled using specialized systems. Examples

of these spectroscopic methods include: Fourier transform infra-red spectroscopy (FTIR),

near infra red (NIR) spectroscopy and Raman spectroscopy. Terahertz spectroscopy probes

solid materials at the particulate level. Furthermore, mass spectrophotometric methods such

as time-of-flight secondary ion mass spectrometry (TOF-SIMS) and matrix-assisted laser

desorption/ionization (MALDI-TOF) a soft ionization technique used in mass spectrometry,

are used for purposes of surface analysis as well as biopharmaceutical research.

xxxvii

Thermal and diffractrometric techniques are also available. More advanced approaches

include isothermal microcalorimetry and X-ray scattering. These methods are very useful

for evaluating amorphous materials as well as cryo-milled materials. Also in the canon of

characterization techniques, imaging has gained momentum in the last few years. These

imaging techniques range from classical light microscopy through electron microscopy to

cryo-transmission electron microscopy (Cryo-TEM) as well as environmental scanning

electron microscopy (ESEM). Spectroscopic imaging and mapping techniques such as Raman

mapping as well as non-linear imaging modalities are also in use. Other important techniques

include magnetic resonance imaging (MRI), electron paramagnetic resonance (EPR)

spectroscopy and in vivo imaging. In the development of drugs and dosage forms the

pharmaceutical scientist has to use a wide range of techniques to get a complete insight into

the nature of the dosage form. Some typical studies include:

• Particle sizing

• Monolayer studies

• In vitro lipolysis models

• Taste sensing, etc.

With all these and many other new and advanced characterization techniques, large

amounts of data are generated and thus an overarching problem emerges: how to

effectively handle this invaluable information. The focus now has shifted to multivariate

data analysis.

xxxviii

1.4 Excipients used to prepare polyelectrolyte complexes of the present study

This work focused on polymethacrylates. These are a group of synthetic polymers

produced by bulk polymerization reactions.

1.4. 1 Eudragits ® : Polymethacrylates

The trade name Eudragit®

is a composite of the Greek έύ, meaning “good” or “functional ”

and the German dragieren, meaning “(sugar) coating”; thus the meaning of the trademark is

“excellent functional coating” (74,75). The product line includes pharmaceutical copolymers

from esters of acrylic or methacrylic acid whose properties are determined by functional

groups.

The individual grades differ in their proportion of neutral, alkaline, or acid groups and thus in

terms of their physicochemical properties (75-80). Amongst the polymers, a distinction is

made between polycations designated as the E, RL and RS types and the polyanions L, S, and

FS types (81). The letters in the trade names refer to chemical information and functionality

while the numbers that follow indicate the polymer concentration (%-w/w) (74, 75).

1.4.1. 1 Eudragit®

E100

The polymer Eudragit®

E 100 is a cationic polyelectrolyte which is manufactured by bulk

polymerization and extrusion (82). It is commercialized as granules for solvent coating

processes. Recently a micronized modification, Eudragit E PO, with a particle size of

approximately 10 μm, was developed, enabling aqueous coating processes from a colloidal

solution (83). Eudragit® E100 is built up of the cationic monomer dimethylaminoethyl-

methacrylate (DMAEMA), copolymerized with methyl and butyl methacrylate. It exists in

some official compendia as follows:

• European Pharmacoepia -Ph. Eur. Basic Butylated Methacrylate Copolymer

xxxix

• United States Pharmacopeia/National Formulary- USP/NF Amino Methacrylate

Copolymer-NF

• Japanese Pharmacopeia JPE Aminoalkyl Methacrylate Copolymer E

Traditionally since its emergence in the pharmaceutical excipient market, Eudragit®

E100 has

been widely employed as a protective coating material mainly for moisture protection and

taste masking (84-89). Its taste masking ability is linked to the presence of the dimethyl

aminoethyl group as its functional building block. Normally its exertion of taste masking

follows upon the swelling of its entire structure in solutions having pH 5. Additionally, the

added coating is capable of rapid dissolution owing to its formation of salts at acidic pH

values lower than pH 5. It has been observed that even thin coatings of 10 µm thickness

which corresponds to a polymer application of 1mg/ cm2 are effective. Coatings made with

Eudragit®

E100 are known to provide odour masking, moisture protection, insulating

coatings, economical applications, low viscosity, high pigment binding capacity, good

adhesion, and low polymer weight gain (90). In recent times owing to the developments in

drug delivery research, it has been observed that the Eudragit ®

polymers are being brought

into the field of novel drug delivery formulation research. It is no longer a rarity to come

across formulation strategies involving novel drug delivery platforms such as the formulation

of microspheres and nanoparticulate delivery vehicles. Eudragit E100 has been utilized

intensively to formulate microspheres and microparticles containing model drugs such as

ranitidine hydrochloride and indinavir (90-95).

The structure of the monomer is shown in Figure 3. Details of the physicochemical properties

of Eudragit ®

E100 are given in Table 2.

xl

Figure 3: Eudragit®

E 100

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1.4.1.2 Eudragit® L100 -55

Eudragit®

L100- 55 is an anionic polyelectrolyte whose powder form containing 50%

(w/w) of methacrylic acid was developed for solvent based coating processes providing drug

release above pH 6 (74) The ester monomer is ethylacrylate (EA) and has within its

molecular configuration , carboxylic acid (-COOH) functional groups. The structure of the

monomer is shown in Fig .4. Monographs of this polymer can be found in key official

compendia as indicated below:

• European Pharmacopeia : Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) Type A

• USP/NF Methacrylic Acid Copolymer, Type C-NF*

• Methacrylic Acid and Ethyl Acrylate Copolymer –NF**

o *Current monograph name valids until Dec , 2015.

o **New monograph names valid as of Dec 1, 2010.

Mandatory as of Dec 1, 2015.

• Japanese Pharmaceopeia - Dried Methacrylic Acid Copolymer LD

This material is usually employed to target drugs to the duodenum (84). Eudragit L100 -55 is

amenable to a wide range of applications. It has been used to formulate matrix tablets and

other drug delivery platforms (96-99).

xlii

Figure 4: Eudragit®

L100 55

xliii

Table 2: Some key physicochemical properties of pharmaceutical methacrylate

copolymers (culled from Ref. (74)

Type Mw

(g/mole)

Glass

transition

temperature

Tg (oC)

Mean film

forming

temperature

(oC)

Thermal

stability of

functional

group

Elongation

at break

Eudragit®

E100 47,000 48 NA 220 70

Eudragit®

L100

55

278,000 110 25 157 14

xliv

1.5 Combination of polyelectrolytes to produce polyelectrolyte complexes

The combination of solutions of oppositely charged polymethacrylates at room

temperature leads to the formation of a polyelectrolyte complex. This complex which is a

result of spontaneous self-assembly is attributed to the electrostatic interaction between the

oppositely charged macromolecules. This current research focused on the combination of a

pair of oppositely charged polymethacrylates which are mentioned in the foregoing section.

1.6 Self-assembly

The process of self-assembly may be referred to as the autonomous organization of

components into patterns or structures without the intervention of human beings. Self

assembling processes are common in nature and technology (100). Examples range from

molecular structures like crystals to even planetary realities like weather systems. In the

context of the present investigation, it is deemed that the formation of the interpolyelectrolyte

complex is a consequence of the self-assembly of the molecules of the polycations and

polyanions into the emergent structures of the complex. A transformation from molecules to

monolayers.

1.7 Solubility of polymers

Not all polymers can be dissolved, and even when they are soluble, the dissolution process

may take up to several days or weeks (101). There is an assemblage of general rules for

polymer solubility, based on experimental observations, from which interesting conclusions

can be derived. The dissolution of polymers depends not only on their physical properties, but

also on their chemical properties, such as: polarity, molecular weight, branching, cross

linking degree, and crystallinity. The general principle “like dissolves like” is also

appropriate in the case of polymers. Polar macromolecules like poly (acrylic acid), poly

(acrylamide) and polyvinyl alcohol, among others, are soluble in water. Conversely, nonpolar

xlv

polymers or polymers exhibiting low polarity such as polystyrene, poly(methyl

methacrylate), poly(vinyl chloride), and poly(isobutilene), are soluble in nonpolar solvents.

Also, the molecular weight of polymers plays an important role in their solubility. In a given

solvent at a particular temperature, as molecular weight increases, the solubility of the

polymer decreases. This same behaviour is also noticed as crosslinking degree increases,

since strongly crosslinked polymers will inhibit the interaction between polymer chains and

solvent molecules, preventing those polymer chains from being transported into solution. A

similar situation occurs with crystalline macromolecules, although in such cases the

dissolution can be forced if an appropriate solvent is available. In addition, warming the

polymer up to temperatures slightly below its crystalline melting point (Tm) could lead to its

dissolution in the solvent in question. For example, highly crystalline linear polyethylene (Tm

= 135 º C) can be dissolved in several solvents above 100 ºC. Nylon 6.6 (Tm = 265 º C), a

crystalline polymer which is more polar than polyethylene, can be dissolved at room

temperature in the presence of solvents with enough capacity to interact with its chains,

through for example, hydrogen bonding. Branched polymer chains generally bring about an

increase in solubility, although the rate, at which this solubility occurs, depends on the

particular type of branching. Chains containing long branches, cause dense entanglements

making difficult the penetration of solvent molecules. Therefore the rate of dissolution in

these cases becomes slower than if it was short branching, where the interaction between

chains is practically non-existent.

