PREFORMULATION STUDY TO ENHANCE SOLUBILITY OF ALBENDAZOLE

BY

CHEROGONY ROBERT KIPLAGAT

U53/81076/2015

Department of Pharmaceutics and Pharmacy Practice

School of Pharmacy

University of Nairobi

A dissertation submitted in partial fulfillment of the

requirements for the award of the degree of Master of

Pharmacy in Industrial Pharmacy of the University of Nairobi.

2017

i

DECLARATION OF ORIGINALITY

This dissertation contains my original work which has not been submitted to any

university/institution for the award of a degree.

Signature ……………………………………………………Date……………………………

CHEROGONY ROBERT KIPLAGAT, B. PHARM

U53/81076/2015

Department of Pharmaceutics and Pharmacy Practice

School of Pharmacy, University of Nairobi

Supervisors

1. Dr.Shital Maru PhD

Signature………………………………………..Date……………………………..

Department of Pharmaceutics and Pharmacy Practice

School of Pharmacy, University of Nairobi

2. Dr. Stanley Ndwigah, PhD

Signature…………………………………………Date……………………………..

Department of Pharmaceutical Chemistry

School of Pharmacy, University of Nairobi

ii

UNIVERSITY OF NAIROBI DECLARATION OF ORIGINALITY

Name of student

Cherogony Robert Kiplagat

Registration of Number

U53/81076/2015

College

Health Sciences

School

Pharmacy

Department

Pharmaceutics and Pharmacy Practice

Course name

Master of Pharmacy in Industrial Pharmacy

Title of work

Pre-formulation study on enhancing solubility of Albendazole

for purposes of developing a formulation

1. I understand what plagiarism is and I am aware of the University’s policy in this regard.

2. I declare that this dissertation is my original work and has not been submitted anywhere

for examination, award of a degree or publication. Where other people’s work has been

used, it has properly been acknowledged and referenced in accordance with the University

of Nairobi’s requirements

3. I have not used the services of any professional agencies to produce this work.

4. I have not allowed, and shall not allow anyone to copy my work with the intention of

passing it off as his/her work.

5. I understand that any false claim in respect of this work shall result in disciplinary action,

in accordance with the University Plagiarism Policy.

Signature___________________________ Date________________________

iii

TABLE OF CONTENTS

DECLARATION OF ORIGINALITY ............................................................................................ i

UNIVERSITY OF NAIROBI DECLARATION OF ORIGINALITY .......................................... ii

ABBREVIATIONS AND ACRONYMS ....................................................................................... v

ACKNOWLEDGEMENT ............................................................................................................ vii

DEDICATION ............................................................................................................................. viii

ABSTRACT ................................................................................................................................... ix

CHAPTER ONE: INTRODUCTION ............................................................................................. 1

1.1 Helminth infestations ............................................................................................................ 1

1.2. Management of Helminthiasis. ............................................................................................ 2

1.3. Pharmacokinetics of Albendazole. ....................................................................................... 2

1.4. Dose Regimen of Albendazole ............................................................................................ 3

1.5. Side effects of Albendazole ................................................................................................. 3

CHAPTER TWO: LITERATURE REVIEW ................................................................................. 4

2.1 Nomenclature of the Active Pharmaceutical Ingredient ....................................................... 4

2.2. Physicochemical properties ................................................................................................. 4

2.3. Brand product characterization: ........................................................................................... 4

2.4. Composition of the Brand Albendazole tablets ................................................................... 5

2.5. Biopharmaceutical Classification System Class of Albendazole ........................................ 5

2.6. Improving Drug release profiles of water insoluble Active Pharmaceutical Ingredients. . 6

2.7 Solid Dispersions .................................................................................................................. 7

2.7.1 Benefits of Solid Dispersions............................................................................................. 7

2.7.2 Arguments against solid dispersions .................................................................................. 8

2.7.3 General Methods of Manufacture of solid dispersions. ..................................................... 8

2.7.4. Melting Process ................................................................................................................. 9

2.7.5 Solvent evaporation ......................................................................................................... 10

2.8 Solubility Parameters .......................................................................................................... 11

2.9 Crystallinity Index .............................................................................................................. 12

2.10. Problem statement. ........................................................................................................... 13

2.11. Study justification ............................................................................................................ 14

2.12 Limitations of the study .................................................................................................. 15

iv

2.13 Study Objectives ............................................................................................................. 15

2.13.1 General objective ........................................................................................................... 15

2.13.2 Specific objectives ......................................................................................................... 15

CHAPTER THREE: METHODOLOGY ..................................................................................... 16

3.1. Study Location: .................................................................................................................. 16

3.3. Equipments ........................................................................................................................ 16

3.4. Pre- formulation studies. .................................................................................................... 16

3.4.1 Drug Powder Identification. ............................................................................................. 16

3.4.2 Appraisal of Albendazole powder characteristics............................................................ 17

3.5. Procedure for the Pre-Formulation Studies........................................................................ 17

3.5.1. Calculation of drug carrier solubility parameters ........................................................... 17

3.5.2. Preparation of Solid Dispersions .................................................................................... 18

3.5.3. Procedure for preparing solid dispersion ........................................................................ 19

3.5.3.1 Preparation of CMC solid dispersions .......................................................................... 19

3.5.3.2 Preparation of HPMC solid dispersions ........................................................................ 19

3.5.3.3 Preparation of PVP solid dispersions. ........................................................................... 19

3.5.3.4 Preparation of PEG solid dispersions. .......................................................................... 20

3.6 Analysis using UV spectrophotometer. .............................................................................. 20

3.6.1 Preparation of a calibration curve. ................................................................................... 20

3.6.1.1. Procedure ..................................................................................................................... 20

3.6.2 Determination of dissolved ABZ in the solid dispersions. .............................................. 21

3.7. Fourier Transform Infrared Spectroscopy. ........................................................................ 21

3.7.1. Procedure ........................................................................................................................ 21

3.7.2 Calculation of Crystallinity Index (CI) ............................................................................ 23

CHAPTER FOUR: RESULTS ..................................................................................................... 24

4.1 Solubility Parameters .......................................................................................................... 24

CHAPTER 5: DISCUSSION AND CONCLUSION ................................................................... 27

5.1 DISCUSSION ......................................................................................................................... 27

5.2 CONCLUSION ....................................................................................................................... 27

REFERENCES ............................................................................................................................. 29

