Amit Tondare

Enhancement of Solubility and Dissolution of Gliclazide by
Complexation with Hydroxypropyl β-Cyclodextrin

By
Mr. Amit Tondare. B. Pharm.

Reg. No. 09PI127
A dissertation submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

in partial fulfillment
Of the requirements for the degree of
MASTER OF PHARMACY
In
INDUSTRIAL PHARMACY
Under the Guidance of
Mr. SUNIL RAJ RAGA M. Pharm. (Ph.D)
Department of Industrial Pharmacy

K.R.E.S’s Karnataka College of Pharmacy,
BIDAR – 585403 (Karnataka State)
2010-11
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
DECLARATION BY THE CANDIDATE
I hereby declare that the matter embodied in the dissertation entitled
“Enhancement of Solubility and Dissolution of Gliclazide by Complexation with
Hydroxypropyl β-Cyclodextrin is a bonafide and genuine research work
carried out by me under the guidance of Mr. SUNIL RAJ RAGA M. Pharm. (Ph.D)
Department of Industrial Pharmacy, Karnataka College of Pharmacy, Bidar.
Date:
Place: Bidar Amit Tondare

KARNATAKA
CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled “Enhancement of Solubility and
Dissolution of Gliclazide by Complexation with Hydroxypropyl β-Cyclodextrin” is a
bonafide research work done by Mr. Amit Tondare submitted in partial
fulfillment of the requirement for the degree of “Master of Pharmacy” in
Industrial Pharmacy of the “Rajiv Gandhi University of Health Sciences,
Karnataka.
Date:
Place: Bidar
Mr. Sunil Raj Raga M. Pharm. (Ph.D)
Asst. Prof.
Department of Industrial Pharmacy,
Bidar-585 403
KARNATAKA
ENDORSEMENT BY THE PRINCIPAL & H.O.D.
This is to certify that the dissertation entitled Enhancement of Solubility
and Dissolution of Gliclazide by Complexation with Hydroxypropyl β-
Cyclodextrin is a bonafide research work done by Amit tondare Under the
direct supervision and guidance of Mr. SUNIL RAJ RAGA M. Pharm. Ph.d
Department of Industrial Pharmacy, Karnataka College of Pharmacy, Bidar.
Date:
Place: Bidar
Prof. Krantikumar M. Sirse M. Pharm. PhD
Principal & HOD
Bidar-585 403
KARNATAKA
COPYRIGHT
I hereby declare that the Rajiv Gandhi University of Health Science,
Karnataka shall have the rights to preserve, use and disseminate this
dissertation / thesis in print or electronic format for academic / research
purpose.
Date:
Place: Bidar TONDARE AMIT
@ Rajiv Gandhi University of Health Sciences, Karnataka

ACKNOWLEDGMENT
I take this privilege and pleasure to acknowledge the contributions of many

individuals who have been inspirational and supportive throughout my work
undertaken and endowed with the most precious knowledge to see success in my
endeavor.
It is with pleasure of immense gratitude that I express my most cordial and

humble thanks to my esteemed teacher and guide Shri. Sunil raj Raga, M. Pharm.
PhD, assistant Professor, Department of Industrial Pharmacy, Karnataka College
of Pharmacy, for his valuable guidance, keen interest, perennial inspiration and
everlasting encouragement. I shall for ever remain indebted to him for having
inculcated in me a quest for excellence, a spirit of diligence and perseverance, a
sense of humility, honesty and respect for the moral and ethics which govern our
sciences and without whom this work would not have seen the light of the day.
I am gratefully indebted to Prof. Sirse KrantiKumar, M. Pharm. PhD, the

honorable principal of Karnataka College of Pharmacy, Bidar, for providing
necessary facilities to carryout my work and for his constant support and
encouragement.
I consider it as a great privilege to express my heartfelt gratitude and sincere

thanks to Mr. S.B.Dana, M. Pharm. (Ph.D) and Mr. AjayKumar Patil, M. Pharm. (Ph.D),
Assistant Professor, Industrial Pharmacy, Karnataka College of Pharmacy, for his
valuable suggestions, deep inspiration and cooperative nature, with due respect in
my heart.
I extend my sincere thanks to Dr. Baswaraj Raga, Dr. Kashinath Naubade,

Dr. Malikarjun patil, Mr.Vijayakumar Trilapure, Mr.Shivanand Noola
Department of Pharmaceutical chemistry, Mr. Raghavendra Patil, Mr.V V Shastri
& Mr. Sunil G Department of Pharmacology, and I am thankful Mr. Mallikarjun
Mugli, Mr. S. Chikpety, and other staff members of our college for their help and
interest in the present work
I take this opportunity to express my sincere thanks to teaching and non-

teaching staff members, Karnataka College of Pharmacy, Bidar.
My special thanks and appreciation goes to all my seniors, especially, Mr.
irfani ,bilal,vijaya,vasisht,sudhir,zaheer,imran, Nadeem, Waseem for their good
wishes timely help and unstinted support during the course of study.
I will not forget the help and company given by my junior, Sandeep, Shrutin,
Satish, Azhar, Vinod, Zia, Younus, Sharfaraz, Ilyas,
Om,Ramya,Priyanka,Shivleeia,Nauman,Anil and dearest friends Mr
Ravi,abhijit,shridhar,yogesh,sachin,Anil,Neha,Akash,Ganesh,Nilesh,Gargi and all
my friends for their moral support good company and encouragement.
I would like to express my sincere thanks to Aditya,atul,varsha,Deepak and

all the seniors of M. Pharm for their moral support, good company and
encouragement.
I would like to express my sincere thanks to Deepak,basavraj,Kvamshi,

Madhuri,Swati,shravanti,Mrudula and all the juniors of B. Pharm for their
moral support good company and encouragement.
Words are not sufficient to express my deepest love and appreciation to my

affectionate, beloved Parents and my sister ashwini for their support and boosting
encouragement throughout my career.
Finally I consider this as an opportunity to express my gratitude to all the

dignitaries who have been involved directly or indirectly with the successful
completion of this dissertation.
Date:
Place: TONDARE AMIT.

Dedicated to
My
Beloved
Psarents
IX
&
sirshreeji
X
ABSTRACT
Gliclazide is a second generation sulphonylurea oral hypoglycemic agent. It is
practically insoluble in water. In the present study attempt has been made to prepare and
characterize inclusion complexes of Gliclzide with HP-β-CD. The phase solubility
analysis indicated the formation of 1:1 molar inclusion complex of Gliclazide and HP-β-
CD. Apparent stability constant (KC) was 256.3 M-1 for HP-β-CD complexes
respectively. The inclusion complexes were prepared by three different methods viz.
physical, kneading and method. The prepared complexes were characterized using FT-IR
DSC and differential scanning calorimetry. The inclusion complex prepared with HP-β-
CD by kneading method exhibited greatest enhancement in solubility and fastest
dissolution) of Gliclazide.
Further, this inclusion complex GLZ: HP-β-CD with different ratios was
formulated into tablets using microcrystalline cellulose, potato starch, Talc, Mg sterare
and lactose. The tablets prepared with HP-β-CD by kneading method exhibited fastest
dissolution of Gliclazide. The prepared tablets were evaluated for various post
compression parameters like hardness, friability, weight variation, thickness, drug
content, in-vitro dissolution and FT-IR and DSC studies.
Key words: Gliclazide, β-CD, HP-β-CD, Physical method, Kneading method,
XI
LIST OF ABBREVIATIONS
Abbreviations Complete Name
β-CD Betacyclodextrin
GLZ Gliclazide
HP- β-CD Hydroxypropyl betacyclodextrin
o
C Degree centigrade
hrs Hours
Mcg/μg Microgram
mg Milligram
min Minute
ml Milliliter
nm Nanometer
% Percent/ Percentage
rpm Rotations per minute
MC Microcrystalline cellulose
SD Standard deviation
λmax Wavelength maximum
X
TABLE OF CONTENTS
SR.NO CHAPTER PAGE NO.
1 INTRODUCTION 1
2 OBJECTIVES 47
3 REVIEW OF LITERATURE 48
4 METHODOLOGY 62
5 RESULTS 77
8 SUMMARY, CONCLUSION 111
9 BIBLIOGRAPHY 119
XII
TABLE OF CONTENTS
SR.NO CHAPTER PAGE NO.
1 INTRODUCTION 1
2 OBJECTIVES 47
3 REVIEW OF LITERATURE 48
4 METHODOLOGY 62
5 RESULTS 77
8 SUMMARY, CONCLUSION 111
9 BIBLIOGRAPHY 119
XII
LIST OF TABLES
Table
No. Title Page No.
1 Characteristics of Cyclodextrins 2
2 Physicochemical properties of cyclodextrin 3
3 CD-enhanced Solubility and Dissolution 12
4 CD Effect on Drug Stability 17
5 Modification of the Drug Release 30
6
Applications of Various CD Derivatives 31
7 59
Materials and their Sources
Equipments and their source
8 60
9 68
Formulae of Tablets.
10 Calibration curve data of Gliclazide 75
11 Solubility (mg/ml) of gliclazide in various fluids 76
12 Effect of pH on solubility of glicazide. 76
Phase Solubility Study Profile of gliclazide with HP β-CD

13 77
Drug Content Profile of Gliclazide HP-β-CD inclusion
Complexes
14 80
XIII
Drug Content Profile of Gliclazide HP-β-CD Physical
86
Mixtures
15
Percentage of drug release Profile of Gliclazide inclusion

16 complex with HP-β-CD 87
(Kneading Method)
Percentage of drug release Profile of Gliclazide complex with

HP-β-CD
17 (Physical Mixture) 88
Correlation Coefficients (R2) Values in the analysis of

Glicazide HP-β-CD Dissolution data profile as per Zero order
18 and First order 86
Dissolution Parameter Profile of Gliclazide- HP-β-CD

19 95
Percentage of drug release Profile of Gliclazide- HP-β-CD

20 Tablets 96
. Correlation Coefficients (R2) Values in the analysis of

Glicazide HP-β-CD Tablets Dissolution data profile as per Zero
21 order and First order 98
Dissolution Parameter Profile of Gliclazide- HP-β-CD
Tablets
22 100
Hardness Profile of Gliclazide-HP-β-CD Tablets.

23 100
24 Disintegration Time Profile of Gliclazide HP-β-CD Tablets. 101
25 Friability Percentage Profile of Gliclazide-HP-β-CD Tablets 101
26 Weight Variation Profile of Gliclazide HP-β-CD Tablets. 102
XIV
Drug Content Profile of Gliclazide HP-β-CD Tablets
27 after Stability Test 102
Percentage of drug release Profile of Gliclazide- HP-β-CD

28 Tablets After Stability Study 103
Hardness Profile of Gliclazide-HP-β-CD Tablets after stability

29 test. 105
Disintegration Time Profile of Gliclazide HP-β-CD Tablets

30 after stability test 105
Friability Percentage Profile of Gliclazide-HP-β-CD Tablets
after stability test.