1.8. Solubility profile of polyelectrolyte complexes

Generally, polyelectrolyte complexes are known to be insoluble in aqueous systems

(102). The solubility of a polymer complex is an important determinant of its

physicochemical properties which concomitantly influences the possible applications of such

xlvi

a complex. Hence in any study of a complex, it is imperative that the solubility of the

material be assessed in a wide range of solvent systems. For most materials that are to be

utilized as healthcare materials for oral administration, aqueous solubility assessment is of

capital importance. Additionally, in most processing operations in the pharmaceutical

industry, owing to the versatility of the existing types of organic solvents, they are important

candidates for use as solvents and as such, it is necessary to appraise their ability to solubilize

the relevant materials. In recent times owing to concerns for the damage caused to the

environment by many volatile organic solvents (VOSs), there has arisen a truly global

clamour for the use of “green solvents” with minimal adverse effects on the environment

(103).

1.8.1 Solubility in water

This is of pivotal importance for materials that are designed and prepared to be used

in the human body. The established fact that the entire human body is composed of over 70%

water serves as a constant reminder that the majority of materials aimed for use in the human

body should in principle have a high solubility in water.

1.8.2 Solubility in organic solvents

This is very essential especially for materials that may be subjected to common industrial

processing steps which inherently involve the use of this class of solvents. In consonance

with the “green movement” there is now a growing clamour for the replacement of organic

solvents by solvents that are more environment friendly (104).

xlvii

1.8.3 Solubility in ionic liquids (ILs)

The solubility of polymers in ionic liquids is a corollary of the chemical nature of the

polymer in question and the ionic liquid with which it is in contact. Ionic liquids are a class

of substances which are salts in the liquid state. This set of substances has been variously

called liquid electrolytes, ionic melts, ionic fluids, fused salts, liquid salts and ionic glasses

(105-106). In a number of contexts, the term has been restricted to salts with melting point

below some arbitrary temperature such as 100 0C (212

0F) (107). While, ordinary liquids like

water and petrol are largely made up of electrically neutral molecules, ionic liquids (ILs) are

made up of ions and short lived ion pairs (108). They offer great flexibility in the design of

cationic and anionic structures and their combinations. In principle, it is possible to

manipulate their properties as required hence their designation as “designer solvents” (109).

Ionic liquids are currently regarded as one of the most versatile class of green solvents for use

in a myriad of industrial applications such as in catalysis and synthesis of some vital organic

materials (110-111).

The attractive properties of ILs include the following (112-114);

� Literally no vapour pressure

� No inflammability

� High thermal and mechanical stability

� Broad liquid range

� High electrochemical stability

� Exceptional dissolution properties

Additionally, it has been established that these novel solvents could be utilized in a broad

spectrum of industrial applications such as the following (115-117):

� Chemical processing

� Cellulose processing

xlviii

� Engineering fluids

� Electrolytes

� Functional liquids

Owing to the immense importance of cellulose given the established fact that it is the most

abundant renewable bio-material in the ecosystem and the undiminished relevance of

cellulose based materials in the chemical industry, many studies have been conducted to

assess the solubility of cellulose in a wide range of ionic liquids. Several reviews on this

theme have been published (113). Ionic liquids serve as nonderivatizing solvents used for

cellulose. Ionic liquids containing 1-butyl-3-methylimidazolium cations ([C4mim]+) have

been employed as solvents for cellulose (114). The fact that many ionic liquids have been

found to be suitable for the dissolution of cellulose has served to enhance the utilization of

cellulose in several basic industries (112).

1.9. Tablets- definition and types

Tablets together with capsules are the most frequently used solid dosage forms (118).

Tablets have been in existence since the nineteenth century, and are unit dosage forms, made

up of a blend of ingredients presented in a single rigid entity, usually containing an accurate

dose of a drug (119). Tablets are generally intended for oral administration and for systemic

delivery of drugs. There are several types of tablets and these range from relatively simple,

immediate – release dosage forms to complex modified release systems (120). Tablets offer

advantages for both patients and manufacturers which include the following:

� Ease of handling

� Variety of manufacturing methods

� Mass production at low cost

� Consistent quality and dosing precision

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� Amenable to self - administration

� Enhanced mechanical, chemical, and microbiological stability compared to liquid

dosage forms

� Tamperproof

� Lend themselves to adaptation for other profiles, e.g., coating for sustained release.

Most tablets are intended to be swallowed whole and to rapidly disintegrate and release drug

in the gastrointestinal tract. Tablets are classified by their route of administration or their

function, form, or manufacturing process. For example, some tablets are designed to be

placed in

the oral cavity and to dissolve there or to be chewed before swallowing, and there are many

kinds of formulation designed for sustained or controlled release.

1.9.1 Methods of tablet production

1.9.1.1 Direct compression:

This method has the elegance of simplicity in the sense that it involves very few processing

steps and a truncated production process consisting essentially in the mixing of the active

pharmaceutical excipient with the diluent and a lubricant followed by the compression of the

resulting mixture to give the desired tablet using a standard tablet press (121), It is highly

restricted to a few active pharmaceutical ingredients and excipients with the desired

compressibility profile.

l

1.9.1.2 Dry granulation

This method, as the name implies, is typified by the granulation of the mixture of the active

pharmaceutical ingredient and the excipients in a manner that restricts the inclusion of water

to give the granules. It is highly suitable for drugs that are sensitive to moisture.

1.9.1.3 Melt extrusion

This method is defined by the use of industrial extruders to push out previously melted

mixtures of the active pharmaceutical ingredient and the excipients through an orifice to

produce a resultant mass of material known as the extrudate (122). The extrudate is

subsequently subjected to compression in a suitable tabletting machine. This method is now

gaining in popularity owing to the adoption by wide sectors of the pharmaceutical industry.

1.9.1.4 Wet granulation

This method of tablet production is typified by the use of a solvent as a granulation aid

(122). Normally water is used though there are some variants of this basic method which

involve the use of organic solvents as granulation aids. Additionally, this process while being

employed for a wide range of active pharmaceutical principles is not suitable for moisture

sensitive drugs. It also suffers from the limitations imposed by its relative high cost and the

extra amount of energy expended in the process owing to the need for drying of the

granulates after the granulation procedure prior to tableting after the addition of a suitable

lubricant. Binders traditionally used for this granulation process include cellulose

derivatives, starches, polysaccharides and a broad range of synthetic polymers (123).

li

1.9. 2 Orally disintegrating tablets

The demand for fast-dissolving/disintegrating tablets or fast-melting tablets capable of

dissolving or disintegrating in the mouth has been on the rise in recent times due to the

upsurge in the number of patients with difficulties in swallowing tablets (disphagia) such

as the elderly and children. These tablets are variously referred to as fast dissolving,

orodispersible, and fast melting tablets. The US FDA has adopted the term orally

disintegrating tablets (ODTs) (124-128). Patients with persistent nausea or those who have

little or no access to water could also benefit from the ingestion of ODTs. Additional

advantages include product differentiation and market expansion. Veterinary applications of

this class of products are also a possibility. Orally disintegrating tablets disintegrate and/or

dissolve rapidly in the saliva without the need for water, within seconds or a few minutes.

Some patented orally disintegrating tablet technologies currently in the market include

OraSolv®, DuraSolv®, Zydis®, FlashTab®, WOWTAB®etc (128).

Generally, they are prepared by freeze drying, compaction, or moulding. The formulations

are friable and moisture sensitive, therefore requiring specialized packaging (128) .Most

commercial ODTs have been developed using mannitol as the bulk excipient of choice

because of its extremely low hygroscopicity, exceptional compatibility, high compressibility,

enhanced sweetness, and relatively slower dissolution kinetics (127). Although lactose also

has a relatively low aqueous solubility compared with other excipients that have acceptable

palatabilities. The dispersibility of a bulk excipient is more important than its aqueous

solubility for a successful ODT. Formulation strategies are now available to simplify the

process of ODT manufacturing by direct compression. Direct compression is the most

convenient process for manufacturing ODTs. Conventional equipment can be employed and

high dose tablets can be produced. Excipients play a primodial role in the successful

lii

formulation of ODTs. Superdisintegrants, hydrophilic polymers, and effervescent compounds

may be included in ODT formulations.