APPENDICES .............................................................................................................................. 32

v

ABBREVIATIONS AND ACRONYMS

ABZ

API

BP

CMC

PVA

SP

WHO

ICH

INN

IUPAC

ABZ:

PEG:

CMC:

PVP:

HPMC:

Albendazole

Active Pharmaceutical Ingredient

British Pharmacopoeia

Carboxy Methyl Cellulose

Polyvinyl alcohol

Solubility Parameters

World Health Organization

International Conference on Harmonization

International Non Proprietary Name

International Union of Pure and Applied Chemistry

Albendazole

Poly ethylene glycol 8000

Sodium Carboxy Methyl Cellulose

Polyvinyl pyrrollidine K90

Hydroxypropyl methyl cellulose

vi

LIST OF TABLES

Table 1. Composition of the Brand Albendazole tablets ........................................................ 5

Table2: Calculation of Solubility Parameter of ABZ ........................................................... 17

Table 3: Quantity of ABZ and polymers as used to make the solid dispersions. ................. 18

Table 4: Preparation of calibration curve. ............................................................................. 20

Table 5:Vibrational Spectra and Frequency Assignments for ABZ ..................................... 22

Table 6: Solubility parameters of ABZ and the Polymers. ................................................... 24

Table 7: Calculated Crystallinity Index of the solid dispersions .......................................... 24

Table 8: Percentage of dissolved ABZ in the solid dispersions............................................ 25

LIST OF FIGURES

Figure 1. Chemical structure of Albendazole. ................................................................... 4

Figure 2: Manufacturing processes to produce solid dispersions ...................................... 8

Figure 3: Calculation of Crystallinity Index in relation to changes in absorption peaks

1630/1450 cm-1 infrared spectrum. ................................................................................... 23

Figure 4: Bar graph of calculated Crystallinity Index. ..................................................... 25

Figure 5: Graph of percentage dissolved ABZ against ratio of drug in polymer. ............ 26

vii

ACKNOWLEDGEMENT

I would like to express my sincere gratitude to the following people:

My Supervisors, Dr.Shital Maru and Dr Stanley Ndwiga for their invaluable input, support and

encouragement throughout the project.

The Chairman of Department of Pharmaceutical Chemistry; Dr.Abuga K.O for allowing me to

use the facilities at the Drug Analysis and Research Unit.

The Director of the National Quality Control Laboratory; Dr.Hezekiah Chepkwony for allowing

me to use the facilities at the Laboratory

Mrs. Agnes Mathenge, Mr. Achoki and Mr. Mugo for their technical support throughout the

duration of this project.

My classmates, Titus, Nicole, Anastasia and Martha for the team work and support during our

studies.

My parents and siblings whose love and support have encouraged and motivated me, not only in

this project, but throughout my life.

viii

DEDICATION

This work is dedicated to my loving and caring wife, Elizabeth and our children Ruth, Lonah,

Benjamin and Nicole for their love, support, patience and encouragement throughout the

duration of this project.

ix

ABSTRACT

Many drug molecules that have been discovered in the recent past or are in the pipeline to be

introduced into the medicine market belongs to either BCS class II or BCS class IV. These

classes all have low aqueous drug solubility in common which presents a challenge during their

formulation. Orally formulated drugs are popular to patients because they are cheap and also

easy to administer as solid dosage forms or as liquids for the young and elderly. Orally

administered drugs must undergo dissolution in the gastrointestinal tract in order to be absorbed

into the body. These molecules (BCS class II) must have its aqueous solubility increased. One of

the ways of increasing aqueous solubility is by making solid dispersions.

The challenge of making solid dispersion is in choosing minimal amounts of appropriate carrier

that would increase the drugs aqueous solubility while keeping the overall oral dosage size small.

Solubility parameters have been used to predict solubility of drug in a carrier because the drug

solubility in a carrier (a water soluble carrier) would determine the extent of the increase of the

solubility in an aqueous medium.

However solubility parameters alone are not enough to assure success due to other factors such

as viscosity. To further perfect formulation, use of other parameters such as crystallinity index

after analysis using FTIR can greatly go a long way in choosing carriers that can be used to

improve solubility of drug molecules during formulation. Use of crystallinity index can assist in

predicting the carriers that would show high solubility.

This study used Solubility parameters and crystallinity index to choose the carriers which had

potentiality of increasing the aqueous solubility of albendazole. Four polymers (PEG 8000,

HPMC, PVP and CMC) were used as carriers. The study showed that CMC was a poor drug

carrier with low dissolved albendazole though the solubility parameter difference was 4.PEG

though having a small difference in SP (0.5) did not show the highest solubility among the

carriers possibly due to recrystallization. PVP had the best aqueous solubility attested by both the

solubility parameter and the crystallinity index. HPMC though expected to have low solubility

because of high solubility parameter difference (8.4), showed good aqueous solubility of

albendazole. Both solubility parameters and crystallinity index when used together have the

potential of decreasing the time used in developing new oral dosage forms.

1

CHAPTER ONE: INTRODUCTION

According to the World Health Organization Intestinal and extra-intestinal worm infestations

affect more than two billion people in the world. They affect mostly people who live in squalor

conditions having no income with almost non-existent sanitation(Pearson, 2011). Africa is

afflicted with these pathetic conditions and the worms decimate the poorest populations affecting

economic activities by initiating morbidity and suffering though it can be easily be treated and

prevented by medicines. Over half of Kenya’s populations are poor and worm infestation is

endemic. This section of the population would require drugs that are effective and affordable to

the poorest sections of society to treat and prevent worm infestations. To decrease the disease

burden on these populations, the drugs should not only be inexpensive but should be capable of

being administered by non-medical personnel(teachers and social workers) to ensure constant

reach to widest proportion of the disadvantaged inhabitants.

1.1 Helminth infestations

Helminth infections forms major part of the thirteen core neglected tropical diseases that carry

highest- burden. The helminth infections include the soil transmitted helminth infections (ascaris,

trichuriasis and hookworm infections), lymphatic filariasis, onchocerciasis, dracunculiasis and

schistosomiasis. These helminth infections have serious economic consequences to the affected

populations. They reduce family income by affecting the health of children through reduced

growth, development and decreased physical well-being; and increasing child mortality.

Healthcare where available is high-priced and either inappropriate or futile. These infections are

keeping people away from agricultural work, from productive lands and decrease worker

productivity. Worm infestations also make children stay away from school(Hotez et al., 2009).