31 106
Weight Variation Profile of Gliclazide HP-β-CD Tablets after

32 Stability Study. 106
XV
LIST OF FIGURES
Page
Fig. No. Title
No.
1 Structure of Cyclodextrins 11
2 the effect of complex stability constant on drug degradation. 19
3 Mode of penetration enhancement by CDs 23
4 Phase solubility diagram 42
5 Standard Calibration Curve for Gliclazide 75
6 Phase Solubility Study Profile of Gliclazide with HP β-CD 77
7 IR Profile of Gliclazide and its HP β-CD inclusion complexes 78
8 IR spectra of Gliclazide and its HP β-CD Physical Mixture 79
DSC Profile of Gliclazide and its HP β-CD Inclusion

9 complexes 80
10 DSC Profile of Gliclazide and its HP β-CD Physical Mixture 81
XRD Profile of Gliclazide and its HP β-CD Inclusion

11 complexes 82
12 XRD Profile of Gliclazide and its HP β-CD Physical Mixture 84
Dissolution Rate Data Profile graph of Gliclazide and its

13 Inclusion Complex (Kneading Method) 89
XVI
Dissolution Rate Data Profile graph of Gliclazide and it’s
14 Complex(Physical Mixture) 90
% Drug Remained Profile of Glaclazide HPβ-CD Inclusion

15 complex. 87
% Drug Remained Profile of Glaclazide HPβ-CD Physical

16 Mixture 92
Log % Drug Remained Profile of Glaclazide HPβ-CD Inclusion

17 complex 93
Log % Drug Remained Profile of Glaclazide HPβ-CD Physical

18 Mixture 94
Dissolution Rate Data Profile graph of Gliclazide- HP-β-CD

19 Tablets 97
20 % Drug Remained Profile of Glaclazide HPβ-CD Tablets. 99
21 Log % Drug Remained Profile of Glaclazide HPβ-CD Tablets 99
Dissolution Rate Data Profile graph of Gliclazide- HP-β-CD

22 Tablets After Stability Study. 104
XVII
INTRODUTION
Cyclodextrins have been used as complexing agents to increase the aqueous
solubility of poorly water soluble drugs and to increase their membrane permeability,
bioavailability and stability.1, 2 In addition; CDs have been used to reduce gastrointestinal
or ocular irritation, to mask unpleasant taste and to prevent drug-drug and drug-additive
interactions1, 2
The permeability through biological membrane is enhanced by the
presence of cyclodextrin. Cyclodextrin and their derivatives play an important role in the
formulation development due to their effect on solubility, dissolution rate, chemical
stability and absorption of a drug 3, 4.
Cyclodextrins are cyclic (α-1, 4)-linked oligosaccharides of α-D-glucopyranose
containing a hydrophilic outer surface and hydrophobic core. Owing to lack of free
rotation about the bonds connecting the glucopyranose units, the cyclodextrins are not
perfectly cylindrical molecules but are toroidal or cone shaped.1 Based on this
architecture, the primary hydroxyl groups are located on the narrow side of the cone
while the secondary hydroxyl groups are located on the wider edge as shown in Figure 1.
The commonly used CDs are α-cyclodextrin (α-CD), β-cyclodextrins (β-CD), and γ-
cyclodextrins (γ-CD), which consist of six, seven and eight glucopyranose units,
respectively.
Chemical and physical properties of the most common CDs are given in Table N0
1. Partially prehydrolysed starch, a mixture of acyclic dextrins, is converted by
cyclodextrin-glucosyl transferase enzyme, which is produced by microorganism Bacillus
Department of Industrial Pharmacy, KRES’s KCP, BIDAR Page 1
macerans to a mixture of cyclic and acyclic dextrins. From the mixture, cyclic dextrins,
the pure homogenous crystalline CD are isolated.
The aqueous solubility of β-CD is low; hence chemically modified β-CD is used.
Β-CD is used widely because of low cost, optimum cavity size and better complexing
efficiency.2 Modified β-CD has more aqueous solubility and improves the association
with guest molecules. Modified β-CD such as methylated cyclodextrin (Mβ-CD),
hydroxypropylated cyclodextrins (HPβ-CD), hydroxyethyl cyclodextrin (HPβ-CD) and
their physicochemical properties are given in Table N0 2.
The main reason for the solubility enhancement in these derivatives is that
chemical manipulation frequently transforms the crystalline CDs into amorphous
mixtures isomeric derivatives. For e.g.,(2-hydroxy propyl)- β-CD is obtained by treating
a base –solubilized solution of β-CD with propylene oxide, resulting in an isomeric
system that has an aqueous solubility well in excess of 60%(w/v)197. Several studies
reported the Cyclodextrin complexation of a variety of drugs for various purposes.
Table 1: Some characteristics of α-, β-, and γ-cyclodextrins
No of glucopyranose units α β γ
Molecular weight 972 1135 1297
Central cavity diameter (Ao) 4.7-5.3 6.0-6.5 7.5-8.3
Water solubility (g/100 ml at RT) 14.5 1.85 23.2

(α) D 250
(optical rotation) 150 + 0.5 162.5+ 0.5 177.4 + 0.5
Cavity diameter (Ao) 4.7-5.3 0.0-6.5 7.5-8.3
Height of torus (Ao) 7.9 ± 0.9 7.9 ± 0.9 7.9 ± 0.9
Diameter of outer periphery (Ao) 14.6 + 0.4 15.4 + 0.4 17.5 + 0.4
Approximate Volume of Cavity (Ao)3 174 262 427
Approximate Volume of Cavity in

1 mol -CD (ml) 10 157 250
Table 2: Some physicochemical properties of β-cyclodextrin derivatives and
γ- cyclodextrin.
Name of the cyclodextrin Molecular Weight Solubility in water Specific Rotation

(G/ml, 25o C)
β-Cyclodextrin 1135 1.88 +162.5
Methyl β-Cyclodextrin 1303 >25 +160 – 165
Hydroxyethyl β-Cyclodextrin 1355 >50 +137
Hydroxypropyl β-Cyclodextrin 1250-1400 >50 +125-150
γ-cyclodextrin 1297 25.6 +175.98
Absorption and Toxicity
Cyclodextrins are not absorbed orally and not hydrolyzed during their transit
through the small intestine. They are totally resistant to β-amylase, but can be attacked by
α-amylases. The ability of these enzymes and cyclodextrintransglycoslases to hydrolyze
HPβ-CD is limited. Substitution provides steric hindrance to the binding of the HPβ-CD
to the active site of the enzymes and as a result, the amount of hydrolysis is reduces.
Hydrolysis occurs only in colon (partial hydrolysis occurs with α-CD). The oral
administration of CDs does not result in acute toxicity. Long term administration leads to
no significant change in organs or biological values. Natural CDs are highly toxic when
given parentrally. α- and β-cyclodextrins induce haemolysis and nephrotoxicity upon i.v.
injection γ-CD is relatively less toxic parenterally5.
Formation of Complexes
One of the most important characteristics of CDs is their ability to form inclusion
complexes. Inclusion complexation involves entrapment of a guest molecule totally or
partially in the cavity of host molecule without formation of any covalent bonds. CDs are
typical host molecules and can entrap a wide variety of drug molecules resulting in the
formation of mono molecular inclusion complexes6.
Inclusion complexation occurs when aqueous solutions of CD are shaken with
drug molecules or its solution. In aqueous solution the hydrophobic cavities of CD are
occupied by water molecules, which can be replaced by appropriate drug molecules that
are CD and hence the complex may be precipitated from its saturated solution, as micro
crystalline powder and this powder is subsequently separated by filteration7 .
The central cavity of the CD molecule is linked with skeletal carbon and ethereal
oxygen’s of the glucose residue. It is there fore lipophilic; the polarity of the cavity has
been estimated to be similar to that of the aqueous ethanolic solution8. It provides a
lipophilic microenvironment into which suitably sized drug molecules may enter and be
included. No covalent bonds are formed or broken during CD complex formation, and in
aqueous solutions, the complexes are readily dissociated. Free drug molecules are in
equilibrium with the molecules bound within the CD cavity. Measurements of stability or
equilibrium constants (Kc) or the dissociation constants (Kd) of the drug CD complexes
are important properties of a compound upon inclusion.
Stoichiometry of Complexes
Stoichiometry is usually 1:1 molar ratio of CD to drug, but guest molecule is large
which will not fit into cavity of one host molecule, instead of that 2:1 (CD: Drug) 9 some
times 3:110 or 5:111 complexes are formed. It may also be possible to form 1:212 and 1:3
(CD: Drug) complexes if guest molecule is smaller in size. The stoichiometry of the
complexes can be determined by phase solubility studies, mass spectroscopy, and 1H-
NMR studies. The self-association and association of complexes are also possible.13
In the case of a 1:1 complex, using the following equation one can determine the
equilibrium binding or association constant, K, from the slope of the linear portion of the
curve.
Ka: b = slope/S0 (1 – slope)
Where so is the intrinsic solubility of the drug studied under the conditions.
Equilibrium binding of drug and CD to form a 1:1 complex can be represented as
Drug + CD Drug: CD Complex
Since equilibrium binding usually establishes with half-lives of much less than 1
second, the kinetics of dissociation of drug/CD complexes are generally expected to be
much faster than many physiological processes.14, 15

CDs and their derivatives have
received considerable attention in the pharmaceutical field for the past few years and an
increased number of reviews have been dedicated to their industrial and pharmaceutical
applications.16, 17-25
Degree of Substitution
The physicochemical properties of CDs, including their complexation ability, may
be greatly affected by the type, number, and position of the substituent on the parent CD
molecule. The “degree of substitution” per se does not uniquely characterize a β-CD
derivative such as HP-β-CD. When produced under different conditions, the
physicochemical properties of HP-β-CD samples with same degree of substitution may
not be identical owing to the possible occupancy of hydroxypropyl groups at different
positions on the parent CD molecule. Since the purity of CD can have a significant effect
on the final quality of the drug product and its marketability, it is necessary to have a
proper understanding of the following terms that are used in identification of CD purity.26
Degree of substitution (DS):
The average number of substituted hydroxyls per glucopyranose unit of CD ring.
Since the number of reactive hydroxyls per mole of glucopyranose unit is 3, the
maximum numbers of substituent’s possible for α-, β-, and γ-CDs are 18, 21, and 24,
respectively.
Average molar degree of substitution (MS):
The average number of moles of the substituting agent, e.g., hydroxypropyl, per
mole of glucopyranose. It may not necessarily describe the extent to which the reactive
sites are substituted when the substituting agent itself has reactive sites, or when new
reactive sites are generated during the substitution reaction.
Thus the value of MS can be more than 3 for each glycopyranose unit of
substituted CDs, or more than 18, 21,and 24 for α-, β-, and γ-CDs, respectively.
Degree of polymerization (DP):
The ratio of MS to DS (MS / DS). If no additional reactive sites are produced
during the substitution, MS and DS are equal and the DP becomes 1.
Total Degree of Substitution (TDS):
It avoids the confusion between DS and MS and represents the average number of
substituted groups (e.g., hydroxypropyl) per CD molecule. If the MS and DS are known,
one can calculate the molecular weight (Mw) of HP-β-CD from the following equation
Mw = 58:08* (TSD) + 1135
Where 1135 and 58.08 are the molecular weights of β-CD and propylene oxide
respectively. In the case of β-CD with 7 glycopyranose units, the TDS is 7*MS and hence
the equation becomes
Mw = 406:56* (MS) + 1135
HP-β-CDs
Degree of substitution (DS) plays an important role in balancing the CD water
solubility and its complexing ability. It was reported that increasing the degree of
substitution up to an optimum level improves the CD aqueous solubility, but beyond that,
the steric hindrances of the host molecule impair CD complexing (efficiency) capacity.
HP-β-CD derivatives with a low degree of substitution showed the best complexing
properties with low surface activities. Binding of guests to these CD derivatives was very
similar to β-CD at low degrees of substitution, but, as the substitution increased, the steric
hindrances weakened the binding and the effect was dependent upon the particular guest.
Though increasing the degree of substitution can increase the binding of guests to CDs by
increasing the surface area of binding, in many cases the differences in the binding of
guests with degree of substitution were small, if detectable.27
Drug Solubilization and Enhanced Dissolution:
Solubility of slightly and sparingly soluble drugs can be enhanced by molecular
inclusion within the CDs. The solubility and dissolution rate of sparingly soluble drugs is
enhanced using CD complexes; hence the drug reaches the blood faster and in higher
concentration suggesting the need for reducing the dose size.28 CD applications as
solubilizing agents are summarized in Table No 3.
Charged CD can be powerful solubilizer29 but their solubilizing effects appear to
depend on the relative proximity of the charge to the CD cavity. The farther away the
charge is located the better complexing abilities. For example, (2-hydroxy-3-
[trimethylammonio] propyl-β-cyclodextrin possesses excellent solubilizing effects while
β-cyclodextrin sulfate has a comparatively low complexation potential.
Sulfobutyl β-cyclodextrin, where a butyl ether spacer group has moved the anion
away from the cavity, is an excellent solubilizer. Compared to neutral CD, enhanced
complexation is frequently observed when the drug and CD molecules have opposite
charge but decreased complexation is observed if they carry same type of charge. For
example, (2-hydroxy-3-[trimethylammonio] propyl-β-cyclodextrin is an excellent
solubilizer for many acidic drugs capable of forming anions.
Many ionizable drugs are capable of forming CD complexes; the stability
constant of the complex is much larger for the un-ionized than for the ionized form. For
example, both the un-ionized and the cationic form are 4 times larger than for the cationic
form. In the case of ionisable drugs, the presence of charge may play a significant role in
drug/CD complexation and hence a change in the solution pH can vary the complex
constant. In general, ionic forms of drugs are weaker complex forming agents than their
nonionic forms.30, 31
β-CD complexes.32 When added in small amounts, water-soluble polymers or ion
pairing agents enhance CD solubilizing effect by increasing the apparent complex
stability constant. The polymers or ion pairing agents due to their direct participation in
drug complexation, improve both pharmaceutical and biological properties of drug/CD
complexes, independent of drug’s physiochemical properties.25,33,34-38 Certain additives
may compete with drug molecules for CD cavities and thus decrease the apparent
complex stability constant, eg, additives with positive and negative hydrotropic
effect.39,40 Though water structure forming agents added to CD solutions generally
increase the total drug solubility, they showed opposite effects with clotrimazole.56
Simultaneous complexation and salt formation with hydroxy carboxylic acid (HA)
significantly increased the CD solubilizing power for a sparingly water-soluble amine
type drug by forming drug/ CD/HA multicomponent systems.41 Co-solvents can improve
the solubilizing and stabilizing effects of CDs, eg, use of 10% propylene glycol in
development of an oral itraconazole preparation containing 40% of HP-β-CD.42
Sometimes co-solvents may hinder drug complexation by competitive inclusion, eg,
presence of 10% propylene glycol decreased the solubilizing effect of HP-β-CD for
itraconazole. On dilution, the presence of propylene glycol favored absorption and
precipitation of itraconazole in GI fluids and formulation by providing increased
percentage of the free drug. The increased percentage of the free drug in presence of co-
solvent was reported to be a result of lesser intrinsic solubility of the drug compared with
the dilution concentration line at a given HP-β-CD concentration.43
Temperature changes can affect drug/CD complexation. In most cases, increasing
the temperature decreased the magnitude of the apparent stability constant of the drug/CD
complex and the effect was reported to be a result of possible reduction of drug/CD
interaction forces, such as van derWaals and hydrophobic forces with rise of
temperature.31, 44, and 45
However, temperature changes may have negligible effect when the drug/CD
interaction is predominantly entropy driven (ie, resulting from the liberation of water
molecules hydrated around the charges of guest and host molecules through inclusion
complexation).46
Method of preparation, viz co-grinding, kneading, solid dispersion, solvent
evaporation, co-precipitation, spray drying, or freeze drying can affect drug/CD
complexation. The effectiveness of a method depends on the nature of the drug and
CD.47, 48, 49 in many cases, spray drying, 49-51 and freeze drying52, 53, 54 were found to be
most effective for drug complexation. However, method of preparation showed no
influence on the dissolution performance of tolbutamide.
Reduction of drug crystallinity on complexation or solid dispersion with CDs also
contributes to the CD increased apparent drug solubility and dissolution rate.57, 58 CDs, as
a result of their ability to form in situ inclusion complexes in dissolution medium, can
enhance drug dissolution even when there is no complexation in the solid state.59
SBE-β-CD was shown to be an excellent solubilizer for several drugs and was
more effective than β-CD but not as effective as DM-β-CD.60 CDs can also act as release
enhancers, for example β-CD enhanced the release rate of poorly soluble naproxen and
ketoprofen from inert acrylic resins and hydrophilic swellable (high-viscosity hydroxy
propyl methyl cellulose [HPMC]) tableted matrices. Β-CD also enhanced the release of
theophylline from HPMC matrix by increasing the apparent solubility and dissolution
rate of the drug.193, 194
Figure No.1. The chemical structure (A) and the toroidal shape (B) of the â-cyclodextrins
molecule.
(C) HPβ-CD
C R= CH2CH (OH) CH3 or H
Table No 3. Examples of CD-enhanced Solubility and Dissolution
CD Drug(s) Ref.
β-CD Nimesulide, Sulfomethiazole, Lorazepam,