1.9.2.1 Dissolution testing of ODTs

Taste masking (drug coating) is often necessary for ODTs. The rate of dissolution of the

coating can be the rate-determining step for dissolution/release. In cases where taste masking

is not an issue, the development of dissolution methods is comparable to that for

conventional tablets, hence pharmacopeial conditions should be used (127). Due to its

nature, ODTs disintegrate very rapidly, thus, when using USP monograph conditions,

slower paddle speeds can be used to obtain a profile. Media such as 0.1 N HCl can be

used.USP 2 paddle apparatus is regarded as the most suitable piece of equipment for

assessing ODTs. This apparatus with a paddle speed of 50 rpm is commonly used.

1.10 Model drugs

1.10.1 Stavudine

Stavudine is also known as d4T. Its structure is shown in Figure 5. Stavudine is a

pyrimidine nucleoside antiretroviral agent with in vitro activity against human

immunodeficiency virus (HIV) similar to zidovudine and is employed in the treatment of

HIV- infection as either monotherapy or in combination with other antiretrovirals. D4T

inhibits HIV reverse transcriptase by competing with the natural substrate deoxythymidine

triphosphate and its incorporation into viral DNA, causing termination of DNA elongation.

The recommended dose based on body weight is 40 mg twice daily for patients weighing at

least 60 kg and 30 mg twice daily for patients weighing less than 60 kg.

liii

Figure 5 : Structure of stavudine.

liv

The solubility of stavudine in water was reported as 83 mg/mL at 23 oC. The pH–solubility

profile of d4T at 37.0± 0.50C was determined in 0.01N HCl (78 mg/mL), pH 4.5 (101

mg/mL), and pH 6.8 (76 mg/mL). Stavudine is nonionized at physiological pH 2.5 and its

pKa is 10. The drug belongs to the BCS class 1 typified by both high solubility and high

permeability.

1.10.2 Artesunate

Artesunate is a semi-synthetic derivative of artemisinin. Artesunate is a new effective

derivative of artemisinin now used broadly in antimalarial treatment. It contains a naturally

occurring sesquiterpene endoperoxide hydrogen succinate. Its structure is shown in Figure

6. The chemical formula is C19H28O8 with molecular weight of 384.42 (Fig. 6). It is a white

crystalline powder with melting point range of 132–135o

C and slightly soluble in water.

Artesunate is an antimalarial agent and a hemi-succinate derivative of dihydroartemisinin. It

is activated in vivo by hydrolysis, to dihydroartemisinin, the active metabolite of the drug.

Artemisinin is a sesquiterpene lactone isolated from Artemisia annua, a herb that has been

used traditionally in China for centuries in the treatment of malaria. According to the

Biopharmaceutics Classification system, it is a Class IV drug. It is a weak acid with pka of

6.4.

lv

Figure 6: Chemical structure of artesunate.

lvi

1.10.3 Ibuprofen

Ibuprofen is a BCS Class II drug with characteristic low aqueous solubility and high

permeability. Its bioavailability is limited by its rate of salvation. A correlation between the

invivo bioavailability and the in vitro salvation has been established. The drug is a non-

steroidal anti-inflammatory drug (NSAID) introduced in the late 1960’s into the drug market

as a potent treatment for pain, inflammation, arthritis, fever and dysmenorrhea. Ibuprofen is

a commonly formulated as uncoated and film-coated tablets to be used by a wide variety of

patients. However, its effectiveness is often accompanied by a high incidence of adverse

reactions, especially gastro-intestinal problems and its bitter, irritating taste. To reduce these

side effects, most of the formulations are film coated. Ibuprofen is rapidly absorbed following

oral administration in man. Plasma peak concentrations are observed within 1 to 2 hours.

Plasma half-life is about 2 hours. Absorption is also efficient though slower from

suppositories. Ibuprofen is extensively (up to 99 %) firmly bound to plasma proteins but it is

known to occupy only a fraction of the total drug binding sites at usual concentrations.

It is employed clinically in the treatment of rheumatoid arthritis and osteoarthritis. Other

conditions that bring about mild to moderate pain such as primary dysmenorrhea may be

treated with ibuprofen. Toxic effects of ibuprofen have also been detected especially in

patients with underlying peptic ulceration or with a history of gastric intolerance to

aspirin-like agents. Additionally, ibuprofen is not recommended for use in pregnant women

or breast-feeding mothers.

lvii

Figure 7: Structure of ibuprofen

lviii

1.10.4 Aspirin

Aspirin (Acetylsalicylic acid ) is one of the oldest drugs known to humanity. it is one

of the most remarkable drugs in history. It originates from the bark of the willow

tree. The active ingredient is a bitter glycoside named salicin which was first

isolated in its pure form by Leroux in 1829. The synthetic manuafacture of aspirin

from phenol was accomplished in 1860 by Kolbe and Lautemann. Aspirin is used

clinically in the treatment of inflammation, pain and fever. Upon ingestion, spirin is

rapidly absorbed ,partly from the stomach but mostly from the upper small intestine.

Appreciable quantities are found in plasma with 30 minutes of the administration of

a single dose. A peak value is attained within 24 hours and this gradually declines

with time. Aspirin is classified as a Class III drug in the BCS system and is typified

by a high solubility and low permeability. Absorption is limited by the permeation

rate though the drug is solvated fast. The plasma T 1/2 for aspirin is approximately

15 minutes. Aspirin is mostly administered and only infrequently as a parenteral

formulation. Rectal administration of aspirin suppositories may be necessary in

infants or when oral medication is not retained by the patient. Aspirin is poorly

soluble and has many chemical incompartibilities hence the need to dispense it only

in solid dry form. Controlled release drug formulations of aspirin are of limited value

owing to the long half-life saliccylate. Absorption from enteric-coated tablets is

sometimes incomplete. Aspirin exerts its effect by permanently inactivating the

enzyme cyclooxygenase.

lix

Figure.8: Structure of aspirin

lx

1.11 Rationale for the study

The research described in this thesis was aimed at preparing, characterizing and

evaluating the drug delivery potentials of a novel interpolyelectrolyte complex

produced by the combination of a pair of oppositely charged polymethacrylate

polymers commercially known as the Eudragits.

Polyanions and polycations are known to interact electrostatically to form soluble or

insoluble polyelectrolyte complexes. This work aims at the performance of a

physico-chemical evaluation of polyanion–polycation interactions aimed at better

understanding the in vitro behaviour of polyelectrolyte-based drug delivery (129-

133).

Additionally, the study assesses the multifunctionality of common polymers used for a

wide range of applications in pharmaceutical formulation science. Generally, it has been

customary for researchers to combine polymers in a bid to take advantage of the

physicochemical properties of the individual polymers. Oftentimes, polymers are

brought together by means of chemical cross-linking agents which ordinarily come with

their inherent limitations of use owing to possible toxicity problems.

The prinicipal focus of this project was to carry out a thorough physico-chemical

characterization of polyelectrolyte complexes produced using a pair of counter-charged

polymethacrylate polymers. This work is an assay of pharmaceutical materials science.

Additionally, effort was made to utilize the prepared complexes in drug formulation

studies. Tablets were prepared because of their ubiquity. Drugs chosen for the

formulation studies were selected on the basis of their therapeutic usefulness: artesunate

and stavudine for their use in the treatment of Malaria and HIV/AIDS respectively.

Aspirin and Ibuprofen were chosen because of their continued relevance as widely used

analgesics.

lxi

This work seeks to make a contribution to the quest for novel innovative pharmaceutical

excipients with multifunctionality.

1.12 Objectives of study

The objectives of this study were:

1. To prepare polyelectrolyte complex (PEC) starting from solutions of the

countercharged polyelectrolytes.

2. To carry out liquid-state and solid -state characterization of the resultant complexes

and assess their intrinsic properties and their possible pharmaceutical applications.

3. Evaluation of the formed polyelectrolyte complex in drug delivery.

CHAPTER TWO

MATERIALS AND METHODS

Materials

The following materials were purchased from local suppliers and used without further purification:

acetone, methanol, ethanol, and dimethyl ether (BDH, England). Artesunate was a kind gift from

Emzor Pharmaceuticals Nigeria Limited, stavudine was also a gift from May and Baker, Nigeria,

Limited. Aspirin was obtained from Juhel Pharmaceuticals Nigeria Limited, while Ibuprofen was a gift

from Nemeith, Nigeria, Limited. Distilled water was obtained from the National Centre for

Equipment Maintenance and Development (NCEMD) of the University of Nigeria, Nsukka. Eudragit®

E100 and Eudragit® L100- 55, were received from Evonik Industries, Darmstadt, Germany. Other

reagents were of analytical grade and were used without further purification.

lxii

Methods

Preparation of polyelectrolyte complexes by solution blending

Interpolyelectrolyte complex of Eudragit® E100 and Eudragit® L100 - 55 were prepared using a

method of solution blending. Briefly, the Eudragit(R) E100 methanolic solution was prepared by

dissolving 60 g of Eudragit® E100 in 420 ml of methanol to form a clear sticky and highly viscous

solution. Next, Eudragit ® L100 - 55 methanolic solution was prepared by dissolving 60 g in 420 ml of

methanol. The preparations were made in consonance with the specifications of the manufacturer

that 1 g of either Eudragit(R) E100 or Eudragit(R) L100 – 55 is soluble in 7 g of methanol (134). Upon

mixing of the methanolic solutions of the starting individual polymers, a white precipitate was

formed. The whole set up was allowed to stand for one hour at room temperature, to allow for

complete reaction. Next, the precipitate was collected, and washed with distilled water and filtered.