Extra-intestinal worm infestations has particularly debilitating effects on tissues and organs such

as the liver, muscles, eyes, brain and even affect the blood vessels and lymphatic system.

Cysticercosis, is a condition caused by larval cysts of the helminth Taenia solium (tapeworm).

These larval cysts infect the brain, muscle and other tissues. In most poor countries, brain infection

(neurocysticercosis) by these cysts results in adult onset convulsions. In the brain or the eye it

causes severe indisposition and even death(Mahanty and Garcia, 2010).

2

Hydatidosis (Echinococcosis) is a disease which occurs as a result of taeniid cestodes of the genus

Echonicoccus. Of public health concern are four species- Echonococcus granulosus (cystic

echinococcosis), Echinococcus multilocularis (alveolar echinococcus), Echinococcus vogeli and

Echinococcus oligarthus (both cause polycystic echinococcosis). The hydatid cysts can attain a

volume of several liters and is usually located in the liver. The liver is the most common site of

echinococcal cyst, (>65%), followed by the lungs (25%). Other sites are spleen, kidneys, heart,

bone and central nervous system(Mahanty and Garcia, 2010).

1.2. Management of Helminthiasis.

Helminthiasis forms a big percentage of the core thirteen neglected tropical diseases that affect

populations in the undeveloped world. Among the drugs used to treat helminthiasis are the

following classes based on their chemical structures.

i) Benzimidazoles: e.g. Albendazole (ABZ), Mebendazole.

ii) Piperazines: e.g. Diethyl carbamazine citrate, Piperazine citrate.

iii) Heterocyclics: e.g. Oxamniquine, Praziquantel,

iv) Natural products: e.g. Ivermectin, Avermectin.

v) Vinyl pyrimidines: e.g. pyrantel, Oxantel.

vi) Amide: e.g. Niclosamide

vii) Nitro derivative: e.g. Niridazole

viii) Imidazole derivatives: e.g. Levamisale

ABZ has activity against majority of the helminths whether intestinal or extra-intestinal. This drug

usually forms part of the Essential Drugs List and is always included in majority of hospital

formularies. It is used by both adults and children.

1.3. Pharmacokinetics of Albendazole.

ABZ is rapidly metabolized in man to Albendazole Sulfoxide metabolite. The concentration of

ABZ and ABZ sulfone is undetectable in blood after administration of 400mg ABZ.

ABZ sulfoxide is known to be an active metabolite. In hydatid patients, concentrations of ABZ

sulfoxide were 15 – 40 times when compared with mebendazole.

3

There are major differences in ABZ sulfoxide concentrations in blood of individuals. This is

attributable to differences in absorption of ABZ because of poor dissolution and low aqueous

solubility (about 5µg/ml)(Marriner;Morris;Dickson, 1986).

1.4. Dose Regimen of Albendazole

For the control of intestinal worms, the dose of ABZ is 400mg twice daily for 3-7days (10 –

15mg/kg/day).

ABZ is also effective against extra-intestinal helminthiasis showing superior performance when

compared with mebendazole.

For cysticercosis, the dose is 400mg twice daily for 2- 4weeks.

Echinococcus , the dose is 400mg twice daily for 1 – 6 months(Mahanty and Garcia, 2010).

1.5. Side effects of Albendazole

ABZ generally has good safety profile and is well tolerated with minimal side effects. Some of

the common side effects occurs when the patients are treated for a long time for example in

cysticercosis and echinococcosis. The minor side effects include Elevated liver transaminases,

Abdominal pain, Headache, Distension, Vertigo, Urticaria, Jaundice ,Alopecia,

Thrombocytopenia,Tachycardia,Dyspepsia and Fever(Teggi, Lastilla and De Rosa, 1993).

4

CHAPTER TWO: LITERATURE REVIEW

2.1 Nomenclature of the Active Pharmaceutical Ingredient

Albendazole is a member of the benzimidazole carbamate family. The International Non-

Proprietary Name of the Active Pharmaceutical Ingredient is Albendazole. The IUPAC name is

Methyl [5-(propylthio)-1H-benzoimidazol-2-yl]carbamate

Figure 1. Chemical structure of Albendazole.

2.2. Physicochemical properties

ABZ is a crystalline white odorless powder consisting of small crystals that show a strong tendency

to agglomerate. It is practically insoluble in water (5µ/ml). It has a partition coefficient log P o/w

of 1.27 and melting range of at 207-210oC. The compound has no polymorphic form. It has a

molecular formula C12H15N3O2S and a relative molecular mass of 265.3(Pharmacopoeia, 2016).

2.3. Brand product characterization:

ABZ is marketed under various generic brands including Alben, Albendazole, and ABZ etc. The

innovator brand is Zentel®. It is marketed as 200mg tablets that are off white, circular, bevel-

edged, film -coated tablets that are odourless to almost odourless. They are available in blister

packs of 2 tablets

5

2.4. Composition of the Brand Albendazole tablets

Table 1. Composition of the Brand Albendazole tablets

ZENTEL Tablet 200mg

Film Coating

ZENTEL Tablet 400mg

Albendazole 200mg Albendazole 400mg

Lactose

Maize starch

Polyvidone

Sodium lauryl sulphate

Sodium starch glycollate

Microcrystalline cellulose

Sodium saccharin

Magnesium stearate

Purified water

Methylhydroxypropyl

cellulose

Propylene glycol

Purified water

Lactose

Microcrystalline cellulose

Maize starch

Croscarmellose sodium

Povidone

Sodium lauryl sulphate

Sunset yellow lake

Sodium saccharin

Magnesium stearate

Orange flavor

*From Glaxosmithkline packets insert

2.5. Biopharmaceutical Classification System of Albendazole

ABZ is a classified as BCS class II active pharmaceutical Ingredient due to its nature as being

practically insoluble in water but unlimited intestinal permeability(FDA, 1997). The ABZ tablets

have erratic bioavailability attributed to slow dissolution in biological fluids. It is therefore very

crucial to make it soluble and to enhance its dissolution in order to increase absorption and have a

predictable bioavailability(Marriner;Morris;Dickson, 1986)

6

2.6. Improving Drug release profiles of water insoluble Active Pharmaceutical

Ingredients.

For BCS class II drugs, drug release is a critical and restrictive phase for drug bioavailability.