Ketoprofen, Griseofulvin, 48, 54, 59, 61-
69
Praziquantel,Chlorthalidone, Etodolac,
Piroxicam,, Itraconazole
Ibuprofen
α-CD Praziquantel 59
γ-CD Praziquantel, Omeprazole, Digoxin 59,70,71
HP-β-CD Albendazole, DY–9760e, ETH–615,

Levemopamil HCl, 52, 46,
Sulfomethiazole, Ketoprofen, 33, 72, 54
Griseofulvin, Itraconazole, 62, 64, 68, 57,
Carbamazepine Zolpidem, Phenytoin, Rutin 73-75
DM-β-CD Naproxen, Camptothesin 58, 76
SBE-β-CD DY– 9760e, Danazol, Fluasterone, Spiranolactone 45,46,77,78
RM-β-CD ETH–615, Tacrolimus 33, 79

80
Permeability Enhancement
Masson81 reported that cyclodextrins could enhance the permeation of poorly
soluble drugs through biological membranes. However, the permeability will decrease at
higher concentration of cyclodextrin in excess of the concentration needed to solvate the
drug. The effect of cyclodextrins cannot be explained as solely due to increased solubility
of the drug in the aqueous donor phase nor can it be explained by assuming that
cyclodextrins act classical permeation enhancer. It was concluded that cyclodextrins act
as permeation enhancers by carrying the drug through the aqueous barrier which exists
before the lipophilic surface of biological membranes.
Martin82 explained nasal permeation is enhanced by interaction with nasal
epithelium by modifying tight junction and lipid and protein content of the membrane,
which enhances the permeation of membrane. The enhanced effect is proportionally some
extent with increase in concentration up to a critical value and further increase in
concentration failed to increase the permeation. At high concentrations of CD, the
permeability coefficient decreases due to decreased drug activity in the donor phase.83
The transport enhancing properties of the CD were found to follow the
lipophilicity of the core in their cyclic structure was observed by Hovgaard.84 Dimethyl-
β-CD (DM-β-CD) caused in an increase in the permeability of the cytoplasm membrane
in a concentration dependent manner. Hovgaard et al further observed that the
basolateral membrane was significantly more sensitive to cyclodextrin than the apical
membrane.
HPβ-CD with a molar substitution of 0.6 and randomly methylated β-CD with
molar substitution of 1.8 and carboxymethyl-β-CD sodium salt with molar substitution of
0.6 were evaluated by Masson et al. Excess of the concentration needed to solvate the
drug the effect of permeation enhancer reduces.85
Moreover it was found from in-vitro electrophysiological experiment that the
change in enhanced permeability caused by β-CD occurred primarily in the transcellular
pathways, rather than in the paracellular pathways of the small intestine. They suggested
that the enhancement of intestinal absorption by β-CD, after removal of the mucin layer
from the intestinal surface, is due to the interaction between the membrane components
and CD. This interaction would induce disorder in cell membrane lipid, resulting in the
increased permeability of the transcellular route.2
Safety of CD in Oral Drug Delivery
Safety of CD in oral drug delivery is proved. It was reported that the acute LD50
of β-CD is more than 12.5 g/kg in mice, 18.8 g/kg in dogs. The acute LD50 of γ-CD is
more than 16 g/kg in mice and more than 8 g/kg in rats.87, 88 In another 90-day and 6-
month oral toxicity studies in rat (Long Ewans, 5 weeks old), daily of 200, 400, and 600
mg/kg β-CD did not show any growth depressant effect. At end of the experiment,
examination of the urine for colour, pH, protein, blood glucose, urobilinogen, bilirubin,
ketenes’ and sediment did not show any changes due to treatment with CD. Even
hematological examination, which was conducted at the end of experiment and
comprised of hemoglobin, cell volume, counts of erythrocytes, and of total and
differential leucocytes, showed only values that were within the normal range.
Biochemical variables, including glucose, serum alkaline phosphatase; total
bilirubin, total protein and creatinine did not show any abnormalities.89, 90
Further in
autopsy, the weights of the heart, lungs, liver, kidneys and spleen were found to be in
normal range. Microscopic examination of the liver, spleen, kidneys, gonads, uterus,
stomach, small intestine, pancreas, adrenals, lungs, myocardium and brain showed that
there are no pathological changes that could be attributed to treatment with β-CD.
Based on other studies, CD administered orally to rats and dogs is considered to
be non-toxic if the daily dose is less than 600 mg/ kg or not more than 3% of the diet. No
signs of teratogenicity at 200, 400, 600 mg/kg β-cyclodextrin as an oral daily dose in
female rats. There was no evidence for an effect of treatment on the number of
implantations, the percentage of resorptions, and the percentage of dead and live fetus.
CDs have been used to ameliorate the irritation caused by drugs.91 the increased
drug efficacy and potency (i.e., reduction of the dose required for optimum therapeutic
activity), caused by CD-increased drug solubility, may reduce drug toxicity by making
the drug effective at lower doses.
β-CD enhanced the antiviral activity of ganciclovir on human cytomegalovirus
clinical strains and the resultant increase in the drug potency reduced the drug toxicity.92
The toxicities associated with crystallization of poorly Water-soluble drugs in parenteral
formulations can often be reduced by formation of soluble drug: CD complexes.
Formulation of phenytoin with HP2-β-CD showed considerably reduced tissue
irritation compared with a commercial injection of the drug in a BALB/c mouse model.93
Further CD entrapment of drugs at the molecular level prevents their direct contact with
biological membranes and thus reduces their side effects (by decreasing drug entry into
the cells of nontargeted tissues) and local irritation with no drastic loss of therapeutic
benefits.23
Inclusion complexation with HP-β-CD reduced the side effects of 2–ethyl hexyl–
p–dimethyl aminobenzoate (a UV filter) by limiting the interaction of the UV filter with
skin.94 In a study with patients, piroxicam/β-CD inclusion complex showed better
tolerance with lower incidence and severity of gastrointestinal side effects compared with
the free drug.95
HP-β-CD alleviated the intrinsic irritancy effect observed on IV administration of
CKD-732 hemioxalate against blood vessels.96 SBE7-β-CD inhibited DY-9760e-induced
cytotoxicity toward human umbilical vein endothelial cells and significantly suppressed
the drug-induced vascular damage in rabbits.97 Inclusion complexation with CDs also
reduces ocular drug irritation by limiting the free drug concentration on the precorneal
area to a nonirritating level.98
Effect on Drug Stability
CDs can improve the stability of several labile drugs against dehydration,
hydrolysis, oxidation, and photodecomposition and thus increase the shelf life of drugs.16
Table No 4 summarizes CD effects on drug stability.
Table No 4. CD Effect on Drug Stability
Effect Drug CD Ref.
↑Photostability Promethazine HP-β-CD, DM-β-CD

33
DY–9760e SBE-β-CD
46
2–ethyl hexyl p–dimethyl HP-β-CD
94
aminobenzoate
↑ Shelf life with unaffected
dissolution rates for 4 years Glibenclamide β-CD
99
↑ Thermal stability in solid state Diclofenac sodium β-CD

100
↑Stability against intramolecular
cyclization in solid state Quinaril β-CD, HP-β-CD
101
↑Stability to acid hydrolysis and
photodecomposition Doxorubicin HP-β-CD, HP-γ-CD
102
↑Stability against hydrolysis acyl ester prodrugs of HP-β-CD
62
Ganciclovir
Digoxin γ-CD
71
Rutin HP-β-CD
75
Camptothesin RDM-β-CD
76
Melphalan and Carmustine SBE -β-CD, HP-β -CD
103
Paclitaxel γ-CD, HP-γ-CD, HP-
β-
CD
104
↑ Deacetylation or degradation Spiranolactone SBE-α-CD, SBE-β-
CD,
HP-β-CD, γ-CD,β-CD
105
↑Photoreactivity Flutamide β-CD 106
↑, increased effect
It was reported that CD-induced enhancement of drug stability may be a result of
inhibition of drug interaction with vehicles and/or inhibition of drug bioconversion at the
absorption site.107 by providing a molecular shield, CD complexation encapsulates labile
drug molecules at the molecular level and thus insulates them against various degradation
processes. SBE-β-CD showed greater stability enhancement of many chemically unstable
drugs than other CDs.60
The stabilizing effect of CDs depends on the nature and effect of the included
functional group on the drug stability and the nature of the vehicle. Both the catalyzing
effects of the nitro group as well as the stabilizing effect of the halogen and cyanogen
groups on photodegradation of 1, 4 dihydropyrimidine derivatives were reduced by
complexation with CDs.108
HP-β-CD significantly reduced the photodegradation of 2–ethyl hexyl p–
dimethyl aminobenzoate in solution than in emulsion vehicle.94 CDs improved the
photostability of trimeprazine (when the solution pH is reduced) 109 and promethazine.110
CDs also enhanced the solid state stability and shelf life of drugs.99-101
CDs were reported to enhance the physical stability of viral vectors for gene
therapy, and the formulations containing sucrose and CDs were stable for 2 years when
stored at 20°C.111 Since the hydrolysis of drugs encapsulated in CDs is slower than that
of free drugs, 102 the stability of the drug/ CD complex, ie, the magnitude of the complex
stability constant, plays a significant role in determining the extent of protection.46,