The white mass (the macromolecular complex) was obtained and dried in a desiccator and stored for

future use.

Determination of the stoichiometry of the polyelectrolyte complex

This was determined by means of turbidity measurements of solutions of combinations of the

starting polymers. Nine different mixtures of the solutions were prepared by adding different

volume ratios of a 1% Eudragit® E100 (EE) methanolic solution to volumes of 1% methanolic

Eudragit ® L100-55 (EL) solution in order to obtain different EE: EL100 ratios, ranging from 1:9 (0.11)

to 9:1 (9.00), with constant final volume of 10 ml. The process was repeated for all the mixtures but

with the inversion of the order of addition of the polymers. Samples were then allowed to stand for

1 h at room temperature and then vigorously agitated. Turbidity was immediately measured at 600

nm in a UV/VIS spectrophotometer (Model 6405, Jenway UK), which was the wavelength at which

no absorption due to the polymers occurred.

Evaluation of solubility of complex in different solvents

The solubility of the complex was evaluated in a broad array of solvents ranging from the

common organic solvents through aqueous solutions of different pHs to the novel class of neoteric

solvents, ionic liquids. Briefly, minute quantities of the complex were collected and added to about 5

ml of each solvent earlier placed in a test-tube. Thereafter, the test-tube was agitated and allowed

to stand so as to observe whether the complex will go into solution. The observations made were

then recorded. Tests were carried out in triplicate. The various solvents tested included methanol,

ethanol, acetone, dioxane, diethylether, n-hexane, tetrahydrofuran, ethylacetate, xylene,

chloroform, concentrated hydrochloric acid and concentrated NaOH .

Solubility of IPEC in ionic liquids

Briefly, A 1.2 g quantity of ionic liquid was placed in a sample vial with the addition of a 0.1g

quantity of the test polymer complex material. All samples were stirred overnight at

lxiii

50 0C. Nine different ionic liquids were evaluated. They are listed below in Table 3.

lxiv

Table 3: Ionic liquids used for solubility of polymer complex.

lxv

Retrievability of polyelectrolyte complex from ionic liquids

Further tests were conducted to evaluate the retrievability of the interpolymer complex from the

ionic liquids. Briefly, into the best ionic liquid solvents determined, that is B, E and G; more polymer

was added to give about 30 % mass of the mixture. Next, the mixtures were stirred for 1 hr at 80 oC.

The transformation of the samples was then observed. The most appropriate approach to retrieve a

polymer from its ionic liquid solution is to cast a drop of the solution into a vial containing a solvent

capable of solubilizing the ionic liquid and not the polymer.

Morphologies of the complexes using scanning electron microscopy (SEM)

Images of EE100, EL100-55, and EE100–EL100 physical mixture and of the IPEC were captured using

a Zeiss EVO MA10 model with a multi-sector diode detector (Carl Zeiss, Oberkochen, Germany). The

acceleration voltage was 4–5 kV. Magnifications used ranged from x 500 to x 50000.

Thermal analysis of starting polymers and the formed complex

DSC thermograms were obtained using a differential scanning calorimeter (DSC Q100 V8.2 Build 268,

TA Instruments, USA) operated under a nitrogen gas flow of 20 ml/min. Calibration of the DSC

instrument was carried out using indium as a standard. Sample powders (3 to 5 mg) were weighed

into an aluminum pan and heated from 30 to 300 o C at a rate of 10 oC min− 1 from 30 to 300 °C.

Experiments were carried out in triplicate and the best readings were taken.

Fourier transform infrared (FTIR) studies on starting polymeric materials and the

formed interpolyelectrolyte complex

FT-IR spectra of EE, EL100, EE:EL100 physical mixture, and of the solid IPEC were obtained using an

FT-IR Spectrometer 3100 Excalibur Series (Varian, USA).Samples were analyzed under nitrogen

atmosphere by Attenuated Total Reflectance – ATR with 100 scans and 4cm-1 resolution.

Wide angle x-ray diffraction studies (WAXD)

X-ray diffraction analyses (XRD) were performed using a Rigaku Miniflex diffractometer employing

nickel filtered CuK α radiation (λd= 1.5418 Å) at 30 kV and 15 mA. Readings were recorded from 2

theta of 2 to 10° at 2 theta rates of 0.05°/min.

Raman spectrophotometric studies

The analyses were carried out in a VITEC equipment model Alfa 300AR, to obtain Raman spectra of

the starting polymers, physical mixtures, and interpolyelectrolyte complex via an air-cooled CCD

detector. The MR Probe System fiber-optic sampling device was equipped with an extruder

compatible optic. A 785-nm NIR-laser was used for excitation.IC Raman software served for data

collection and transfer. Raman spectra were plotted using Origin software for Windows.

lxvi

Tablet pre-formulation evaluation

Flowability

The flow properties of the macromolecular complex were semi-quantitatively evaluated by

measuring the dynamic angle of repose. A funnel filled with the complex was maintained at 2 cm

above a graduated surface, the funnel was then drained and the angle of repose (θ) was calculated

measuring the diameter of the base of the cone formed.

��� ∅ =��ℎ� � ℎ���

����� � ���� � ℎ��� − − − − − − − − − − − − − − − 1

Bulk density

Apparent bulk density in (g/ml) was determined by placing pre-sieved bulk powder blend into a

graduated cylinder and measuring the volume and weight of powder blend.

���� ������ =��ℎ� � � ���� �����

� ���� � � ���� ����� − − − − − − − − − 2

Tapped density

This was determined by placing a graduated cylinder, containing a 20 g mass of powder and

tapping the measuring cylinder for up to 500 times. Using the weight of powder in a cylinder and its

tapped volume, the tapped density was computed.

The value of the tapped density is calculated using the Equation 3.

������ !����� =��ℎ� � � ���� �����

������ " ���� � � ���� ����� − − − − − − − 3

Carr’s index

This is an important determinant of the compressibility of a given powder blend. Taking into account

the density and tapped density, Carr’s index can be determined by using the following equation:

$��� � ���% &%( =������ ������ − ���� ������

������ ������ % 100 − − − − − − − − − 4

lxvii

Formulation studies

Formulation of matrix tablets

Matrix tablets were prepared using direct compression. Details of the formulas used for the chosen

model drugs are shown in Tables 4 to

Prior to the formulation studies on the tablets produced, some basic tests on the powder material

were conducted to assess the attributes of the complex prepared which could impact on the

properties of the final tablet dosage form.

lxviii

Table 4: Composition of stavudine tablets

Formulations

Ingredients

(Mg/tablet)

F1 F2 F3 F4 F5 F6 F7 F8 F9

Stavudine 80 80 80 80 80 80 80 80 80

IPEC 40 80 120 - - - - - -

Eudragit

E100

- - - 40 80 120 - - -

Eudragit

L100-55

- - - - - - 40 80 120

Talc 9 9 9 9 9 9 9 9 9

Magnesium

stearate

3 3 3 3 3 3 3 3 3

lxix

Table 5 : Composition of Aspirin matrix tablets

Formulations

Ingredients (mg) F1 F2 F3 F4 F5

Aspirin 100.0 100.0 100.0 100.0 100.0

IPEC 100.0 200.0 300.0 400.0 -

NaCMC 300.0 200.0 100.0 - 400.0

Magnesium stearate

% 0.5 w/w

2.5 2.5 2.5 2.5 2.5

lxx

Table 6 : Composition of Ibuprofen matrix tablets

Formulations

Ingredients (mg) F1 F2 F3 F4 F5

Ibuprofen 100.0 100.0 100.0 100.0 100.0

IPEC 100.0 200.0 300.0 400.0 -

NaCMC 300.0 200.0 100.0 - 400.0

Magnesium stearate

% 0.5 w/w

2.5 2.5 2.5 2.5 2.5

lxxi

Table 7 : Composition of artesunate matrix tablets

Formulations

Ingredients (mg) F1 F2 F3 F4 F5

Artesunate 50.0 50.0 50.0 50.0 50.0

IPEC 50.0 100.0 150.0 200.0 -

NaCMC 300.0 250.0 200.0 - 400.0

Magnesium stearate

% 0.5 w/w

2.5 2.5 2.5 2.5 2.5

lxxii

Tablet compression

Tablets were compressed from prepared mixtures of the relevant active pharmaceutical ingredients

pre-selected along with other excipients.