Enhancing the drug release profile makes it possible to improve bioavailability and reduce side

effects.

A number of techniques have been used to enhance solubility of practically water insoluble active

pharmaceutical ingredients. They can be classified into physical and chemical alterations of drug

substance and other approaches.

Physical alterations encompasses particle size lessening like micronization and nanosuspension;

changing of crystal habit like polymorphs, amorphous form and cocrystallization, drug dispersion

in carriers like eutectic mixtures, solid dispersions, solid solutions and cryogenic approaches.

Chemical alterations include changes in pH, use of buffer, derivatization, complexation, and salt

formation.

Other methods are the supercritical fluid process, use of adjuvant like surfactants, solubilizers,

co-solvency, hydrotrophy, and unusual excipients (Savjani, Gajjar and Savjani, 2012).

All of the above approaches still have disadvantages.

7

2.7 Solid Dispersions

Tablets made by Solid dispersion approaches have higher drug dissolution profiles when

compared to tablets formulated by the corresponding physical mixtures(Vasconcelos and Costa,

2007)(Kohri et al., 1999).

The term Solid dispersions refers to molecular mixtures ( in amorphous or crystalline particles) of

hydrophobic drugs in hydrophilic carriers (hydrophilic matrix can be crystalline or amorphous),

which present drug release profiles that is driven by the polymer properties(Vasconcelos,

Sarmento and Costa, 2007) .

2.7.1 Benefits of Solid Dispersions

Solid dispersions have advantages over other techniques such as salt formation, solubilization and

size reduction (micronization) when used to improve bioavailability. Salt formation requires

incorporation of polar groups or ionizable groups in the main drug structure resulting in formation

of prodrugs. It can only be used for weakly acidic or basic drugs and not neutral drugs. Furthermore

the salts get converted to weak acids or bases in vivo negating any solubility gains. Besides, the

sponsoring company is obligated to perform new clinical trials because salt formation results in a

new chemical entity. Solid dispersions on the other hand are easier to produce and more applicable.

Solubilization end result is always a liquid which is not preferred by patients due to handling issues

unlike solid dispersions that gives rise to solid masses.

Grinding or micronization increases solubility by increasing the specific surface area but is limited

by particle size reduction limit of 2-5µm. This is inadequate to improve solubility of water

insoluble drugs. Again handling is a challenge because the micronized particles are cohesive and

have flow constraints(Vasconcelos, Sarmento and Costa, 2007).

8

2.7.2 Arguments against solid dispersions

The limiting consideration that derails the use of solid dispersions in pharmaceutical dosage forms

is stability concerns. The product may undergo stress during processing and storage that may

convert the amorphous active ingredient into the crystalline form. Scale up is also still a challenge

in the production of solid dispersions.(Vasconcelos, Sarmento and Costa, 2007).

The approach of solid dispersions greatly increases drug dissolution, absorption and consequent

bioavailability of BCS Class II the drugs.

2.7.3 General Methods of Manufacture of solid dispersions.

Solid dispersions are prepared by two ways mainly- solvent evaporation and melting as

illustrated in the schematic diagram below.

Figure 2: Manufacturing processes to produce solid dispersions(Vasconcelos, Sarmento and Costa,

2007)

9

2.7.4. Melting Process

The making of Solid Dispersion by melting process entails heating the physical mixture of the

hydrophobic drug and the hydrophilic carrier until both melts. The ensuing molten entity is then

solidified rapidly by cooling while stirring meticulously.

Cooling and solidifying the melted mixture is done using several ways such as;

i) Ice bath agitation

ii) Stainless steel thin layer spreading followed by a cold air stream

iii) Solidification on petri dishes at room temperature in a desiccator

iv) Spreading on plates over dry ice.

v) Immersion in liquid nitrogen

vi) Storage in desiccators(Vasconcelos, Sarmento and Costa, 2007).

The final solid mass is then ground to form granules and screened. The granules can then be

transformed using excipients into tablets by compression.

It is necessary that the drug and the matrix be miscible in the molten form. The drug and matrix

must withstand the melting temperatures(Savjani, Gajjar and Savjani, 2012).

The melting method can have the disadvantages of degradation and incomplete miscibility

between the drug and carrier.

To overcome these disadvantages, modifications were made to the original method such as hot-

melt extrusion, Meltrex® or melt agglomeration.

Solid dispersion tablets made by melting process have higher solubility and quicker dissolution

profiles than those made by solvent evaporation process(Chiou and Riegelman, 1969).

Melting approach is also easily scalable to industrial manufacturing for drugs that are thermostable

and also present little regulatory hurdles.

10

2.7.5 Solvent evaporation

Solvent evaporation entails dissolving both the drug and carrier in a volatile organic solvent which

is later vaporized. Organic solvents that can be used includes chloroform(Majerik et al., 2007),

ethanol(Yoshihashi et al., 2006) or a mixture of ethanol and dichloromethane(Tanaka et al., 2006).

The resulting films are pulverized and sized(Tanaka et al., 2006). Differences in the solvent

evaporation processes results from modifications of the vaporization procedures.

They include the following;

i) Drying in vacuo(Yoshihashi et al., 2006)

ii) Heating of the mixture on hotplate(Desai, Alexander and Riga, 2006)

iii) Slow solvent vaporization at low temperature(Yoshihashi et al., 2006)

iv) Use of rotary evaporator(Ceballos et al., 2005)

v) A stream of nitrogen

vi) Spray-drying

vii) Freeze-drying

viii) Use of supercritical fluids

The main advantage of this method is that solvent evaporation is done at low temperatures thus

avoiding thermal decomposition of both drugs and carriers.

However it suffers from the disadvantages of:

i) Higher costs of production.

ii) Difficulty of completely removing organic solvent.

iii) Possible adverse effects of minute amounts of the solvent on the chemical stability of

the drug.

iv) The selection of common volatile solvent.

v) The difficulty of reproducing crystal forms(Savjani, Gajjar and Savjani, 2012).

11

2.8 Solubility Parameters

Solubility parameter (δ) can be defined as the square root of cohesive energy density (cohesive

energy per unit volume). Cohesive energy represents the total attractive forces within a condensed

state (e.g. solid dispersions) and is the amount of energy required to separate the atoms/ molecules

of a solid or liquid to a distance where the atoms or molecules have no interactions between

them(e.g. during vaporization). Thus it’s the extent of attractive forces that occurs between atoms

or molecules .(Hancock, York and Rowe, 1997)

δ = (CED)0.5 = (ΔEv /Vm)0.5. (1)

where δ = Hildebrand’s solubility parameter and

CED = Cohesive Energy Density(Hansen, 2004).