76,103,112
Very low concentrations of HP-β- CD (1% or lower), due to formation of a more
physically unstable complex, did not protect taxol as effectively as higher CD
concentrations. The effect of complexation on drug stability can be represented by the
following equation (Figure 2)
1 1 1
---------- = ---------------------- + ----------
k0 − kobs Kc (k0− kc) (CD) (k0− kc)
Figure No.2. A simple model representing the effect of complex stability constant on
drug degradation.104
Enzymatic Degradation, Absorption
One of the outstanding properties of CDs is their resistance to enzymes that
hydrolyse starch. CDs are resistant to β-amylases, since they do not contain terminal
groups susceptible to attack by the enzyme. By contrast, α-amylases, which do not
require free terminal groups and attack the inside of the molecule is capable of
hydrolyzing cyclodextrins, though, usually at a low rate. Gerloczy reported that 2% of the
input radioactivity could be detected in blood after 6 to 12 hours, when the labeled β-
cyclodextrin was administered orally. Hence oral absorption of cyclodextrin is very less.
113,114
Increased Bioavailability
Enhanced oral bioavailability of a drug from a cyclodextrin-containing
formulation mainly results from increases in the apparent solubility of the drug. The
mean absorption time and mean residence time was shortened with an increase in the
molar ratio of cyclodextrin to drug. The maximal AUC was observed with a 1:30
kneaded mixture. The bioavailability of each mixture was almost the same as or slightly
higher than a commercial cyclosporine preparation.
CDs enhance the bioavailability of insoluble drugs by increasing the drug
solubility, dissolution, and/or drug permeability. CDs increase the permeability of
insoluble, hydrophobic drugs by making the drug available at the surface of the biological
barrier, e.g., skin, mucosa, or the eye cornea, from where it partitions into the membrane
without disrupting the lipid layers of the barrier. In such cases it is important to use just
enough CD to solubilizing the drug in the aqueous vehicle since excess may decrease the
drug availability (Figure 3).115, 116, 117
At low RM-β-CD concentrations, when hydrocortisone was in suspension,
increasing the CD concentration increased the drug flux. At higher CD concentrations,
when the drug was in solution, increasing the CD concentration decreased the flux.118 It
was found that addition of polymers can further enhance the drug permeability from
aqueous CD solutions. Carboxy methyl cellulose (CMC) enhanced triclosan
bioavailability from toothpastes containing β-CD by forming a drug/CD/CMC complex
with improved substantivity.119
CDs increased the bioavailability of lipophilic itraconazole from both an oral
solution and an intravenous formulation by improving the drug solubility and
absorption.120
In the case of water-soluble drugs, CDs increase drug permeability by direct
action on mucosal membranes and enhance drug absorption and/or bioavailability.107, 115
Solubilization of specific membrane lipids of human erythrocytes through inclusion
complexation with CDs and their ability to cause perturbation of membrane integrity,
were suggested to contribute to CD-induced promotion of drug absorption and toxicity.
It was reported that CDs, because of their ability to remove cholesterol, may
increase membrane fluidity and induce membrane invagination through a loss of bending
resistance and cause cell lysis. On the other hand, removal of phospholipids, especially
phosphatidyl choline and sphingomyelin from the outer half of the membrane bilayer by
CDs causes bilayer imbalance; the removal may also contribute in part to the formation
of stomatocytes through an inward bending of membranes. CD induced lysis of artificial
membranes composed of lecithin and cholesterol by a similar solubilization process.
Detergents first incorporate themselves into membranes, and then extract the
membrane components into micelles and cause membrane solubilization/ lysis. However,
unlike detergents, CDs were reported to solubilizing membrane components without
entering into the membrane, and hence the perturbing effects of CDs can be mild and
reversible.
In the presence of CDs, the new lipid containing compartment in the aqueous
phase with extracted components from the erythrocyte surface equilibrated freely with
the cell surface by a reversible process.
Compared with other absorption-promoting agents and preservatives commonly
used in nasal formulations, CDs exerted a rather mild and reversible effect on the ciliary
beat frequency of both chicken embryo trachea and human nasal adenoid tissue in vitro in
a concentration-dependent manner.21 DM- β-CD caused enhancement of enoxaparin nasal
absorption by solubilizing membrane components and opening tight junctions but the
effect was reversible after 6 hours.121
Watanabe et al122 reported that rectal membrane recovers its barrier function
probably 24 hours after the administration of DM-β-CD (at least 30 mg).107 Even at high
doses, the effects of HP-β-CD on kidneys were reversible and similar to those of osmotic
agents currently used in parenteral formulations.115 Labile drug stabilization by CDs71,75
and their ability to ameliorate drug irritation, and thus improve drug contact time at the
absorption site in nasal, ocular, rectal, and transdermal delivery,115 are some other
important factors that contribute to the CD-improved bioavailability. α-CD improved the
rectal bioavailability of morphine by inhibiting the drug’s upward movement from areas
impacted by first pass metabolism.107
Figure No.3. Mode of penetration enhancement by CDs.91
CD APPLICATIONS IN DRUG DELIVERY:
Oral Drug Delivery
When a drug becomes part of a CD complex, its physicochemical properties such
as crystallinity, Solubility, dissolution and chemical stability are modified.123 hence, some
of pharmaceutical formulation problems may be solved. CD technology has also been

124
applied for naproxen, indomethacin125 in order to decrease drug irritation in oral
administration.
Applications of CDs in oral drug delivery include improvement of drug
bioavailability due to increased drug solubility, improvement of rate and extent of
dissolution, and/ or stability of the drug at the absorption site, eg, the gastrointestinal tract
(GIT) or in formulation, reduction of drug induced irritation, and taste masking (Table
10). CD complexation was found to decrease local drug irritation and also modify the
time of drug release during GI transit.115, 22
CDs enhance the mucosal drug permeability mainly by increasing the free drug
availability at the absorptive surface.126, 127

CD complexation can provide better and
uniform absorption of low-soluble drugs with poor and erratic absorption79 and also
enhance the drug activity on oral administration128,129,130 CD complexation increased the
absorption of poorly water-soluble drugs, delivered via buccal or sublingual mucosa.131-

134
Complexation can also mask the undesirable taste of drugs. With the assumption
that only the free drug molecule exhibits bitter taste, the extent of the suppression was
reported to be dependent on the availability of free drug, regardless of the kind and
concentration of CD.135
The relative safety, efficacy in terms of complexation, cost, and acceptance in
pharmacopeias are some important factors to be considered in selecting a CD for drug
complexation. HP-β-CDs were shown to have a better oral safety profile than β-CD and
other parent CDs, but only limited data are available on the oral safety of the methylated
CDs. However, for oral administration all CDs can be considered practically nontoxic
due to lack of CD absorption through GIT and, hence, the relative safety profile of CDs is
a concern of drug doses used in drug/CD complexes and the LD50 of CD.115 β-CD is the
most cost-effective compound of all CDs, whereas HP-β- and SBE-β-CDs are more
expensive. Monograph of β-CD is already incorporated in various pharmacopeias and
national formularies (NF).16 Hence, β-CD can be considered optimum for oral use when
it is effective for drug complexation and modified CDs like HP-, SBE-β-, and DM-β-CDs
may be used when they are more effective and when their peculiar property is required in
formulation, e.g., SBE-β-CD, owing to its osmotic property, was used in the preparation
of osmotic pump tablets.136,137
In Parenteral Drug Delivery
The sparingly water soluble drugs for intravenous and intramuscular dosing can
be given in the form of cyclodextrin complex by increasing solubility, decreasing
irritation at the site of administration of these parentrally administered drugs and
stabilization of drugs which are unstable in an aqueous environment. γ-CD, 2-HP-β-CD,
sulfobutylether β-CD, sulphated-β-CD and maltosyl-β-CD seems to be safe when
administered parentrally other cyclodextrins cannot be used in parenteral dosage forms.
One factor is whether the target drug solubility can be achieved with the use of an
acceptable cyclodextrin concentration. In addition, the cyclodextrin safety data must
support the concentration and total dose of cyclodextrin required to solubilizing the
required amount of drug. Many other factors such as the linearity of the relationship
between drug solubility and cyclodextrin concentration might also affect the acceptability
of a given concentration. Important critical factor could be whether the drug will be
completely released from the cyclodextrin dosage form.13
Intravenous Administration
So far SBE4-β-CD or HP-β-CD was utilized for I.V. administration. Significant
changes in the Pharmacokinetics of a drug were also demonstrated in the work of Frijlink
139.
They reported that higher values in some tissues may be due to transitory alteration in
protein binding.
The absorption, distribution and excretion of intravenously and orally
administered β-CD and glucosyl-β-CD in rats were studied by Kubota140. They reported
that 90% unchanged β-CD and glucosyl-β-CD was recovered in urine after 10 hours and
pharmacokinetics of the both complexing agents is similar.
Ophthalmic Applications of Cyclodextrin
Recently the strengths and weaknesses of the use of CD in this application have
been recognized. First to be considered is there should have affect on integrity of cornea.
It was assumed that only free drug, not the complex of drug with cyclodextrin penetrates
across biological membranes.
Cyclodextrin and Corneal Permeability
CD may increase the ophthalmic delivery of drugs through multiple routes. One
route would be to increase the solubility of poorly water-soluble drugs. A second route
would be to alter corneal permeability by damaging the corneal membrane. The most
beneficial area of CDs might be the solubilization of drugs intended for ophthalmic use.
Usayapant141 studied and showed that the solubility, chemical stability, and
ophthalmic delivery of dexamethasone were improved in the presence of HPβ-CD.
Cyclodextrins as anti-irritants
As high concentration of drug is used in ophthalmic, irritation is a common
drawback in ophthalmic drug development, which may decrease patient compliance.
Mainly CDs may decrease the irritation of drugs by formation of inclusion complexes,
thereby masking the irritating nature of the drug. Since ophthalmic drug irritation is
mostly related to drug concentration on the corneal surface tissues, CDs may be able to
eliminate the ocular irritation by changing the rate of drug absorption.142
Cyclodextrins are useful excipients in eye drop formulations for a variety of
lipophilic drugs. They will facilitate eye drop formulations for drugs that otherwise might
not be available for topical use, while improving absorption and stability and decreasing
local irritation.
Prevention of additive-drug interaction
Due to carbopol-propranolol interaction, insoluble complex is formed which alters
the properties of polymer such as swelling, releasing and bioadhesion. This interaction
was reduced when drug is complexed with β-CD.143
Cyclodextrins are not only well-known solubilizers, but constitute very powerful
tool as permeation enhancers. CD enhances the permeability of drug either by decreasing
the resistance of aqueous barrier or by modification of the structural lipid layer of
biological membrane. In addition, CDs are used to reduce or prevent GI or ocular
irritation, reduce or eliminate unpleasant tastes, prevent drug-drug interactions or drug-
additive interaction.
Nasal Drug Delivery
CDs are effective excipients in nasal drug delivery. CDs improve nasal drug
absorption either by increasing aqueous drug solubility and/or by enhancing nasal drug
permeability. However, large interspecies differences were found in CD-enhanced nasal
drug absorption. The safety and nontoxicity of CDs in nasal drug formulations have been
demonstrated by the clinical data with CDs showing no adverse effects.
Merkus et al195 demonstrated that CDs can be safely used to improve nasal
bioavailability of drugs, especially peptides.
CDs can also be used to reduce the nasal toxicity of other enhancers without
affecting their absorption-enhancing property.
Rectal Drug Delivery
Applications of CDs in rectal delivery include enhancing drug absorption from a
suppository base either by enhancing drug release from the base or by increasing drug
mucosal permeability, increasing drug stability in the base or at the absorption site,
providing sustained drug release, and alleviating drug induced irritation.107, 15
Drug release from the suppository base is important in rectal absorption because
of the high viscosity of rectal fluids. The effect of CDs on rectal drug absorption can be
influenced by partition coefficient of the drug and its CD complex, magnitude of the
complex stability constant, and nature of the suppository base (oleaginous or
hydrophilic). Hydrophilic CDs (especially methylated and hydroxylpropyl CDs) enhance
the absorption of lipophilic drugs by improving the drug release from oleaginous vehicles
and/or by increasing the drug dissolution rate in rectal fluids.
Formation of hydrophilic CD complexes was found to inhibit the reverse
diffusion of drugs into oleaginous vehicles by reducing the drug/vehicle interaction. CDs
may not affect drug release if the drug/CD complex dissociates in the vehicle itself.
The CD complex, once released from the base, mostly releases the free drug for
absorption. The competing sites for the free drug released at the absorption site are CD
cavity, suppository base, and the rectal mucosa. The extent of drug diffusion into these
sites depends on drug’s partition coefficient, magnitude of the stability constant of the
drug/CD complex, and the relative lipophilicity of the competing sites. In the case of
lipophilic drugs with a high partition coefficient, there might be some back diffusion of
the released free drug into the lipophilic base. Since a part of drug may get absorbed as
the CD complex, the partition coefficient of the complex also becomes important.
CDs enhance the rectal absorption of inabsorbable, hydrophilic drugs such as
antibiotics, peptides, and proteins by their direct action on the rectal epithelial cells.107
CDs enhance rectal drug stability either by inhibiting the drug/vehicle interaction
(by making the drug insoluble in oleaginous base) or by inhibiting the drug bioconversion
in the rectum.
Controlled Drug Delivery
CDs, due to their ability either to complex drugs or to act as functional carrier
materials in pharmaceutical formulations, can serve as potential candidates for efficient
and precise delivery of required amounts of drugs to targeted site for a necessary period
of time.
β-CD derivatives are classified as hydrophilic, hydrophobic, and ionizable
derivatives. The hydrophilic derivatives improve the aqueous solubility and dissolution
rate of poorly soluble drugs, while the hydrophobic derivatives retard the dissolution rate
of water-soluble drugs from vehicles. Hence hydrophilic and hydrophobic CD derivatives
are used in immediate and prolonged release type formulations, respectively.
The ionizable CD derivatives, on the other hand, improve inclusion capacity;
modify drug dissolution rate, and all eviate drug irritation, e.g., use of CME-β-CD to
obtain delayed release type formulations. Highly hydrophilic derivatives, such as 2HP-β-,
G2-β-, and SBE-β-CDs were used in immediate release formulations that dissolve readily
in the GIT and enhance the oral bioavailability of poorly soluble drugs.
CDs, both natural and chemically modified, are used in the design of immediate,
delayed release, and targeted drug delivery systems (Table 5). The pH-dependent
solubility of CME-β-CD (ie, limited solubility under the acidic conditions of stomach
with the complex solubility increasing with pH), which provides selective dissolution of
drug/CD complex, makes it useful in the design of enteric formulations. When
molsidomine tablets containing CME-β-CD were studied in gastric acidity–controlled
dogs, the absorption of the drug was significantly retarded under high gastric acidity
compared with low gastric acidity conditions.145, 146
Table No 5. Modification of the Drug Release Site and/or Time Profile by CDs145
Release Pattern Aim Use of CD
Immediate release Enhanced dissolution and absorption HP-β-, DM-β-,