The granules were mixed with magnesium stearate and compressed into tablets using the Manesty

single punch tableting machine (Manesty type F3), Liverpool, England. The tablet batches were

formulated to contain artesunate, stavudine, ibuprofen, and aspirin respectively. Target weight of

tablets was 300 mg.

Tablet evaluation tests

The following quality control tests were carried out on the different batches of the tablets.

crushing strength, friability and weight uniformity evaluation.

Crushing strength

Ten tablets were randomly selected from each batch of the tablets and a Vernier caliper

(G.T. Tools, Japan) was used to determine the tablet thickness and diameter of each of the tablets.

The breaking force of each tablet was determined using the Monsanto hardness tester. The result

was recorded and the standard deviation was calculated.

Friability

Ten tablets were randomly selected,de-dusted weighed and the initial weight was recorded. The

Erweka friabilator which rotated at 25 revolution per minute was used to test the tablets for 4 min.

The weight of the ten tablets was determined and the percentage friability calculated using the

differences in the initial and final weights.

+��,����� -������ =�. − �/

�.

× 100 − − − − − − − − − − − 5

Where WI = Initial weight of 10 tablets before shaking

Wf = final weight of 10 tablets after shaking

Weight uniformity

Twenty tablets were selected at random from each batch of the tablets. The weight of each of the

twenty tablets was determined using an electronic weighing balance (Adventurer OHAUS, China).

lxxiii

The weight determined was recorded; the average weight and variations were then compared with

the individual weights of the tablets for each batch.

Disintegration time test

This was carried out using a disintegration test apparatus (Manesty Multi- Unit Disintegration

Apparatus, England). A tablet was placed in each of the six tubes whose lower ends were closed by a

screen of 2 mm nominal aperture. The tubes were raised and lowered in a bath of fluid (water) and

maintained at 37 ± 1.0 oC. The average time for disintegration of the six tablets per batch were

calculated and recorded.

CHAPTER THREE

RESULTS AND DISCUSSION

3.1. Yield of polyelectrolyte complexes

Percentage yield of interpolyelectrolyte complex of Eudragit® E100 and Eudragit® L100 was 94.68%.

The high yield is most likely attributable to the profound affinity existing between the starting

polymers employed in the formulation of the polyelectrolyte complex. Additionally, it may be

inferred that the reaction kinetics of the complexation process driven by the interaction proceeds

without significant loss of the reacting materials . At a more fundamental level, the interaction

between the candidate polyelectrolytes involves the vital mechanism of self-assembly of the

constituent molecules in a manner reminiscent of the formation of some of the fundamental

molecular building blocks of the human body such as the vital proteins, carbohydrates and lipids

(100).

3.2. Stoichiometry of polyelectrolyte complex

The stoichiometry of the complexation reaction between methanolic solutions of the two test

starting polymers portrays the relative quantities of the candidate polymers required for the

reaction between the two polymers. The simple turbidimetric assay designed to study this

combination of solutions of the oppositely charged methacrylate demonstrates that a 1:1 ratio

brings about production of the polyelectrolyte complex. This finding appears to be in symphony with

the results obtained by Margulis and Moustafine (52). Additionally, the report of Gallardo et al;

seems to validate this observation (80).

lxxiv

0

0.2

0.4

0.6

0.8

1

1.2

0 0.5 1 1.5 2 2.5 3 3.5

EE/EL

EL/EE

Re

lati

ve

Tu

rbid

ity

Composition of Mixtures (Z= EL/EE)

Figure 9 : Stoichiometric analysis of interaction between Eudragit E100® and Eudragit® L100-55.

3.3. Solubility of polyelectrolyte complex in common solvents

The polyelectrolyte complex produced was found to be insoluble in all the common solvents

tested and this sparked off a quest to discover a suitable solvent for it. Solvents assessed

ranged from water, the universal solvent, to the hydro-alcohols such as methanol, ethanol.

organic solvents like chloroform and other solvents such as tetrahydrofuran (THF) and

lxxv

dimethylsulphoxide (DMSO. After an unsuccessful search among the common solvents and

their combinations, the focus was shifted to the novel class of solvents, the ionic liquids,

which emerged in the 1990s as the new solvents that could be used to dissolve materials that

are not soluble in the common solvents (103-105).

3.4. Solubility of polyelectrolyte complex in ionic liquids

Nine ionic liquids were screened for their suitability as solvents for the polyelectrolyte complex. Our

findings indicate that only three of the tested ionic liquids can serve as solvents for the

polyelectrolyte complex namely 1-alkyl-3-methylimidazolium oxaloacetate, Tetraalkyl phosphonium

oxaloacetate, and 1-alkyl-3- methylimidazolium thiocynate.

Additionally, it needs to be stressed that in contemporary chemical science, there is a clamor for the

replacement of hazardous solvents by green solvents like the ionic liquids (105). Furthermore, some

authors even now advocate for the formulation of common drugs such as aspirin in ionic liquids as

this mode of presentation of the drug could eliminate problems such as polymorphism associated

with the presentation of drugs in the common solid dosage forms especially tablets (138).

3.5. Retrievability of polyelectrolyte complex from ionic liquids

The assessment of the retrievability of the polyelectrolyte complex from the ionic liquids studied has

is aimed at evaluating whether the complex can be reversibly obtained from its solutions in ionic

liquids. Here, what was studied is the capacity of the candidate ionic liquids to dissolve the complex

without derivatizing the material in a manner analogous to how many ionic liquids are known to

dissolve cellulose (117).

3.6. Morphology of polyelectrolyte complexes using scanning electron

microscopy (SEM)

The morphology of the candidate polymers and the resultant polyelectrolyte complex are shown

in Figure 10. Fig. 10a depicts the surface of Eudragit® E100. The morphology that emerges appears

to be that of a massively convoluted surface with a great abundance of grooves and crevices, which

could serve as holding places for molecules of other materials that may be brought in contact with

the polymer.

lxxvi

a) Eudragit® E100 X 500

b) Eudragit® E 100 X 1000

Figure 10: SEM plates of the individual polyelectrolytes (a to b )

lxxvii

c) Eudragit® L100- 55 x 500

d) Eudragit ® L100- 55 x 1000

Figure 10: SEM plates of the individual polyelectrolyte and the polyelectrolyte

complexes (c to d)

lxxviii

e) IPEC x 500

f) IPEC x 1000

Figure.10: SEM plates of the individual polyelectrolyte and the

polyelectrolyte complexes (e to f)

lxxix

g) IPEC x 500

h) IPEC x 500

Figure 10: SEM plates of the individual polyelectrolyte and the polyelectrolyte

complexes (g to h)

lxxx

3.7. Thermal analysis of sample polymers and polyelectrolyte complexes

Results of the thermal analysis of the individual starting polymers and the interpolyelectrolyte

complex formed are shown in Figure 11.Thermal analytical methods are used extensively

to investigate the behavior of materials when subjected to heating. Traditionally, the value

that serves as the surrogate marker for the assessment of the impact of heating on the thermal

properties of an amorphous test material is the glass transition temperature (Tg) (139-140).

Using this method, the Tg of pure polymers or blends formed from the two test polymers may

be detected. Normally, when two polymers are miscible, the resultant complex should exhibit

only one Tg (141) and not display the two original Tg of the individual starting polymers. Fig.

11a and Fig. 11b shows the DSC thermograms of the two starting polymers while Fig.11c

shows the thermogram of the formed complex. When two amorphous polymers are

combined following a reaction between them, their chains become intertwined at different

points leading to the formation of a net like structure. The Tg value for this structure has to be

much more higher than the Tg values of the individual starting polymers due to the lesser

flexibility of the polymer combination (142-144). In Figure. 11, the Tg value of the formed

complex is between the Tg values of the individual pure polymers. A corollary of this finding

is that even the emergence of the net structure does not bring about a reduction in the

flexibility of the complex. Additionally, this value could be further explained by two factors.

First, the nature of the solvent used in the preparation of the mixture. Recall that methanol

was the solvent used and it appears to act as a plasticizer, its complete removal from the final

complex is virtually impossible owing to its capacity to persist in the system as an almost

ineradicable residual solvent (142-143). Second, the relative amount of each individual

polymer at the point where these two polymers react is extremely low giving rise to a

situation where the polymer chains have a great deal of flexibility. This flexibility could

lxxxi

impact on the possible range of applications of the resultant material in the sense that with

greater flexibility will lead to the possibility of the polymer chains intercalating with a wide

array of ligands to give rise to multiple structures of novel materials some of which could be

relevant to pharmaceutical formulation.

The Tg of a polymer blend may be calculated by the application of the Gordon-Taylor equation

(144-145). -------------7

Where Tg = Glass transition temperature of the polymer blend (k)

w1 = weight fraction of component one.

w2 = Weight fraction of component two

Tg1 = Glass transition temperature of component one.