Cohesive energy density is obtained from dividing the latent heat of vaporization (ΔEv) by the

molar volume, Vm, of the liquid concerned, and taking the square root of this number (Equation 1).

In the mid-1960s, Hansen realized that all the cohesive bonds holding a liquid together was broken

when it evaporates. These bonds comprising of “nonpolar” bonds, permanent dipole-permanent

dipole bonds and hydrogen bonds were all broken down during the evaporation process.

Thus Hansen divided the Hildebrand’s solubility parameter (δ) into three components:

( δ)2 = (δD)2 + (δP)2 +(δH)2 (2)

Where

δ= Hildebrand’s solubility parameter.

δD = atomic, nonpolar interactions

δP = molecular, dipolar interactions

δH = molecular, hydrogen bonding interactions.

δD, δP and δH are also called Hansen’s solubility parameters (Hansen, 2004).

Hildebrand’s solubility parameters have also been used to describe many physico-chemical

properties of materials (e.g. solubility, melting point, incompatibility). They have been used to

12

predict interactions between materials. Solubility parameters have been used to predict

solubility/miscibility and can be used in pharmaceutical dosage form design (e.g. to select

pharmaceutical active ingredients and polymers in solid dispersions). Drugs and carriers

(polymers) that have similar solubility parameters, where differences between the parameters are

less than 7 MPa0.5, are predicted to have good miscibility whereas differences that are greater than

10MPa0.5 are anticipated to have immiscibility issues(Greenhalgh et al., 1999). Many methods

exist for estimating the solubility parameters of materials and includes solubility studies of test

materials in solvents of known solubility parameters e.g.

- Refractive index values using reverse gas chromatography

- Heat of vaporization data.

- Calculation using group contribution methods(Greenhalgh et al., 1999).

There are several methods for calculating solubility parameters using group contribution methods

such as Hansen’s methodology. The solubility parameters are calculated for drugs and polymers

from the chemical structure using the group contribution as described by Hoftyzer and Van

Krevelen(Forster et al., 2001)

In this study group contribution method was used to estimate the solubility parameters of the drug

and the polymers used.

2.9 Crystallinity Index

An amorphous form of a drug has higher apparent solubility than its crystalline form(Grohganz et

al., 2013). In making solid dispersions, the aim of the formulator is to decrease crystallinity

(amorphization) of the active pharmaceutical ingredient (API) in order to increase its apparent

solubility in water during dissolution process in the gastrointestinal fluids with the goal of

increasing the bioavailability in the BCS Class II drugs (high permeability, low solubility).

The extent of the decrease in crystallinity of an API during the formulation can be determined by

measurement of crystallinity in the solid dispersions. Crystallinity is connected to the crystal size

and the amount of order within crystals which is of great concern in formulation(Sa et al., 2017).

13

The crystallinity index (CI) is defined as the volume fraction of crystallinity of one phase in a

given sample and represents a measure of average crystal size, perfection and ordering in a

sample(Reyes-Gasga et al., 2013). It is a quantitative measure of crystallinity.

Since early last century, investigators have developed various methods to directly calculate the CI.

These methods include X-Ray Powder Diffraction (XRPD),Fourier Transform Infrared

Spectroscopy (FTIR) and Raman Spectroscopy(Sa et al., 2017).The CI is measured from analysis

of their spectra.

In the FTIR spectra, crystallinity fluctuations are linked to a few IR absorption areas. These

areas include: the CH stretching region (the CH stretching region (2986 to 2878 cm-1), the C=O

stretching region (1600-1800 cm-1) and the CH2 groups and ester bonds stretching region (1400-

800 cm-1). The 1400-800 cm-1 area contains spectral peaks that are very sensitive to the

crystallinity changes. Interchanging spectral peaks that are sensitive to crystallinity changes are

contained in the 1400-1800cm-1 area (Kann, Shurgalin and Krishnaswamy, 2014). It is the above

areas that were used to calculate the CI in this study.

In this study, solid dispersions made using solvent evaporation technique was used to do a pre-

formulation study that is anticipated to lead to formulation of Albendazole tablets that will have

superior drug release profiles and hence increased bioavailability

Solubility parameter was used as a tool to choose possible suitable carriers and Crystallinity Index

(CI) was calculated from analysis of FTIR spectra to evaluate the degree to which crystallinity was

decreased in the formulations.

2.10. Problem statement.

Helminthiasis encompasses the Soil Transmitted Helminth infections (STH), that forms part of the

core thirteen Neglected Tropical Diseases. These diseases are among the most prevalent conditions

in the world’s poorest people. Over half of Kenya’s populations live below the poverty line of

USD 2 per day. These are the people who carry the burden of high worm infestation that can easily

be prevented and treated(Hotez et al., 2009)

14

Though worm infestation can be treated with an array of drugs in the market, none has a broad

spectrum like ABZ. It is also one of the safest and effective drugs against the majority of intestinal

worm infections. It is also used in management of extra-intestinal worm infestations such as

Trichinellosis, Toxocariasis etc, and other tissue infections such as cysticercosis and hydatidosis.

In almost all these infections, ABZ is a first line drug. WHO recommends ABZ both for prevention

and treatment of worm infestations.

The ABZ brands (generics) have poor solubility and dissolution leading to erratic

bioavailability(Marriner;Morris;Dickson, 1986). Therapeutic effectiveness of these drugs is

therefore doubtful.

The innovator brand available in the market is expensive besides its dissolution is not satisfactory.

It is out of reach for the world poor and Kenyan poor in particular.

A well formulated ABZ tablet that is bioavailable and affordable would be very effective and

would benefit the world’s poorest in decreasing the worm infestation burden and reinfection.

2.11. Study justification

The benefit of using a bioavailable and affordable ABZ tablets would greatly benefit the poorest

people in East Africa to decrease the worm infestation burden. The dissolution of current ABZ

brands in the market is unpredictable and slow and is the limiting factor for drug absorption. These

drugs show inconsistent bioavailability and require escalation in dissolution rate in order to

increase bioavailability(Chowdary and Kumar, 2013).