SB-β-,
of poorly water soluble drugs and branched-
β-CDs
Prolonged release Sustained release of water-soluble Ethylated β-

CDs, acylated β-CDs drugs
Modified release More balanced oral bioavailability Simultaneous

use of
With prolonged therapeutic effect different
CDs and/or
other
excipients
Delayed, pH-dependent
Release (Enteric) Acid protection of drugs CME-β-CD
Site-specific release Colon-targeting Drug/CD

conjugate
Hydrophobic CDs, such as alkylated and acylated derivatives, are useful as slow-
release carriers in prolonged release formulations of water-soluble drugs. Applications of
various CD derivatives in formulation of modified-release preparations are summarized
in Table 6.
Table 6. Applications of Various CD Derivatives in the Formulation of Modified
Release Preparations145, 146
Derivative Drug Summary
Diethyl-β-CD Diltiazem Sustained release for oral use

Buserelin acetate Sustained release for
subcutaneous use
Nitroglycerine Sustained release for
percutaneous use
Isosorbide dinitrate Sustained release
Tiaprofenic acid Delayed release
Triacetyl-β-CD Flufenamic acid Prolonged release for oral use
Peracylated-β-CD (TB-β-CD) Molsidomine Sustained release for oral use

Salbutamol Prolonged release for oral use
Captopril Sustained release
Al-β-CD-sulfate Recombinant
human basic
fibroblast Sustained release for oral use
growth factor enhanced stability
O-carboxymethyl- Molsidomine
O-β-CD Diltiazem HCl Delayed release
Combination of short-chain and long-chain peracylated β-CDs in an appropriate
molar ratio was suggested to be useful to provide an effectively controlled release rate of
water-soluble drugs, eg, markedly retarded release rate of molsidomine on complexation
with peracylated β-CDs.147
CDs can also be used along with other carrier materials to optimize drug release
rate. Quaglia et al148 reported that CDs can be used to modulate drug delivery from
swellable systems.
HP-β-CD, because of its dissolution enhancing effect, was found to be more
effective than β-CD in the development of controlled release nicardipine formulations.149
Combination of drug complexes with hydrophilic and hydrophobic CDs in appropriate
ratios can be a promising drug delivery system for prolonged therapeutic effect and
balanced bioavailability.
In rabbits, a sustained release nicardipine formulation, developed by mixing the
drug complexes with HP-β-CD (fast release fraction) and with hydrophobic TA-β-CD
(sustained releasing portion) in appropriate ratios, showed markedly retarded drug release
with prolonged maintenance of plasma levels.150
A sustained release 2-layered nifedipine tablet formulation was developed by
using the drug complexes with β- and HP-β-CDs.151
Use of CDs with a hydroxyapatite matrix was indicated to control the release of
chemotherapeutic agents containing toxic metals, such as Rhodium II citrate and
butyrate, and to provide localized antitumor chemotherapy with minimal side effects.15
Colon-Specific Drug Delivery
CDs are barely hydrolyzed and only slightly absorbed in the stomach and small
intestine but are absorbed in the large intestine after fermentation into small saccharides
by colonic microbial flora. The peculiar hydrolyzing property of CDs makes them useful
for colon drug targeting.
CD-based prodrug approach was used for colon-specific and delayed drug
delivery, eg, when tested in rats with carageenan induced inflammation, the absorption of
BPAA from γ-CD prodrugs was found to be from cecum and colon in contrast to that
from the highly soluble β-CD complex, which was mainly from the small intestine.153
When studied in rats, it was found that both sugar-degrading and ester-
hydrolyzing enzymes are necessary for colon-specific release of butyric acid from its β-
CD ester conjugates.154
Drug conjugation with α-CD resulted in a delayed release–type prodrug
formulation for colon-specific delivery that all eviates the side effects of drugs while
maintaining their therapeutic effect. Complexation of triamcinolone acetonide (TA) with
β-CD improved the sphericity of microcrystalline cellulose (MCC)–β-CD-TA spherical
pellets (5:90:5) prepared by extrusion and spheronization for colon targeting.
TA complexation with the CD also facilitated the application of coating resistant
to gastric and small intestinal media and maintained the pellet integrity in dissolution
medium with no premature bursting of coatings on granule swelling.155
Peptide and Protein Delivery
Various problems associated in practical use of therapeutic peptides and proteins
are their chemical and enzymatic instability, poor absorption through biological
membranes, rapid plasma clearance, peculiar dose response curves, and immunogenicity.
CDs, because of their bioadaptability in pharmaceutical use and ability to interact with
cellular membranes, can act as potential carriers for the delivery of proteins, peptides, and
oligonucleotide drugs.156
The existence of efflux pumps may serve as an additional barrier for nonspecific
uptake of peptides and thus can cause low peptide bioavailability. P-glycoprotein (P-gp)
is an efflux transporter present in the apical region of epithelial cells in the brain, kidney,
liver, and GI tract. Pgp opposes the transcellular drug movement in the epithelial cells
and many peptide drugs, especially hydrophobic peptides like cyclosporin A, 157
Therapeutic use of peptides across the blood brain barrier (BBB) is greatly
hindered by their very low penetration and it was reported that P-gp substrates, such as
synthetic hydrophobic peptides, can stimulate the transport of drugs across the BBB.
It was also reported that Pgp–mediated transport of peptides might play an
important role in greatly reducing their delivery to the central nervous system in vivo.158
Hence, whenever unexplainable poor peptide absorption is seen, the role of efflux pumps
should be examined.159 It was found that CDs can inhibit or impair the efflux function of
P-gp and multidrug resistance associated proteins (MRP2).
CDs can enhance physical and chemical stability of protein and peptide drugs,
and the maximum enhancing effects were reported at low CD concentrations. The
proteolytic degradation of basic fibroblast growth factor was decreased by water-soluble
β-CD sulfate.16
Β-CD improved insulin loading of alginate microspheres prepared by an
emulsion-based process. The process was suggested to be useful in the development of an
oral insulin drug delivery system as the absorption of insulin from optimized
microspheres was found to take place from the GI region.160
Gene and Oligonucleotide Delivery
The toxicity and immunogenicity associated with viral vectors led to the
development of nonviral vectors for gene delivery. Besides the plasmid or virus-based
vector systems, “naked” nucleotide derivatives have also been investigated for possible
use as therapeutic agents through several routes of administration. Gene delivery
technologists are now testing CD molecules in the hope of finding an optimal carrier for
the delivery of therapeutic nucleic acids, however, the limitations of CDs, such as CD-
associated toxicity (e.g., DM-β-CD) have to be considered before their clinical use.161
CDs can solve many of the problems associated with in-vivo delivery of
oligonucleotides (Ons), such as their limited ability to extravasate from blood stream and
traverse cellular membranes, high degree of susceptibility to endonucleases with potential
toxicity of their breakdown products, polyanionic nature leading to nonspecific
interactions with extracellular and intracellular cationic molecules, and potential
immunogenicity. CDs can improve cellular uptake of ONs and also delay their
degradation by increasing their stability against endonucleases. Ons-adamatane
conjugates associated with HP-β-CD provided significantly increased cellular uptake of
Ons. Substitution of at least a single nucleotide of Ons with CDs improved the cellular
uptake and/or stability of Ons.
On conjugation with CDs, Ons may be delivered to the colon, an advantageous
absorption site to achieve acceptable therapeutic levels of Ons. CDs can also modulate
undesirable side effects of Ons treatment such as immune stimulation and reduction of
platelet counts.162, 163
Neutral and amphipilic as well as cationic CDs have been used for synthesis of
novel gene delivery vectors. Neutral CDs like β-, DM-β-, and HP-β-CDs were reported to
increase DNA cellular uptake by increasing its permeability.
Polyplexes (polycation polymer/DNA composite structures) of linear, cationic, β-
CD–containing polymers (βCDPs) were found to be suitable for DNA delivery due to
their increased transfection efficiency and stability against enzymatic degradation with
low in vitro and in vivo toxicity.164
The ability of CDs to complex hydrophobic adamantine was exploited for steric
stabilization of βCDPs with hydrophilic polymers like poly (ethylene glycol). Steric
stabilization of βCDPs prevents their self-aggregation but facilitates their targeted
delivery by preventing their undesired interactions with non–self-entities.165
CDs were also found to enhance plasmid or viral-vector–based delivery of genes.
Positively charged quarternary amino and tertiary amino β-CDs significantly enhanced
the transfection efficiency of negatively charged adenoviral vector-based gene
formulations.
It was reported that the transfection enhancement by the cationic β-CDs could be
a result of increased viral internalization caused by increased viral binding to cell and
improved cell membrane permeability.166 CDs also enhanced the physical stability of
viral vector formulations for gene therapy.111
Dermal and Transdermal Delivery
CDs have been used to optimize local and systemic dermal drug delivery.
Applications of CDs in transdermal drug delivery include enhancement of drug release
and/or permeation, drug stabilization in formulation or at absorptive site, alleviation of
drug-induced local irritation, sustaining of drug release from vehicle, and alteration of
drug bioconversion in the viable skin. Parent CDs (α-, β-,and γ-CDs) and various
chemically modified CD derivatives with extended physicochemical properties and
inclusion capacity have been used in transdermal drug delivery.107
Drug thermodynamic activity in vehicles as well as its skin/vehicle partition
coefficients can significantly affect CD induced changes in the drug permeability through
skin. CDs, by enhancing apparent drug solubility, enhance the drug thermodynamic
activity in vehicles and thus cause enhancement of drug release from vehicles. The
enhancement of drug release from vehicles by CDs in turn enhances the dermal drug
absorption by improving the drug availability at the lipophilic absorptive barrier surface
(ie, skin).107, 23
Although the drug partition coefficient (eg, a lipophilic drug) may be decreased
on complexation with CDs (eg, with hydrophilic CDs), the increased drug solubility and