Tg 2 = Glass transition temperature of component two

K = parameter1 = density of the components (g/ml)

Tg2 corresponds to the component with higher Tg.

When the Tg and weight fraction of the components and the value of the density of the poly

(meth)acrylate (which is approximately 1.11 g/ml), the theoretical value of calculations >> + (Mo).

3.7.1 Differential scanning calorimetry (DSC)

The DSC plots of the samples evaluated are shown in Figure 11. DSC measurements serve to

establish whether or not there has been a formation of a polyelectrolyte complex usually

indicated by a unique Tg value.

The measurements were carried out using as samples the individual starting polymers, the

physical mixture of equal portions of both polymers and the complex formed following the

lxxxii

mixing of the methanolic solutions of the individual polymers. The plot for sample A

(Eudragit® L100 55) (Fig.11a) shows two curves of heating: downwards = 1st heating and

upwards= 2nd

heating (1000C/min). The first heating curve showed an endothermic peak that

seems to be due to enthalpic relaxation (146). This behaviour is common in aged amorphous

polymers (147-150). When the sample was heated for a second time the enthalpic relaxation

did not appear, but the Tg appeared. For this sample Tg was about 120 oC. Sample B

(Eudragit ® E100). showed the same behaviour (enthalpic relaxation) in the first heating but

with different intensity. In this case, Tg= 46. 29 (2nd

heating). Sample C (Polyelectrolyte

complex) also showed enthalpic relaxation and it was similar to sample A. The Tg was

97.59 oC, which demonstrated that the two polymers did interact with each other to form a

complex. In opposite case, i.e., if they did not interact, we would have 2 Tgs. The new Tg

value was found to be higher than the Tg values of the individual polymers used. Eudragit®

E100 has an established glass transition temperature of 48 o

C while that of Eudragit®

L100

55 is 110 oC.

lxxxiii

Figure 11a: DSC thermogram of Eudragit® E100

lxxxiv

Figure 11b : DSC thermogram of Eudragit® L100-55

lxxxv

3.7.2 Thermogravimetric analysis (TGA)

This evaluation served as a probe to assess the stability of the complexes at various temperatures

(144). The determination of the temperature where the first loss of mass occurs was the objective of

these studies. This loss of mass can be traced to the decomposition of the product upon rise in

temperature. Details of the thermogravimetric analysis are shown in Figure.12. It can be observed

that in all cases, the measurement followed similar patterns.

A first loss in mass is observed between 2-7% at about 174.55 oC in the case of interpolyelectrolyte

complex. Additionally, a second transition point occurs at around

346.07 oC. (Figure 12a).

lxxxvi

Figure

11c:

DSC

thermo

gram of

IPEC

lxxxvii

Figure 11d: Thermogram of Eudragit® L100 55

lxxxviii

Figure 11e:Thermogram of Eudragit ® E100

lxxxix

Figure 11f: Thermogram of IPEC

3.8 Fourier-transform infrared spectroscopy (FTIR)

The infrared spectrum of a macromolecule is often times remarkably simple despite the large

number of molecules involved (151-156). Investigating solid-state interactions should explicate that

interpolyelectrolyte complexation occurs by means of electrostatic interactions of the starting

polyelectrolyte complexes following self-assembly (157). These studies were performed with the

goal of ascertaining how the principal functional groups in the two starting individual polymers

reacted during complexation. The IR spectra of the solid complex showed some significant

xc

differences when compared to those of a physical mixture of Eudragit® E100 and Eudragit® L100 55

at a weight ratio of 1:1. IPEC, according to FTIR spectra has a band at 1570 cm-1, which can be

assigned to the absorption band of the carboxylate groups that form the ionic bonds with the

protonated dimethylamino groups of Eudragit E100. This phenomenon is close to those observed in

previous studies for EPO/L100 (L100-55) systems (159-161) .Additionally, it may be posited that this

observation which is a corollary of the disappearance of a carboxylate group of the constitutive

ethylacrylate monomers of Eudragit® L100 55 polyelectrolyte may point to an intermolecular

electrostatic interaction between these representative functional groups of the combined

polyelectrolytes. The disappearance of the signals due to protonation of the dimethylaminoethyl

group (136, 137, 158) can be explained by the interaction of the protonated dimethylamino groups

with the carboxylate groups of the interacting polyelectrolytes to form a complex. The FTIR spectra

for the starting polymers as well as that of the equimolar physical mixture of the starting polymers

and that of the formed complex are shown in Figure 12.

xci

Figure 12a: FTIR spectrum of Eudragit® L100- 55

xcii

Figure 12b: FTIR Spectrum of Eudragit® E100

4000 3000 2000 1000 0

0

10

20

30

40

50

IPEC B%

Tra

nsm

itta

nce

Wavenumber

xciii

Figure 12c: FTIR Spectrum of IPEC

xciv

Figure 12d: Superimposition of FTIR spectra of individual polyelectrolytes and IPEC.

xcv

3.9 Wide angle x-ray diffraction studies

These studies served to highlight the solid state properties of these materials especially to probe

their degree of crystallinity (163-165). Details of the results obtained are portrayed in Figure 13.

The WAXD diffractograms show a typical profile for an amorphous material (10). In all cases, it was

observed that there was a proliferation of halos as opposed to sharp reflections. This may be

attributed to the amorphicity of all the test samples. However, the amorphous halos formed by the

individual polyelectrolytes around 2θ = 20.0◦ for Eudragit® E100, and 2θ = 19.0◦ for Eudragit® L100 -

55 merged and tended toward lower angles in the diffractograms of the IPECs. This observation is

suggestive of a possible complexation reaction. Additionally, a close inspection of the diffractograms

would suggest that each test material has a slight variation in its response to x-rays with different 2θ

positions of the amorphous halos. However, it appears that of all the samples studied, Eudragit®

L100-55 (About 1800) gave the lowest intensity while the formed IPEC displayed higher intensity.

These findings seem to validate the outcome of the other studies, such as those of the thermal

analysis, leading to the inference that the combination of Eudragit® E100 and Eudragit® L100-55,

which are both amorphous materials lead to the formation of an amorphous polyelectrolyte

complex. It is pertinent at this point to reiterate that ever since the introduction of solid dispersions

in the 1960s by Sekiguchi and Obi (166), there has been an abiding interest of pharmaceutical

researchers in formulation of some drugs in certain amorphous formulations especially because such

formulations will tend to dissolve rapidly in the liquid media found in animals and human beings who

are the principal consumers of medicinal formulations. Complexes were classed as solid dispersions

recently (167) in the sense that “a solid dispersion is defined as a “dispersion of one or more active

ingredients in an inert carrier or matrix at solid state” (168). Though they might also be characterized

as single-phase amorphous systems, their constituent molecules are associated with each other

stoichiometrically by electrostatic interactions (158). The fact that the starting polyelectrolytes and

the interpolyelectrolyte complex produced from them appear to be all amorphous points to the fact

that these materials could be suitable for use in a myriad of pharmaceutical formulations in which

the inclusion of amorphous excipients will be an added advantage.

xcvi

Figure 13a: WAXD plots of Eudragit® L100-55

0 10 20 30 40 50

0

200

400

600

800

1000

1200

1400

1600

1800

2theta

IPEC A

Intensity

xcvii

Figure 13b: WAXD plot of Eudragit® E100

0 10 20 30 40 50

0

200

400

600

800

1000

1200

1400

1600

1800

2000

2theta

Intensity

IPEC B

xcviii

Figure 13c: WAXD plot of IPEC

0 10 20 30 40 50

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Intensity

2theta

IPEC C

xcix

Figure 13d: WAXD plots for individual polyelectrolytes and the complex

3.10 Raman spectra

Raman spectroscopy facilitates the study of the interactions of the vibrational and rotational

energies of atoms or groups of atoms within molecules (169). Raman measurements were

conducted to emphasize the proof of complex formation in the IPEC (170-171). Raman spectra of

both starting individual polymers, Eudragit® E100 and Eudragit® L100-55 are shown in Figure 14. Of

0 10 20 30 40 50

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Intensity

2theta

----- IPEC C

----- IPEC B

----- IPEC A

c

particular interest were the regions between 1200 cm-1 and 1300 cm-1. It is evident that there are

sharp differences in peaks between the polymers and the final complex. Furthermore, a peak at

1252 cm-1 was found to exist in the spectra of the polyelectrolyte complex. This could be attributed

to the ionic interaction between the carboxylate group of Eudragit® E100 and the

dimethylaminoethyl group of Eudragit® L100-55. This finding seems to be in agreement with the

outcome of the thermal studies and the FTIR studies. The only inference that may be drawn from

these findings is the high probability that in the special cases where solutions of Eudragit® E100 and

Eudragit® L100-55 in methanol are combined, an ionic reaction occurs between their respective

functional groups leading to the formation of a polyelectrolyte complex with its own distinct

physicochemical properties which is not just an additive combination of the inherent properties of

the individual polyelectrolytes brought together.