This research project was aimed at doing a pre-formulation study in order to enhance the solubility

of ABZ in various carriers for the purpose of developing a formulation that would result in an ABZ

tablet that has superior drug release profile at minimal cost and also would greatly benefit the

world’s poor.

15

2.12 Limitations of the study

The following limitations were experienced during this study. The following equipment was not

available within the Department of Pharmaceutics and Pharmacy Practice of the University of

Nairobi;

i. X –Ray Powder Diffraction Equipment

ii. Raman Spectroscopy Equipment.

iii. Scanning Electron Microscope.

iv. Differential Scanning calorimeter.

2.13 Study Objectives

2.13.1 General objective

The main objective was to do a pre-formulation study for purposes of developing a formulation of

ABZ tablets that would increase the oral bioavailability of ABZ tablets by evaluating ABZ

crystallinity in different solid dispersion carriers made by solvent evaporation technique.

2.13.2 Specific objectives

1. To carryout pre-formulation studies on solid dispersions made from ABZ and the following

carriers Carboxymethyl cellulose Sodium (CMC), Hydroxypropylmethyl cellulose

(HPMC), polyvinyl pyrrolidone (PVP K90) and poly ethylene glycol (PEG 8000).

2. To evaluate the degree of crystallinity of ABZ in solid dispersions of each of the four

carriers.

3. To determine the percentage of ABZ dissolved in each of the above four carriers used.

16

CHAPTER THREE: METHODOLOGY

3.1. Study Location:

The study was carried out in the Pharmaceutics Laboratory of the Department of Pharmaceutics

and Pharmacy Practice, School of Pharmacy.

3.2. Materials

Albendazole powder, sodium carboxyl methyl cellulose, hydroxyl propyl methyl cellulose, all

kindly provided by ELYS Industries; Polyvinyl pyrrollidine (PVP K90), kindly donated by BASF;

and Polyethylene glycol 8000 (PEG 8000) kindly donated Universal Corporation. All excipients

were pharmaceutical grade while reagents and solvents were analytical grade.

3.3. Equipments

Fourier Transform Infrared Spectrophotometer (Shimadzu IR Prestige 2.1, Tokyo Japan), Oven

drier (Memmert, Germany), Weighing balance (Satorius, England), Electronic light microscope.

UV spectrophotometer (Shimadzu UV-1800, Tokyo Japan)

Hot plate

3.4. Pre- formulation studies.

3.4.1 Drug Powder Identification.

The identity of albendazole drug powder was confirmed by use of Infrared absorption photometry.

The Fourier Transform Infrared (FTIR) spectrum of the albendazole powder obtained and that of

albendazole powder spectra published in literature was compared for concordance. A KBr disc of

albendazole was prepared and used to get an albendazole IR spectrum in the 1800- 1000 cm-1

region using Shimadzu IR Prestige 2.1 9 Fourier Transform Infra-red (FTIR) spectrophotometer

(Shimadzu Corp., Kyoto, Japan). It uses IR solution software Ver. 1.3.

17

3.4.2 Appraisal of Albendazole powder characteristics.

The particle size of ABZ powder was verified using the certificate of analysis (COA).

It was not be possible to carry out the angle of repose, the bulk and tapped densities, the Hausner’s

ratio and the compressibility index because of the very adhesive nature of ABZ powder particles.

3.5. Procedure for the Pre-Formulation Studies

3.5.1. Calculation of drug carrier solubility parameters

Table2: Calculation of Solubility Parameter of ABZ

Groups Fdi F2pi Ehi ∑zV/cm3mol-1

2 -CH3 840 0 0 67

2CH2 540 - - 32.2

1 –S- 440 -- - 12.0

Phenylene 1270 110 - 52.4

2 –NH- 320 420 6200 9

1 –N= - - - 5

1 –COO 390 490 7000 18

1 C= 70 0 0 5.5

1 ring 190 16

∑ 4060 1020 13200 217.1

4060/217.1 √1020/217.1 √(13200/217.1)

18.70 0.15 √60.8

∑ 20.3

18

3.5.2. Preparation of Solid Dispersions

Albendazole is a Biopharmaceutical Classification System Class II compound implying low

solubility but unlimited permeability. This compound exists as one polymorph which was

employed for this study.

Drug to carrier ratios of 1:2.5, 1:5 and 1:10 (40%, 20% and 10% of Drug by weight) for each of

the carriers chosen (CMC, HPMC, PVP K90, and PEG 8000). The amount of the drug and

carrier was weighed so as to result in 6 grams of each of the batches as shown in the following

table.

Table 3: Quantity of ABZ and polymers as used to make the solid dispersions.

Polymers

Drug to Polymer Ratios (Weight in grams)

1:2.5 1:5 1:10

CMC

Drug 1.72 1.00 0.55

CMC 4.28 5.00 5.45

Total 6.00 6.00 6.00

HPMC

Drug 1.72 1.00 0.55

HPMC 4.28 5.00 5.45

Total 6.00 6.00 6.00

PVP K90

Drug 1.72 1.00 0.55

PVP K90 4.28 5.00 5.45

Total 6.00 6.00 6.00

PEG 8000

Drug 1.72 1.00 0.55

PEG 4.28 5.00 5.45

Total 6.00 6.00 6.00

19

3.5.3. Procedure for preparing solid dispersion:

The solid dispersions were prepared by the solvent evaporation method.

3.5.3.1 Preparation of CMC solid dispersions

The appropriately weighed polymer was dissolved in a minimum amount of water in a 200ml

beaker by heating to 80oC to give it an appropriate consistency and viscosity. The drug was

then wetted in a small amount of ethanol before being mixed with the dissolved CMC while

stirring. The water and alcohol was then evaporated using the hot plate method till a small

amount of water remained before being dried in an oven for 24hours at 80oC to control the

evaporation rate. The resultant solid mixture was pulverized to diminish the particle sizes and

screened using mesh number 60. The ground solid dispersions was then transferred into a labeled

containers.

3.5.3.2 Preparation of HPMC solid dispersions.

The appropriately weighed polymer and drug was dissolved in an equal volume of ethanol and

dichloromethane (1:1 ratio) by heating to 80oC in a 200ml beaker while stirring. The solvent

mixture was then evaporated in a hot plate until a small amount of the solvent mixture remained

before being dried in an oven for 24 hours at 80oC to control the evaporation rate. . The resultant

solid mixture was pulverized to decrease the particle sizes and sieved using mesh number 60.