thermodynamic activity in vehicles can lead to increased drug permeability through skin.
The ability of CDs to increase stability (against light and oxygen) and solubility
of sparingly water-soluble molecules made them useful in the formulation of cosmetic
products.167
Brain Drug Delivery or Brain Targetting
The concept of Bodor’s chemical delivery system (CDS) (ie, covalent coupling of
drugs to 1-methyl-1, 4-dihydronicotinic acid through an enzymatically labile linkage,
which increases drug lipophilicity) was applied for targeting drugs such as steroids,
antitumor agents, and calcium channel antagonists to brain.
Formulation is an important and integral concern in the development of CDS,
especially those for brain targeting. Formulation development of CDS is based on the
need for appropriate dosage form, stability, solubility, and dissolution characteristics.
Brewster and Loftsson168 discussed the use of chemically modified, especially
water-soluble, CD derivatives such as HP-β-CD in the formulation development of CDS.
HP-β-CD contributed to the development and preclinical testing of several CDS by
providing a stable and water-soluble dosage form suitable for parenteral administration.
Use of CDs in the formulation of CDS can be demonstrated by the significantly improved
solubility, stability, and pharmacologic activity of CDS of thyrotropin-releasing hormone
analogs on complexation with HP-β-CD.169
The very low penetration across the BBB greatly hinders the therapeutic use of
peptides, and whenever unexplainable poor peptide absorption is seen the role of the
efflux pumps should be examined.
It was reported that P-gp–mediated peptide transport may play an important role
in greatly reducing the peptide delivery to the central nervous system in-vivo158, 159 it was
also indicated that CDs such as DM-β-CD, due to their inhibitory effect on P-gp efflux
function, may enhance drug delivery to brain.170
CD APPLICATIONS IN THE DESIGN OF SOME NOVEL DELIVERY
SYSTEMS:
Liposomes
In drug delivery, the concept of entrapping CD-drug complexes into liposomes
combines the advantages of both CDs (such as increasing the solubility of drugs) and
liposomes (such as targeting of drugs) into a single system and thus circumvents the
problems associated with each system.
Liposomes entrap hydrophilic drugs in the aqueous phase and hydrophobic drugs
in the lipid bilayers and retain drugs en route to their destination. The fact that some
lipophilic drugs may interfere with bilayer formation and stability limits the range and
amount of valuable drugs that can be associated with liposomes. By forming water
soluble complexes, CDs would allow insoluble drugs to accommodate in the aqueous
phase of vesicles and thus potentially increase drug-to-lipid mass ratio levels, enlarge the
range of insoluble drugs amenable for encapsulation (i.e., membrane-destabilizing
agents), allow drug targeting, and reduce drug toxicity.
Problems associated with intravenous administration of CD complexes such as
their rapid removal into urine and toxicity to kidneys, especially after chronic use, can be
circumvented by their entrapment in liposomes.171-174
Liposomal entrapment can also alter the pharmacokinetics of inclusion
complexes. Liposomal entrapment drastically reduced the urinary loss of HP-β-CD/drug
complexes but augmented the uptake of the complexes by liver and spleen, where after
liposomal disintegration in tissues, drugs were metabolized at rates dependent on the
stability of the complexes.172, 175 CD complexation can increase liposomal entrapment of
lipophilic drugs and also reduce their release from the carrier, ie, liposomes. To
encapsulate large amounts of lipophilic drugs in liposomes, a CD molecule forming an
inclusion complex with a high drug:CD ratio should be selected.
HP-β-CD, with a more lipophilic interior and considerably higher aqueous
solubility incorporated higher drug amounts in vesicles than β-CD. However, HP-β-CD,
as a result of its ability to get entrapped in higher amounts in the vesicles, also showed a
higher velocity of destabilizing effect on vesicles than β-CD.196 Complexation with CDs
can improve the stability of liposomes. Inclusion complexation can greatly increase the
chemical stability of labile drugs in multilamellar liposomes.
Microspheres
In the presence of a high percentage of highly soluble hydrophilic excipients,
complexation may not improve the drug dissolution rate from microspheres. Study of in
vivo release behavior (over 24 hours) of β-CDfrom β-CD/poly (acrylic acid) (PAA)
microspheres, prepared by a water/oil solvent evaporation technique, and indicated a high
encapsulating efficiency (990%) with potential covalent binding of the CD.176
Microcapsules
It was suggested that cross linked β-CD microcapsules, because of their ability to
retard the release of water-soluble drugs through semi permeable membranes, can act as
release modulators to provide efficiently controlled release of drugs.
Nanoparticles
Nanoparticles are stable systems suitable to provide targeted drug delivery and to
enhance the efficacy and bioavailability of poorly soluble drugs. However, the safety and
efficacy of nanoparticles are limited by their very low drug loading and limited
entrapment efficiency (with classical water emulsion polymerization procedures) that
may lead to excessive administration of polymeric material.177, 178
Two applications of CDs have been found very promising in the design of
nanoparticles: one is increasing the loading capacity of nanoparticles and the other is
spontaneous formation of either nanocapsules or nanospheres by nanoprecipitation of
amphiphilic CDs diesters.
Both the new techniques were reported to be useful due to great interest of
nanoparticles in oral and parenteral drug administration. CDs increased the loading
capacity of poly (isobutylcyanoacrylate) nanoparticles. The increased loading capacity
was reported to be a result of increased drug concentration in the polymerization medium
on addition of the drug: CD complex and increased number of hydrophobic sites in the
nanosphere structure on association of large amounts of CDs to the nanoparticles.178, 179
It was indicated that during nanoparticle formation the free drug gets
progressively incorporated into polymer network, driven by the drug partition coefficient
between the polymer and polymerization medium though there may be a simultaneous
direct entrapment of some drug/CD complex.179, 180
Compared with natural CDs, β-CDs, particularly those derivatives with 6C
aliphatic chains on the primary face, form biodegradable, nonsurfactant, highly loaded
nanospheres and nanocapsules with low hemolytic activity.177,181,182 The their ability to
nanoassociate or form stable nanospheres.
The amount of partially acylated species in β-CDsa was also found to play an
important role in regulating the mean diameter size and suspension stability of
nanospheres.183 The β-CDa derivatives formed inclusion complexes with the drugs and
with the nanoprecipitation technique the derivatives gave nanospheres of less than 300
nm with no use of surfactants. Loading techniques and also the type of β-CDa can
influence the loading and release properties of the nanospheres.
CD USE AS EXCIPIENTS IN DRUG FORMULATION:
As excipients, CDs have been finding different applications in the formulation
and processing of drugs. Β-CD, due to its excellent compactability (varied with source)
and minimal lubrication requirements, showed considerable promise as a filler binder in
tablet manufacturing but its fluidity was insufficient for routine direct compression.
Β-CD was also found to be useful as a solubility enhancer in tablets. The ability
of β-CD to complex progesterone by wet granulation was found to be dependent on both
binder solution and mixture type.184 Complexation can cause subtle changes in the
tabletting properties of drugs or CDs that can substantially affect the stability and
tabletting performance of tablet formulations containing drug/CD complexes.
CDs also affect the tabletting properties of other excipients, eg, microcrystalline
cellulose codried with β-CD showed improved flowability, compactability, and
disintegration properties suitable for direct compression.185
In the case of high-swelling wheat starches, β-CD (1%) increased the peak
viscosity (PV) but decreased the cool paste viscosity (CPV) and in the case of low
swelling starches, the same CD slightly decreased the PV but increased the CPV.
However, β-CD reduced the heat paste viscosity of both the starches.186
CDs were used as pellatization agents in extrusion and spheronization processes
and in the presence of β-CD up to 90% by weight, the process provided satisfactory
products.187 CDs were also indicated to stabilize protein and peptide pharmaceuticals
during spray drying.
SBE- and HPderivatives of β- and α-CDs, with different total degree of
substitution (TDS), exhibited different colligative properties, especially their osmotic
pressure (OP) increased with their TDS. With substituted CDs, the OP was above their
theoretical values but with unsubstituted γ-CD, the OP was below the expected value.
Self-association of the unsubstituted γ-CD molecules was reported to be the possible
reason for the observed low OP value of the CD.
These findings relating the OP properties of CDs can be useful in the formulation
of parenteral and ophthalmic solutions, where maintenance of OP is an important
consideration.188
Interaction of CDs with the preservatives in the formulation is an important factor
and should be investigated. It was reported that such interaction can result in reduction of
both the solubilizing effect of CD and the antimicrobial activity of preservatives, e.g.,
interaction of HP-β-CD with preservatives like benzalkonium chloride, chlorhexidine
gluconate, chlorambutanol, methylparaben, and propylparaben.189
Methods for detection of inclusion complex formation and Determination of
complex stability constant
One of the most interesting properties of CDs is their ability to form inclusion
complexes with a wide variety of guest molecules. Molecular encapsulation may occur
both in solution and solid state. In solution there is equilibrium between complexed and
non complexed guest molecules, in solid state guest molecules can be enclosed within
the cavity or may be aggregated to the outside of CD molecule190. Upon inclusion within
the CD cavity a guest molecule experiences changes in its physico-chemical properties.
These changes provide method to detect whether guest molecules are really included in
the in the CD cavity
Detection inclusion complexation in the solution state
Detection of inclusion complexation in solution states can be done by
spectroscopic methods like UV/VISIBLE, Fluorescence, circular dichroism, ESR, NMR,
methods. The 1H-NMR and 13