Figure 14a: Raman spectra of Eudragit® L100 55

Key to Samples:

a. Eudragit L100 -55

b. Eudragit E100

c. IPEC

0 200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Region 1

(b) Region 2

(c) Region 3

ci

Figure 14b: Raman spectra of Eudragit® E100

Key to Samples:

a. Eudragit L100 -55

b. Eudragit E100

c. IPEC

200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Region 1

(b) Region 2

(c) Region 3

cii

Figure 14c: Raman spectra of IPEC

Key to Samples:

a. Eudragit L100 -55

b. Eudragit E100

c. IPEC

200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Region 1

(b) Region 2

(c) Region 3

ciii

Figure 14d: Raman spectra of region 1 of all the samples*

Key to Samples:

d. Eudragit L100 -55

e. Eudragit E100

f. IPEC

200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Sample A

(b) Sample B

(c) Sample C

200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Sample A

(b) Sample B

(c) Sample C

civ

Figure 14e: Raman spectra of region 2 of all the samples.

Key to Samples:

a. Eudragit L100 -55

b. Eudragit E100

c. IPEC

Figure 14f: Raman spectra of region 1 of all the samples*

Key to Samples:

a. Eudragit L100 -55

b. Eudragit E100

c. IPEC

200 400 600 800 1000 1200 1400 1600 1800 2000

(c)

(b)

(a)

Inte

nsity (

a.u

.)

Raman shift (cm-1)

(a) Sample A

(b) Sample B

(c) Sample C

cv

cvi

3.11 Preformulation studies

The preformulation studies provided data on the fundamental and derived properties of the

powders comprising of the active pharmaceutical ingredients and the excipients to be employed in

tablet formulations. Details of the flow properties of the powders are shown in Tables 8 to 11. The

various powders displayed good to moderate flow properties which indicated that their

formulations could be adaptable to direct compression mode of tablet manufacture. The bulk and

tapped densities of the powders indicate that these matrerials are moderately bulky and hence

amenable slight deformation during the transfer of the powder mass from the mixing vessel to the

moving parts of the tabletting machine. Additionally, the values of the Carr’s compressibility index

is a surrogate marker which highlights the extent of consolidation of the powders. Quick

consolidation is essential to uniform filling on tablet machines in situations in which powder flows at

its minimum bulk density into the die and consolidates to approach the maximum bulk density prior

to compression.

cvii

Table 8 : Flow properties of stavudine powder mix

Formulation

Code

Angle of repose

(θ)*

Bulk density

(gm/cm3)*

Tapped density

(gm/cm3)*

Hausner ratio

(HR)*

Carr’s index

(CI)*

F1 21.28 ± 0.22 0.745 ± 0.01 0.836 ± 0.01 1.124 ± 0.001 11.13 ±0.06

F2

21.19 ± 0.55 0.740 ± 0.02 0.822 ± 0.02 1.122 ± 0.002 10.94 ±0.05

F3 20.55 ± 0.48 0.743 ± 0.03 0.823 ± 0.01 1.125 ± 0.000 11.10 ± 0.06

F4 21.11 ± 0.22 0.746 ± 0.04 0.824 ± 0.02 1.124 ± 0.001 10.96 ± 0.07

F5 20.82 ± 0.24 0.756 ± 0.01 0.826 ± 0.03 1.123 ± 0.002 10.98 ± 0.06

F6 20.86 ± 0.25 0.754 ±0.02 0.832 ±0.02 1.125 ± 0.001 10.97 ±0.05

F7 21.28 ±0.26 0.746 ± 0.01 0.834 ± 0.01 1.126 ± 0.002 10.96 ± 0.06

F8 20.59 ±0.23 0.743 ± 0.02 0.836 ± 0.02 1.125 ± 0.002 11.12 ± 0.05

F9 20.82 ± 0.28 0.747 ± 0.03 0.837 ± 0.00 1.124 ± 0.001 10.99 ± 0.04

*All the values are expressed as mean ± SE, n=3

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Table 9: Flow properties of Aspirin granules

Formulation

Code

Angle of repose

(θ)*

Bulk density

(gm/cm3)*

Tapped density

(gm/cm3)*

Hausner ratio

(HR)*

Carr’s index

(CI)*

F1 20.21 ± 0.20 0.735 ± 0.01 0.826 ± 0.01 1.123 ± 0.001 10.13 ±0.06

F2

21.16 ± 0.55 0.739 ± 0.02 0.821 ± 0.02 1.121 ± 0.002 10.92 ±0.05

F3 21.25 ± 0.48 0.733 ± 0.03 0.813 ± 0.04 1.117 ± 0.000 10.68 ± 0.04

F4 21.16 ± 0.22 0.726 ± 0.04 0.814 ± 0.02 1.124 ± 0.001 10.56 ± 0.08

F5 21.12 ± 0.26 0.755 ± 0.03 0.816 ± 0.04 1.121 ± 0.002 10.78 ± 0.05

*All the values are expressed as mean ± SE, n=3

cix

Table 10: Flow properties of Ibuprofen granules

Formulation

Code

Angle of repose

(θ)*

Bulk density

(gm/cm3)*

Tapped density

(gm/cm3)*

Hausner ratio

(HR)*

Carr’s index

(CI)*

F1 21.22 ± 0.21 0.725 ± 0.02 0.816 ± 0.03 1.119 ± 0.001 10.11 ±0.04

F2

20.14 ± 0.53 0.729 ± 0.08 0.821 ± 0.06 1.118 ± 0.002 10.83 ±0.05

F3 21.18 ± 0.48 0.727 ± 0.03 0.812 ± 0.03 1.127 ± 0.001 10.56 ± 0.03

F4 21.15 ± 0.23 0.725 ± 0.04 0.814 ± 0.02 1.123 ± 0.001 10.46 ± 0.18

F5 21.11 ± 0.27 0.723 ± 0.03 0.814 ± 0.04 1.121 ± 0.002 11.78 ± 0.05

*All the values are expressed as mean ± SE, n=3

cx

Table 11: Flow properties of Artesunate granules

Formulation

Code

Angle of repose

(θ)*

Bulk density

(gm/cm3)*

Tapped density

(gm/cm3)*

Hausner ratio

(HR)*

Carr’s index

(CI)*

F1 20.21 ± 0.25 0.724 ± 0.02 0.817 ± 0.03 1.118 ± 0.001 10.12 ±0.05

F2

20.13 ± 0.53 0.728 ± 0.08 0.819 ± 0.07 1.119 ± 0.003 10.76 ±0.06

F3 20.17 ± 0.46 0.725 ± 0.03 0.815 ± 0.03 1.128 ± 0.001 10.55 ± 0.02

F4 21.13 ± 0.23 0.724 ± 0.04 0.812 ± 0.02 1.122 ± 0.001 10.44 ± 0.17

F5 21.11 ± 0.27 0.721 ± 0.05 0.813 ± 0.03 1.119 ± 0.002 11.76 ± 0.05

*All the values are expressed as mean ± SE, n=3

cxi

3. 12 Formulation studies

In the course of the investigation, the preparation and evaluation of tablets containing some model

drugs namely aspirin, artesunate, ibuprofen and stavudine were attempted. The method of tablet

manufacture chosen was direct compression because of its established advantages, especially its

simplicity and rapidity. Results of the physicochemical evaluation of the tablets are shown in Tables

12 to 15. Findings obtained demonstrate that owing to the physicochemical properties of these

candidate drugs, not all are amenable to direct compression which is largely dependent on the

crystallinity and high compressibility of the drug (Active pharmaceutical ingredient, API).

Additionally, the use of the formed polyelectrolyte complexes as direct compression excipients did

not yield tablets of high hardness. Thus, the net result observed was the production of tablets of

rather low hardness, which disintegrated rapidly upon coming into contact with the release media.

In an attempt to explain the physical behaviour of the various batches of prepared tablets, scouring

of the literature led to the consideration of the resultant tablets as fast disintegrating or orally

disintegrating tablets (172-175). Orally disintegrating tablets are formulated for distinct populations

of pediatric and geriatric patients especially persons with swallowing difficulties (dysphagia). The US

FDA defines this class of tablets as those tablets which are capable of complete disintegration within

30 s of contact with the dissolution medium. Tablets produced in this work did not disintegrate

within 30 s but within 2-3 mins (120 – 180 s) for want of another category, they may be added to the

class of rapidly disintegrating tablets. Our findings appear to be different from similar studies that

have been conducted by other workers especially Moustafine et al. (136) and Prado et al. (145).