The ground solid dispersions was then transferred into labeled containers.

3.5.3.3 Preparation of PVP solid dispersions.

The weighed PVP polymer and drug was dissolved in a minimum amount of ethanol in a 200ml

beaker by heating to 80oC while stirring. The ethanol was then evaporated using a hot plate until

a small amount of ethanol remained before drying in an oven at 80oC for 24 hours to control the

drying. The solid dispersions were then cooled and pulverized to decrease the particles sizes.

They were then screened by passing through mesh number 60. They were then transferred to

labeled containers.

20

3.5.3.4 Preparation of PEG solid dispersions.

The weighed PEG polymer and drug was dissolved in a minimum amount of ethanol in a 200ml

beaker by heating to 80oC while stirring. The ethanol was then evaporated using a hot plate until

a small amount of ethanol remained before drying in an oven at 80oC for 24 hours to control the

drying. The solid dispersions were then cooled and pulverized to decrease the particles sizes.

They were then screened by passing through mesh number 60. They were then transferred to

labeled containers.

Samples of the different solid dispersions were then analyzed by UV spectroscopy to determine

the percentage of dissolved ABZ before being subjected to Infrared spectroscopy.

3.6 Analysis using UV spectrophotometer.

3.6.1 Preparation of a calibration curve.

3.6.1.1. Procedure

An accurately weighed 10mg of ABZ was transferred to a 100ml volumetric flask and dissolved

with 2ml of acidified methanol. It was then made up to the volume using 0.1N NaOH as the

diluent. This stock solution was the diluted as per the following table:

Table 4: Preparation of calibration curve.

Volume of stock solution (ml) Volume of diluent (ml) Final concentration (mcg/ml)

0 100 0

3 97 3

5 95 5

10 90 10

15 85 15

The absorbance at 350nm and 308 nm of each of the diluted solutions was recorded using a

Shimadzu UV-1800 spectrophotometer. A calibration curve of the absorbance difference

between 308nm and 350nm in the y-axis and concentrations in the x-axis was then plotted.

21

3.6.2 Determination of dissolved ABZ in the solid dispersions.

An equivalent of 25mg of each batch of solid dispersion was dissolved in 100ml of 0.1N HCl by

stirring at 38oC for 20 minutes followed by filtration using a filter paper. 4 ml of the filtrate was

diluted to 100ml in a volumetric flask with 0.1 N NaOH as the diluent. The absorbance at 350nm

and 308nm was recorded.

3.7. Fourier Transform Infrared Spectroscopy.

An Infra-red spectra of the drug, Carboxymethyl cellulose, Hydroxypropyl methylcellulose,

Polyvinyl pyrrollidine K90 and Polyethylene glycol 8000 carriers, the Physical mixtures of the

carriers and ABZ (1:1 ratios) and the solid dispersions was obtained and recorded on FTIR

spectrophotometer in the range of 4000- 400cm-1 using potassium bromide discs. Shimadzu IR

Prestige 2.1 Fourier Transform Infra-red (FTIR) spectrophotometer (Shimadzu Corp., Kyoto,

Japan) operating on IR Solution software Ver. 1.3 was used for this purpose.

3.7.1. Procedure

Potassium Bromide (KBr) was first dried for 1 hour at 100oC in an oven. 3 mg of the samples of

ABZ, the Physical mixtures and each milled solid dispersions was weighed and 300mg of KBr

was accurately weighed and transferred to a mortar and pestle. It was then ground to a fine

mixture before being subjected to a pressure of about 10 tons/in2 in an evacuated die. This results

in a transparent after the mixture sinters in the die. The disc is the examined in an FTIR

spectrophotometer. The spectrum was then printed and analyzed.

22

Table 5:Vibrational Spectra and Frequency Assignments for ABZ (Gunasekaran and Uthra,

2008)

Wavenumber cm-1 Vibrational band assignment.

3540-3340 N-H stretching

2958 CH3 CH2 CH stretching.

2672 C-H stretching

1710 Amide I band

1630 Aromatic ring stretching

1450 CH2 deformation

1327 CH2 deformation

1270 Amide III band

1192 CH2 wagging

1097 C-O/C-S stretching

958 C-H in-plane deformation

847 C-H out-of-plane deformation

806 C-H out-of- plane deformation

605 N-H out-of-plane deformation

512 C-C out -of-Plane deformation

23

3.7.2 Calculation of Crystallinity Index (CI)

Wavenumber cm-1

Figure 3: Calculation of Crystallinity Index in relation to changes in absorption peaks 1630/1450 cm-1

infrared spectrum.

Crystallinity Index is calculated by the following formula

CI = a/b is the ratio of peak intensity at around 1630cm-1 to peak intensity at around 1450cm-1

which were determined by baseline method figure 3 above (Razva et al., 2014)(Ramasamy and

Suresh, 2009).

The CI is inversely proportional to crystallinity. It therefore follows that when CI is minimum

the sample shows high levels of crystallinity and if CI is maximum, the sample is considered to

show low levels of crystallinity (i.e. high level of amorphization)(Ramasamy and Suresh, 2009).

Abs

1750 1500 1350

b

1630cm-1

1450cm-1

a

24

CHAPTER FOUR: RESULTS

4.1 Solubility Parameters

The solubility parameters of the ABZ and carriers are shown below

Table 6: Solubility parameters of ABZ and the Polymers.

API/Carrier polymer Solubility parameter (MPa1/2)

ABZ 20.3 (calculated)

PEG 19.8 (Özdemir and Güner, 2007)

CMC 24.35 (Derecskei and Derecskei-Kovacs, 2006)

PVP K90 24.3 (Li et al., 2014)

HPMC 28.7 (Dow, 2017)

ABZ: Albendazole, PEG: Polyethylene glycol 8000, CMC: Sodium carboxymethyl cellulose

PVP: Polyvinyl pyrrollidine K90, HPMC: Hydroxy propyl methyl cellulose

4.2 FTIR Crystallinity Index (CI) Results

The absorbance of the peak between 1750 cm-1 and 1500cm-1 and the peak between 1500cm-1

and 1350cm-1 was used to calculate the CI.