C-NMR spectroscopic studies can also be used to
determine the direction of penetration of the guest molecules into the CD cavity. Other
methods include Polarography, conductivity measurement, Microcalorimetry and
Solubility methods191. Phase solubility technique 192 is one of the widely used methods to
detect the inclusion complexation in solution state.
The general experimental operation in studying molecular interaction by means of
phase solubility methods entails the addition of an equal weight (inconsiderable excess of
its normal solubility) of a slightly soluble compound, S (substrate or guest) into each of
several vials containing increasing concentrations of a relatively soluble compound, L
(ligand or host or complex agent), which are closed and brought to solubility equilibrium
at constant temperature. The solution phases are then analyzed, by any suitable means,
for their total concentration of compound S (guest), no matter what its molecular state
may be.
A phase diagram is constructed by plotting, on the vertical axis, total molar
concentration of S found in the solution phase against the molar concentration of L.
Figure No. 4. Theoretical phase solubility diagram
The phase diagrams (Fig 4) are observed to fall into two main classes, type A and
type B with some variation within the classes.
The type A can be further classified in sub types AL , AP and AN, where the guest
solubility of first type increases linearly with CD concentration while those of second and
third type deviate positively and negatively, respectively from the straight line. The
complex formation with a 1:1 stoichiometry gives the AL type diagram where as the
higher order complex formation in which more than one CD molecules are involved in
the complexation gives the AN-type is complicated, because of a significant contribution
of solute-solvent interaction of the complexation. In the case of the Bs type, the initial
ascending portion of the solubility change is followed by a plateau region and then a
decrease in the solubility at higher CD concentration accompanying a microcrystalline
precipitation of the complex. The HP-type diagram is indicative of the formation of
insoluble complexes in water.
The stability constant (Ks) and stoichiometry of complexes are determined by
analyzing quantitatively the phase solubility diagram.
Detection of inclusion complexation in the solid state
Detection of the inclusion complexation in solid state can be done by powder X-ray diffractometry, single
crystal X-ray structure analysis, thermo analytical, thin layer chromatography, Paper chromatography, IR spectroscopy,
Scanning electron microscopy and Dissolution study methods40.
CDs, as a result of their complexation ability and other versatile characteristics, are continuing to have
different applications in different areas of drug delivery and pharmaceutical industry.
However, it is necessary to find out any possible interaction between these agents and other formulation
additives because the interaction can adversely affect the performance of both.
It is also important to have knowledge of different factors that can influence
complex formation in order to prepare economically drug/CD complexes with desirable
properties.
Since CDs continue to find several novel applications in drug delivery, we may
expect these polymers to solve many problems associated with the delivery of different
novel drugs through different delivery routes.
Objectives of the study:
• To perform preformulation studies like, solubility of a drug in water, Blend of water
glycerin and water SLS etc.
• To carry out the Phase solubility study of Gliclazide with HP-β-CD.
• To formulate the inclusion complexes of Gliclazide with HP-β-CD in a different ratios.
• To formulate the inclusion complexes by different methods,(Physical and Kneading
methods).
• To perform compatibility studies using FTIR, DSC and XRD.
• To perform the characterization studies like Drug content, in - Vitro Dissolution studies
and Dissolution parameters of inclusion Complexes.
• To perform the characterization studies of Tablets like Weight variation, Friability test,
Hardness test and Disintegration time.
• To ascertain the release mechanism and kinetics of drug release from tablets.
• To perform the stability studies of Tablets as per ICH guidelines.
REVIEW OF LITERATURE
PROFILE OF DRUG AND EXCIPIENT
Drug Profile:
GLICLAZIDE:
Gliclazide is a second generation sulfonylurea oral hypoglycemic agent, widely used for
the treatment of non insulin dependent diabetes mellitus.
Definition: Gliclazide contains not less than 99.0 per cent and not more than the
Equivalent of 101.0 per cent of 1-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-[(4-
methylphenyl)sulphonyl]urea, calculated with reference to the dried substance.
Chemical Name : 1-(3-azabicyclo [3.3.0] oct-3-yl)-3-p-tolylsulphonylurea.
Molecular Formula : C15H21N3O3S
Molecular Weight : 323.42
Melting point : 180 - 182oC
Structural Formula:
Gliclazide
Action and use: Inhibition of ATP-dependent potassium channels (sulfonylurea);
treatment of diabetes mellitus.
Characters
Appearance : White or almost white powder.
Solubility : Practically insoluble in water, freely soluble in methylene
Chloride, sparingly soluble in acetone, slightly soluble in ethanol
(96 per cent).
Assay : Dissolve 0.250 g in 50 ml of anhydrous acetic acid R.
Titrate with 0.1 M perchloric acid, determining the end-
Point potentiometrically.1ml of 0.1 M perchloric acid is
equivalent
To 32.34 mg of C15H21N3O3S.
Storage : In an airtight container, protected from light.
Pharmacokinetics
Absorption, Fate, and Excretion.
The sulfonylurea has similar spectra of activities; thus, their pharmacokinetic
properties are their most distinctive characteristics. Although there are differences in the
rates of absorption of the different sulfonylureas, all are effectively absorbed from the
gastrointestinal tract. However, food and hyperglycemia can reduce the absorption of
sulfonylureas. (Hyperglycemia per se inhibits gastric and intestinal motility and thus can
retard the absorption of many drugs.) In view of the time required to reach an optimal
concentration in plasma, sulfonylureas with short half lives may be more effective when
given 30 minutes before eating. Sulfonylureas in plasma are largely (90 to 99%) bound to
protein, especially albumin. The volumes of distribution of most of the sulfonylureas are
about 0.2 liter/kg.
The first generation sulfonylureas vary considerably in their half lives and extents
of metabolism. The second generation agents are approximately 100 times more potent
than are those in the first group. Although their half lives are short (3 to 5 hours), their
hypoglycemic effects are evident for 12 to 24 hours, and it is often possible to administer
them once daily. The reason for the discrepancy between the half life and duration of
action of these drugs is not clear.
All of the solfonylureas are metabolized by the liver, and the metabolites are
excreted in the urine. The solfonyluraes should be administered with caution to patient
with either renal or hepatic insufficiency.
Dose: For treating type 2 diabetes:
Adults- 80 milligrams (mg) a day with a meal as a single dose or 160 to 320 mg
divided into two doses taken with the morning and evening meals.
Children- The type of diabetes treated with this medicine is rare in children. However, if
child needs this medicine, the dose would have to be determined by the doctor.
Mechanism of action
Sulfonylureas lower blood glucose in patients with type 2 diabetes by directly
stimulating the acute release of insulin from functioning beta cells of pancreatic islet
tissue by an unknown process that involves a sulfonylurea receptor on the beta cell.
Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and
potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin
binding, kinase activation, and release of insulin-containing granules by exocytosis, an
effect similar to that of glucose. Insulin is a hormone that lowers blood glucose and
controls the storage and metabolism of carbohydrates, proteins, and fats. Sulfonylureas
are effective only in patients whose pancreas is capable of producing insulin.
With chronic sulfonylurea treatment, insulin production is not increased and may
return to pretreatment values, but insulin efficacy continues and is thought to involve
extrapancreatic mechanisms to increase insulin sensitivity in target tissues, such as liver,
muscle, and fat as well as in other cells, such as monocytes and erythrocytes. This can
result in a decrease in hepatic glycogenolysis and gluconeogenesis. It is unclear if the
sulfonylurea's extrapancreatic actions that increase insulin's efficacy are direct or indirect
effects, but it is clear that the mechanism of action is not due to a direct sulfonylurea
action on the insulin receptor. Because this peripheral effect is not apparent in patients
with type 1 diabetes, the evidence suggests that this may not be the clinically significant
mechanism of sulfonylurea action in patients with type 2 diabetes either. However, it is
clear that tissues of sulfonylurea-treated patients with type 2 diabetes become more
responsive to lower concentrations of endogenous insulin. Primary failure of sulfonylurea
therapy may occur if beta-cell function is severely impaired. In addition to stimulating
insulin secretion through the beta cell–sulfonylurea receptor, gliclazide may have a direct
effect on intracellular calcium transport that specifically improves the biphasic response
of the beta cell to a meal, that is, the immediate first phase of insulin release.
Adverse Reactions
Sulfonylureas may cause hypoglycemic reactions, including coma. This is particular
problem in elderly patients with impaired hepatic or renal function who is taking longer
acting sulfonylurea.
Other side effects of sulfonylureas include nausea and vomiting, cholestatic jaundice,
agranulocytosis, aplastic and hemolytic anemia, generalized hypersensitivity reactions,
and dermatological reactions.
Therapeutic uses.
Sulfonylureas are used to control hyperglycemia in type 2 diabetes mellitus patients who
cannot achieve appropriate control with changes in diet alone. Patients with type 2 DM
whose disease is controlled with relatively low doses of insulin (less than 40 U per day)
are more likely to respond to sulfonylureas.
Contraindications to the use of these drugs include type 1 DM, pregnancy, lactation, and
significant hepatic or renal insufficiency.
Excipients Profile:
Hydroxypropyl β-Cyclodextrin
Synonyms: 2-hydroxypropyl β-Cyclodextrin.
Functional category: Solubilizing and stabilizing agents.
Molecular weight: 1548
Structural formula:
Where, R= CH2CH (OH) CH3 or H
Description: White crystalline powder.
Solubility: Greater than 1 in 2 parts of water at 25°C.
Stability and storage conditions: Are stable in the solid state if protected from high humidity. It should be stored in a tightly
sealed container, in a cool and dry place.
Incompatibilities: The activity of some antimicrobial preservatives in aqueous solution
can be reduced in the presence of hydroxypropyl β-Cyclodextrin.
¾ Patel VP, Patel NM, Chaudhary BG investigated the effect of complexation of
glipizide, a practically insoluble antidiabetic drug, with cyclodextrin in presence
of different concentration of water soluble polymers (HPMC,PVP,PEG 4000 and
PEG 6000) on the dissolution rate of the drug. The dissolution rate of the drug
from ternary systems containing PEG 4000 or PEG 6000 seems to be generally
higher than from systems containing HPMC or PVP. The dissolution rate of the
drug from the ternary systems glipizide-HP-β-cyclodextrin-5% PEG 4000 was
high compare to the other systems193.
¾ Doijad RC, Kanakal MM and Manvi FV investigated influence of processing

variables on the solid-state of a model drug, piroxicam in cyclodextrin-based
system and its effect on dissolution behaviour of drug. The complex prepared by
co-evaporation method with hydroxy propyl β-cyclodextrin and was found to
yield better dissolution rate and stability194.
¾ Seoung Wook Jun, Min-Soo Kim prepared the inclusion complexes of insoluble
drug simvaststin (SV),with HP-β-cyclodextrin using a supercritical antisolvent
(SAS) process he complexes were investigated to improve the aqueous solubility
and the dissolution rate of drugs .Inclusion complexation in aqueous solution and
solid state was evaluated by the phase solubility diagram, DSC, PXRD, FTIR and
SEM. FTIR study demonstrated that the presence of intermolecular hydrogen
bonds between SV and HP-β-cyclodextrin in inclusion complex, resulting in the
formation of amorphous form. Aqueous solubility and dissolution studies
indicated that the dissolution rates were remarkably increased inclusion complex,
compared with the physical mixture and pure drug195.
¾ Deshmukh SS, Potnis VV, Shelar DB made an attempt to prepare and
characterized inclusion complexes of ziprasidone hcl with β-cyclodextrin and HP-
β-cyclodextrin. The phase solubility analysis indicated that the formation of 1:1
molar inclusion complex of a drug with β-cyclodextrin and HP-β-cyclodextrin.
The inclusion complexes were prepared co-precipitation, kneading and
microwave method. The prepared complexes were characterized using solubility
study, DSC and XRD. The inclusion complexes prepared with HP-β-
cyclodextrins by microwave method exhibited greatest enhancement in solubility
and fastest dissolution of ziprasidone HCl196.
¾ Tayade PT, Vavia PR prepared ketoprofen cyclodextrins solid systems by

kneading, co-evaporation and freeze drying. The formation of inclusion
complexes with β-cyclodextrins and HP-β-cyclodextrins in the solid state, were
confirmed by DSC, FT-IR, powder X-ray diffractometry, SEM studies and
comparative studies on the in-vitro dissolution and in-vivo absorption of
ketoprofen in human volunteers were carried out .the dissolution rate of
ketoprofen in the inclusion complexes was 15 fold higher, than that of plain drug
powder197.
¾ Chowdary KPR and Vijay Srinivas studied the effect of polyvinyl pyrrolidone on
complexation and dissolution rate of β-and hydroxypropyl β-cyclodextrin
complexes of celecoxib and were markedly enhanced the solubility and
dissolution rate by complexation with β-cyclodextrin and hydroxypropyl β-
cyclodextrin. Solid inclusion complexes of cyclodextrin with polyvinyl
pyrrolidone gave several times higher rates of dissolution than those of celecoxib
and its complexes with cysclodextrin alone.198
¾ Deelip Derle, Sai Hanuman Sagar Boddu and Manoj Magar prepared complexes
of satranidazole inclusion complexes with β -CD. The solid complex prepared by
kneading method was characterized using differential scanning calorimetry,
powder X-ray diffractometry. In vitro study showed that the solubility and
dissolution rate of satranidazole was significantly improved with β-CD.199
¾ Monique WJ den Brok et al. studied the potency of the commercially available
and used cyclodextrins, 2-HP-β-cyclodextrin to extract the preservative 2-Phenyl
Phenol (2PP) from platinum cured silicon tubing the presence of 2PP was
structurally confirmed with HPLC-UV and LC/MS/MS in HP-β-cyclodextrins
solutions after incubation with platinum cured silicone tubing. HP-β-cyclodextrins
concentration and prior tubing sterilization were found not to influence the levels
of 2PP 200.
¾ Nagesh Bandi and Uday B Kompella had determined whether budesonide and
indomethacin HPβ-CD complexes could be formed using a supercritical fluid
process. The process involved the exposure of drug-HPβ-CD mixtures to
supercritical carbon dioxide. The ability of supercritical fluid process to form
complexes was assessed by determining drug dissolution, drug crystallinity and
drug excipients interactions. Thus budesonide and indomethacin HPβ-CD
complexes with enhanced dissolution can be formed using a single step organic
solvent free SCF process.201
¾ Sunil Jambhekar, Casella R and Maher T made an effort to improve the
bioavailability of the insoluble drug indomethacin. Three complexes were
prepared with indomethacin and the soluble complexing agents (β-, hydroxyethyl-
β- and hydroxyl propyl-β-cyclodextrin). Phase solubility analysis confirmed the
formation of complexes and suggested the three complexes were found similarly.
Solubility studies show complexation increase indomethacin solubility. The
bioavailability studies were performed by administering the indomethacin
complex or Indocin capsule to male-ablino, New Zealand rabbits. Hence, it was
observed that the bioavailability of indomethacin was improved by complexation
with only β-cyclodextrins