Perhaps the reason for our findings may lie in the integration of molecules of the solvent used in the

preparation of the polyelectrolytes evaluated. Furthermore, it may be pertinent to address toxicity

cxii

Table 12: Physicochemical characterization of stavudine tablets

Formulation

Code

Thickness

(mm)*

Weight

variation

test (%)*

Hardness

(Kg/f)

Friability

(%)*

Drug content

(%)*

F1 3.17 ± 0.12 ± 2.11 5.7 ± 0.2 0.41 ± 0.05 99.82 ±1.50

F2 3.16 ± 0.11 ± 2.14 5.6 ± 0.3 0.31 ±0.07 99.63 ± 1.3 0

F3 3.15 ± 0.12 ± 2.03 5.5 ± 0.4 0.36 ±0.03 98.79 ± 1.50

F4 3.13 ± 0.10 ±1.89 5.7 ±0.4 0.37 ± 0.02 99.45 ± 0.80

F5 3.14 ± 0.13 ±1.87 5.6 ± 0.4 0.35 ± 0.06 100.28 ± 0.90

F6 3.18 ± 0.12 ± 1.88 5.7 ± 0.4 0.38 ± 0.05 100.02 ± 0.70

F7 3.19 ± 0.14 ± 1.90 5.8 ±0.3 0.37 ±0.04 98.2 ± 0.60

F8 3.20 ± 0.13 ±1.88 5.9 ± 0.3 0.35 ±0.07 99.45 ± 0.80

F9 3.21 ± 0.15 ± 1.91 6.0 ± 0.3 0.34 ± 0.06 99.47 ± 0.50

*All the values are expressed as mean ± SE, n=3

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Table 13: Physicochemical characterization of aspirin tablets

Formulation

Code

Thickness

(mm)*

Weight

variation

test (%)*

Hardness

(Kg/f)

Friability

(%)*

Drug content

(%)*

F1 4.17 ± 0.12 ± 2.12 5.4 ± 0.2 0.42 ± 0.05 99.72 ±1.5

F2 4.16 ± 0.11 ± 2.16 5.5 ± 0.3 0.36 ±0.07 99.53 ± 1.3

F3 4.15 ± 0.12 ± 2.13 5.2 ± 0.4 0.32 ±0.03 98.82 ± 1.5

F4 4.13 ± 0.10 ±1.92 5.3 ±0.4 0.35 ± 0.02 99.55 ± 0.8

F5 4.14 ± 0.13 ±1.94 5.4 ± 0.4 0.33 ± 0.06 100.23 ± 0.9

*All the values are expressed as mean ± SE, n=3

cxiv

Table 14: Physicochemical characterization of ibuprofen tablets

Formulation

Code

Thickness

(mm)*

Weight

variation

test (%)*

Hardness

(Kg/f)

Friability

(%)*

Drug content

(%)*

F1 4.15 ± 0.10 ± 2.09 5.2 ± 0.22 0.41 ± 0.05 99.74 ±1.6

F2 4.13 ± 0.11 ± 2.14 5.3 ± 0.25 0.35 ±0.07 99.52 ± 1.4

F3 4.14 ± 0.18 ± 2.12 5.2 ± 0.43 0.33 ±0.03 98.85 ± 1.5

F4 4.15 ± 0.10 ±1.93 5.3 ±0.42 0.35 ± 0.04 99.57 ± 0.7

F5 4.14 ± 0.15 ±1.95 5.4 ± 0.44 0.33 ± 0.08 100.13 ± 0.8

*All the values are expressed as mean ± SE, n=3

cxv

Table 15: Physicochemical characterization of artesunate tablets

Formulation

Code

Thickness

(mm)*

Weight

variation

test (%)*

Hardness

(Kg/f)

Friability

(%)*

Drug content

(%)*

F1 3.15 ± 0.10 ± 2.07 5.1 ± 0.22 0.39 ± 0.05 99.86 ±1.6

F2 3.16 ± 0.11 ± 2.12 5.2 ± 0.25 0.37 ±0.07 99.58 ± 1.4

F3 3.14 ± 0.18 ± 2.10 4.9 ± 0.43 0.36 ±0.03 98.87 ± 1.5

F4 3.15 ± 0.10 ±1.98 5.1 ±0.42 0.35 ± 0.04 99.48 ± 0.7

F5 3.14 ± 0.15 ±1.96 5.2 ± 0.44 0.36 ± 0.08 100.11 ± 0.8

*All the values are expressed as mean ± SE, n=3

cxvi

issues with respect to the use of methanol as a solvent for the individual starting polymers.

Methanol is a class 2 residual solvent which implies that it does not pose sufficiently high risk to

persons and the environment to preclude its use in pharmaceutical processes and products (176).

Additionally, at this juncture it becomes imperative to emphasize the raison d'etre for our trials with

the neoteric ionic liquids. Recent studies point to a possible role of ionic liquids in the preparation

of novel formulations of drugs to give rise to liquid preparations which will most probably have a

much better pharmaceutical profile than tablets which persist as a versatile dosage form. It is

argued that drug combinations with ionic liquids could yield more bioavailable formulations devoid

of the typical problems frequently associated with solid dosage forms rich in crystalline materials

such as deleterious effects of polymorphism and the need for the solids to dissolve to yield the

active molecules of the loaded drug (177). Opinions are still divided over the possible impact such

new formulations may have on the future direction of drug dosage form design and manufacture.

cxvii

CHAPTER FOUR

SUMMARY AND CONCLUSION

4.1 Summary

This work has taken on the task of attempting to provide a hitherto unknown type of

polyelectrolyte complex of a pair of oppositely charged polymethacrylate polymers. Contrary

to traditional processes of polyelectrolyte complex formation which employ aqueous

solvents, use was made of methanol, an organic solvent. Findings obtained from basic studies

of the stoichiometry of the formed polyelectrolyte complex appear to point to the formation

of a 1:1 complex between Eudragit®

E100 and Eudragit®

L100-55. Attempts to further

characterize the formed polyelectrolyte complex led to the subjection of the complex samples

to a battery of standard tests. Morphological studies were carried out using scanning electron

microscopy. In addition samples were subjected to thermal analysis, fourier transform,

infrared spectroscopy,wide angle X-ray diffraction studies, Raman spectroscopy and then

solubility studies in various common solvents as well as the novel class of ionic liquids.

These physicochemical characterization studies served to bring to light the basic properties

of the complex. The studies also added a little to our knowledge of how these pharmaceutical

materials are constituted, and could be taken collectively as surrogate indicators or

predictive signals of how this complex could behave in pharmaceutical formulations.

At the outset of this endeavour, the initial plan was to study the use of the formed complex as

a key material for the preparation, characterization and evaluation of microparticles of the

selected model drugs but it was impossible to find a common solvent for the formed complex.

These challenges led to the attempt to use ionic liquids and also the application of the

formed complex in the preparation of matrix tablets.

These studies revealed that the complex formed between the pair of oppositely charged

cxviii

polyelectrolyte complex contains equimolar quantities of the starting polymers. It has a

diffuse structure; the complex responds positively to thermal stimulus demonstrating

enthalphic relaxation or physical ageing. Also, the FTIR and WAXD studies indicated the

existence of an ioinic interaction between both polyelectrolytes. The Raman spectra

elucidated the foregoing affirmations. Also, the formulation studies revealed that the formed

complex may be a suitable excipient for the formulation of orally disintegrating tablets.

4.2 Conclusions

It may be concluded in the wake of this work that polyelectrolyte complexes can be

produced using the pair of countercharged polyelectrolytes employed in this investigation.

Additionally, the formed complex can be suitably characterized by means of a broad range of

tools including UV spectroscopy, Infrared and Raman spectroscopy as well as other

pharmaceutical characterization methods.

4.3 Recommendations

The road ahead leads to nanoformulations. Contemporary pharmaceutical science is headed

in the direction of pharmaceutical nanotechnology. Mounting data from a great variety of

sources suggest that owing to the fact that the particles in the nanorange (10-9

) differ in their

functionality from bulk materials owing to quantum mechanical effects, nanomaterials may

yet prove to be effective platforms for enhanced drug delivery effectiveness of traditional

materials. It is envisaged that in the future it will be possible to produce, characterize and

evaluate the drug delivery efficacy of nanoparticles of the polyelectrolytes studied in this

work. Then, it may be possible to assess the molecules and monolayers that could result from

the preparation of these nanomaterials.

Another task worthy of future consideration is the preparation, characterization of and drug

cxix

delivery evaluation of nanocomposites of oppositely charged polymethacrylates synthesized

in ionic liquids which are likely to have altered functionalities.

It is envisaged that in the near future, the polyelectrolyte complexes evaluated in this work

could be further characterized using other more probing studies such as those that could be

carried out using atomic force microscopy (AFM) to assess the complex at a molecular level.

Studies with isothermal titrimetry could also be done as well as ellipsometry.

Furthermore, in silico studies of the interaction of oppositely charged methacrylates could

deserve attention, thanks to the ubiquitous computer and available software.

cxx

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