Table 7: Calculated Crystallinity Index of the solid dispersions

. *Crystallinity Index (CI = a/b)

ABZ to Polymer Ratio PEG HPMC PVP CMC

1:2.5 2.94 4.8 4.4 4.4

1:5 2.73 3.17 7.33 3.17

1:10 2.24 4.17 2.54 4.44

*Calculations done by use of Tangent Basement method.(Razva et al., 2014)

25

Figure 4: Bar graph of calculated Crystallinity Index.

Table 8: Percentage of dissolved ABZ in the solid dispersions.

. Percentage of dissolved ABZ (n=3, ± *SD)

ABZ to Polymer Ratio PEG HPMC PVP CMC

1:2.5 48.1 ± 1.2 70.4 ± 1.05 63.2 ± 1.55 32.5 ± 1.35

1:5 71.9 ± 0.7 65.2 ± 0.85 80.7 ± 0.5 26.8 ± 1.55

1:10 66.4 ± 1.45 69.5 ± 0.8 81.0 ± 0.75 32.1 ± 2.35

*SD Standard Deviation.

0

1

2

3

4

5

6

7

8

1:2.5 1:5 1:10

Cry

stal

linit

y In

dex

Ratio of ABZ to Polymer

PEG

HPMC

PVP

CMC

26

Figure 5: Graph of percentage dissolved ABZ against ratio of drug in polymer.

0

10

20

30

40

50

60

70

80

90

0 2 4 6 8 10 12

Pec

enta

ge d

isso

lved

ratio of ABZ to Polymer

PEG

HPMC

PVP

CMC

27

CHAPTER 5: DISCUSSION AND CONCLUSION

5.1 DISCUSSION

From the calculated solubility parameters in table 5, PEG having solubility parameter of 19.8

would be expected to dissolve the ABZ (SP of 20.3) more readily because of the close values of

their calculated SPs (i.e. difference is 0.5) . However the dissolved ABZ lower than that of PVP

and HPMC.

The Crystallinity index of PEG was also lower than all the other polymers as shown in table 7

and figure 3. The lower CI shows there is higher crystallinity for the PEG solid dispersions

which partly accounts for the lower dissolved drug in the solid dispersions.

The SP parameter of HPMC is 28.7 giving a difference of 8.4. This would have predicted lower

dissolved values of ABZ since good predicted solubility envisages a difference of less than 7

MPa0.5 (Forster et al., 2001). Nonetheless the solubility of ABZ was quite high only lower than

that of PVP. The CI was also higher than that of PEG which was confirmed by the higher

solubility of the API.

The SP of PVP K90 was 24.3 which is practically the same as that of CMC. The difference

between the polymer and drug SP was 4.It also had one the highest CI at 7.33. As an indication

of the extent of amorphousness, the drug had the highest percentage of dissolved drug at 81%.

The CMC polymer had the same SP as PVP giving the same difference of 4 as PVP. However

despite the fact that the CI was high (above 3) the percentage solubility of ABZ was the lowest

among the polymers at about 30%.

5.2 CONCLUSION

HPMC and PVP demonstrated good ABZ solubility in solid dispersions and confirmed why it is

quite popular with drugs marketed as solid dispersion. The SP of HPMC though not expected to

have high solubility a fact that can be attributed to its ability to inhibit crystallization of ABZ

when drying the solid dispersion.

PEG though quite a good solvent may not be preventing crystallization to a large extent when the

solvent is evaporated as was shown by the lower CI from the FTIR spectra.

28

Therefore from the above observations, HPMC and PVP should be investigated further because

they showed the greatest potential of increasing the solubility of ABZ when incorporate into

tablets as solid dispersions containing the drug.

The absence of other equipments that could be used to compare the CI from other methods such

as Raman Spectrometer, X-Ray Powder defractometer and Differential Scanning Calorimeter

was a setback. It is therefore suggested that further investigations be done using this equipments

with the intention of comparing the crystallinity indices.

Further investigations should be done also to compare dissolution of tablets formed by solid

dispersions and tablets made by compression of physical mixtures.

The use of CI in pre-formulation studies can be another tool that a formulating scientist could use

in testing the suitability of polymers in the making of solid dispersions. This is because most

drugs being discovered fall under BCS class II and it has been proven that making solid

dispersions in polymers greatly improves the solubility and dissolution.

29

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32

APPENDICES

Concentration mcg/ml

UV absorption Difference

0 0

3 0.238

5 0.393

10 0.802

15 1.21

20 1.611

Calibration curve of UV Absorption Difference vs. Concentration

Appendix 1: calibration curve.

y = 0.0808x - 0.0045R² = 1

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

0 5 10 15 20 25

UV

Ab

sorp

tio

n

Concentration in Micrograms/ml

33

Albendazole Drug FTIR Absorption spectrum

Appendix 2.

34

Physical Mixture ABZ: HPMC, 1:1 ratio FTIR Spectrum

Appendix 3.

35

ABZ –HPMC SD 1:2.5 Ratio FTIR Spectrum

Appendix 4.

36

ABZ – HPMC SD 1:5 Ratio FTIR Spectrum

Appendix 5.

37

ABZ HPMC Solid dispersion 1:10

Appendix 6.

38

ABZ and CMC Physical Mixture 1:1

Appendix 7.

39

ABZ and CMC Solid Dispersion 1:2.5 ratio FTIR Absorption Spectrum

Appendix 8

40

ABZ TO CMC Solid Dispersion 1:5 ratio FTIR Absorption Spectrum.

Appendix 9

41

ABZ TO CMC Solid Dispersion 1:10 Ratio FTIR Spectrum.

Appendix 10

42

ABZ TP PVP Physical Mixture 1:1 ratio FTIR Spectrum

Appendix 11.

43

ABZ TO PVP Solid Dispersion 1:2.5 Ratio FTIR Spectrum

Appendix 12

44

ABZ TO PVP Solid Dispersion 1:5 Ratio FTIR Spectrum

Appendix 13.

45

ABZ TP PVP Solid Dispersion 1:10 Ratio FTIR Spectrum.

Appendix 14

46

ABZ TO PEG Physical Mixture 1:1 ratio FTIR Spectrum

Appendix 15.

47

ABZ TO PEG Solid Dispersion 1:2.5 FTIR Spectrum

Appendix 16

48

ABZ TO PEG Solid Dispersion 1:5 Ratio FTIR Spectrum

Appendix 17

49

ABZ TO PEG Solid Dispersion 1:10 Ratio FTIR Spectrum.

Appendix 18.