¾
Indap MA et al. have prepared inclusion complexes of quercetin with
hydroxypropyl β-cyclodextrin in 1:5 molar ratios. The maximum tolerated dose
corresponding to the Ld10 was >400 mg/Kg of hydroxypropylβcyclodextrins
complex of quercetin obtained after single intraperitoneal application which
proved to be less toxic than quercetin. There was no apparent toxicity to bone
marrow of irradiated Swiss mice. Previously administered HPBC complex of
quercetrin. The ability to selectively target quercetin via its cyclodextrins
inclusion complex against cancer growth could improve the therapeutic
effectiveness of cyclodextrins preparation as well as reduce adverse effect
associated with quercetin.203

¾
Mourya VK, Saini TR et al. have prepared molecular inclusion complex of
hydroxypropyl β-cyclodextrin with Sparfloxacin. The 1:1 stiochemistry of the
components is suggested by phase solubility studies and Benesi-Hildebrand Plot.
Stability constant evaluated by phase solubility analysis and Benesi-Hildebrand
plot showed deviations. The complex displayed enhanced aqueous solubility and
dissolution.204
¾ Tayade NG and Nagarsenker MS have prepared inclusion complexes of
susquiterpene lactone with hydroxypropyl β-cyclodextrin in 1:1 ratio, the drug in
cyclodextrin when administered orally to the mice infected with plasmodium
yoelli, improved antimalarial activity in terms of increase mean survival time
(MST) and percent inhibition in parasitaemia was observed suggesting in-vivo
advantage.205
¾ Raida S. Al-Kassas et.al. This work investigates preparation of
biodegradable beads with alginate polymer by ionotropic gelation method to
take the advantages of the swelling and mucoadhesive properties of alginate
beads for improving the oral delivery of the antidiabetic agent gliclazide. It
demonstrates that the ionic gelation of alginate molecules offers a flexible
and easily controllable process for manipulating the characteristics of the
beads which are important in controlling the release rate and consequently
the absorption of gliclazide from the gastrointestinal tract. The in vitro
release experiments revealed that the swelling is the main parameter
controlling the release rate of gliclazide from the beads. In vivo studies on
diabetic rabbits showed that the hypoglycemic effect induced by the
gliclazide loaded alginate beads was significantly greater and more
prolonged than that induced by the marketed conventional gliclazide tablet.
The results clearly demonstrated the ability of the system to maintain tight
blood glucose level and improved the patient compliance by enhancing,
controlling and prolonging the systemic absorption of gliclazide.206
¾ S Biswal et.al. The present study was to characterize gliclazide solid
dispersions (SDs) prepared with polyethylene glycol (PEG) 8000 and
compare them with SDs in PEG 6000. Gliclazide SDS containing varying
concentrations of PEG 8000 was prepared using the fusion – solvent
technique, and their phase solubility behavior and dissolution in 0.1N HCl
were assessed at 37 oC. The solubility of gliclazide increased with
increasing amount of PEG 8000 in aqueous medium. Gibbs free energy
values were all negative, indicating the spontaneous nature of Gliclazide
solubilisation. Dissolution studies indicated a significant increase in the
dissolution of gliclazide when dispersed in PEG 8000. FTIR analysis
demonstrated the absence of well-defined gliclazide - PEG 8000 chemical
interaction while DSC and XRD studies indicated the amorphous
microcrystalline state of gliclazide in the SDs207.
¾ Hussien Allaboun et. al. studied to improve dissolution rate of gliclazide
using anionic and cationic surfactants. The intrinsic dissolution rates of
gliclazide in solutions of sodium dodecyl sulfate (SDS) and in solutions of
tetradecyltrimethyl ammonium bromide (TDTMAB) were measured using
the rotating disk method to study the convective diffusion transport of drug-
loaded micelles. Two different approaches were applied to the experimental
data; the convective diffusion model and the film equilibrium model. The
two approaches are based on the same fundamental assumptions differing
only in their interpretation of the diffusional boundary layer. The results
obtained from the film equilibrium model were less satisfactory, and in case
of TDTMAB the model was inapplicable (negative diffusion coefficient).
While excellent results were obtained from the convective diffusion 252
model.208
¾
Roya Talari et.al. The present study is to use in situ micronization process
through pH change method to produce micron-size gliclazide particles for
fast dissolution hence better bioavailability. Gliclazide was recrystallized in
presence of 12 different stabilizers and the effects of each stabilizer on
micromeritic behaviors, morphology of microcrystals, dissolution rate and
solid state of recrystallized drug particles were investigated. The results
showed that recrystallized samples showed faster dissolution rate than
untreated gliclazide particles and the fastest dissolution rate was observed
for the samples recrystallized in presence of PEG 1500. Some of the
recrystallized drug samples in presence of stabilizers dissolved 100% within
the first 5 min showing at least 10 times greater dissolution rate than the
dissolution rate of untreated gliclazide powders.209
¾ Gopal Venktesh Shavi et.al. Study was aimed to formulate solid dispersions
using different water soluble polymers such as polyethylene glycol 4000
(PEG 4000), polyethylene glycol 6000 (PEG 6000) using fusion method and
polyvinyl pyrrolidone K- 30 (PVP K 30) by solvent evaporation method.
The interaction of gliclazide with the hydrophilic polymers was studied by
Differential Scanning Calorimetry (DSC). Pharmacokinetic studies of
optimized formulation were compared with pure drug and marketed
formulation in wistar rats. It was observed that there is a twofold increase in
peak plasma concentration compared to pure drug.210
METHDOLOGY
The solubility, stability and therapeutic efficacy of drugs are closely related to
their physicochemical properties and those of vehicles or carriers used along them. The
dissolution rate of drug from its dosage form is considered as an important parameter in
bioavailability, dissolution is the rate limiting step in the absorption of poorly water
soluble drugs from its dosage forms.
Various intermolecular forces such as Vander Waals forces, ion-dipole and non-
induced dipole forces, hydrogen bonding, crystal lattice interactions etc. between the drug
and vehicle, affect the drug solubility and dissolution rate. By selecting suitable
excipients in proper proportion, drugs stability and desired dissolution rate can be
achieved. The dissolution rate of drug from its dosage form is considered as an important
parameter in bioavailability.
Cyclodextrins (CDS) are cyclic oligosaccharides contains six (α-cyclodextrin)
seven (β-cyclodextrin) or eight (γ-cyclodextrin) α-1, 4 linked glucopyranose units with
hydrophilic outer surface and a hydrophobic cavity . CDS are capable of forming
inclusion complexes with many drugs by taking up a whole drug molecule or part of it,
into the CDs cavity. Such molecular encapsulation will affect many of the
physicochemical properties of drugs such an aqueous solubility and rate of dissolution.
Among the various approaches, preparation of inclusion complexes with cyclodextrin has
proven to be successful in enhancing the solubility of poorly water soluble drugs.
Gliclazide is second generation hypoglycemic sulfonylurea which is useful in the
treatment of type 2 diabetes mellitus and has its poor aqueous solubility5. This limits
several advantages of the drug with respect to its absorption, distribution and therapeutic
efficacy. Hence in the present work cyclodextrin inclusion complexes of Gliclazide will
be prepared to enhance its solubility and dissolution rate
• To perform preformulation studies like, solubility of a drug in water, Blend of water
glycerin and water SLS etc.
• To carry out the Phase solubility study of Gliclazide with HP-β-CD.
• To formulate the inclusion complexes of Gliclazide with HP-β-CD in a different ratios.
• To formulate the inclusion complexes by different methods,(Physical and Kneading
methods).
• To perform compatibility studies using FTIR, DSC and XRD.
• To perform the characterization studies like Drug content, in - Vitro Dissolution studies
and Dissolution parameters of inclusion Complexes.
• To perform the characterization studies of Tablets like Weight variation, Friability test,
Hardness test and Disintegration time.
• To ascertain the release mechanism and kinetics of drug release from tablets.
• To perform the stability studies of Tablets as per ICH guidelines.
A) Materials
Table No.7: Materials and their Sources
Materials Sources
Gliclazide Wallace Pharmaceuticals Pvt.Ltd, Goa.
Hydroxypropyl β-Cyclodextrin Gangwal Chemicals Pvt. Ltd., Mumbai
Potato starch Gangwal Chemicals Pvt. Ltd., Mumbai
Microcrystalline cellulose S.D. Fine chem.
Lactose S.D. Fine chem.
Talc S.D. Fine chem.
Magnesium stearate S.D. Fine chem.
* All the materials were used as procured; without further purification.
* All the other solvents and reagents used for the study were of Analytical Reagent grade.
Table No. 8: Equipments and their sources
Equipments Sources
Dissolution test apparatus Electrolab, USP XXIV
UV Visible spectrophotometer U.V. – 1800, Shimadzu
FTIR Spectrophotometer 8400s, Shimadzu
Differential Scanning Calorimeter Mettler Toledo
Hot air Oven M.C. Dalal and Co., Chennai
Digital Balance Citizen
Gyratory Flask Shaker Remi Electrical
Sieve 100 mesh Indicot India
Glassware Borosil (A) – grade
Tablet Punching Machine (Pilot Press

Chamuda Pharma, Ahemadabad
10 Station)
Stability Chamber Osworld, IRIC-11
Friability Tester Electrolab, USP EF-2
Hardness Tester Monsanto
Digital pH meter Italy(H96107)
Vernier caliper Pico India Ltd.
Analytical method and its Validation.
Methods for the estimation of Gliclazide:
A spectrophotometric method based on the measurement of absorbance at
227nm in phosphate buffer of pH 7.4 was used in the present study for the estimation of
gliclazide.
Reagents:
Phosphate buffer of pH 7.4:
Phosphate buffer of pH 7.4 was made by dissolving 6.8gm of potassium
dihydrogen ortho phosphate and 1.5gm of sodium hydroxide in 1000ml with distilled
water. The pH was adjusted to 7.4.
Standard solution:
10mg of gliclazide was dissolved in methanol in 25ml volumetric flask and the
solution was made up to the volume with methanol.
Procedure:
The standard solution of gliclazide was subsequently diluted with phosphate buffer
of pH 7.4 to obtain series of dilutions containing, 10,20,30,40, and 50µg of gliclazide per
ml of solution. The absorbance of the above dilutions was measured in Elico-UV-Visible
spectrophotometer at 227nm using phosphate buffer of pH 7.4 as blank. The
concentration of Glicazide and corresponding absorbance were given in Table 10. The
absorbance values were plotted against concentration of Glicazide as show in Figure 5.
Validation:
The method was validated for linearity, precision and accuracy. The method
obeyed Beer’s law in the concentration range of 0-50µg/ml, when standard drug solution
was assayed repeatedly (n=6), the mean error (accuracy) and relative standard deviation
(precision) were found to be 0.7 and 0.9% respectively. No interference from excipients
used was observed. Thus method was found suitable for the estimation of gliclazide
content in dissolution fluids. Calibration curve shown in fig: was used for the purpose.
Melting Point:
The melting point of gliclazide was determined by conventional melting point apparatus.
Solubility of Gliclazide.
Solubility of gliclazide in water, the effect of pH (4, 6, 7.4,8 and9) and blend of
water with cosolvents (alcohol, glycerin) and surfactant (SLS) in different concentrations
(0.5%, 1%, 2%, 3%, 4% and 5%) the aqueous solubility of gliclazide was determined.
10mg amount of gliclazide was added to 10ml of distilled water, different pH and blend
of water with cosolvents and solvent respectively in a stoppered conical flasks. The
mixtures were frequently shaken for 1 hour and filtered using wattman filter paper. The
aliquots were diluted suitably and assayed for gliclazide by UV spectrophotometer
(SHIMATZU 1700) at 227 nm. against blanks prepared in the same concentration of
water, pH solutions and different concentrations of co-solvents and solvents respectively
so as to cancel any absorbance that may be exhibited by water, pH and a blend of co-
solvents, solvents. The solubility experiments were conducted in triplicate and calculated
mg/ml.
Phase solubility studies.
The phase-solubility technique permits the evaluation of the affinity between HP-β
CD and gliclazide in water. Phase solubility studies were performed according to the
method reported by Higuchi and Connors192. Gliclazide, in amounts that exceeded its
solubility, was taken in to 25ml stoppered conical flasks to which were added 15 ml of
distilled water containing various concentrations of HP-β-cyclodextrin (1-15 mM). These
stoppered conical flasks were shaken for 48 hours at room temperature on a rotary
shaker. This amount of time is considered sufficient to reach equilibrium. Subsequently,
the aliquots were withdrawn (2 ml), using a syringe at 12 hours intervals, and samples
were filtered immediately by using wattman filter paper and diluted suitably. A portion of
a sample was analyzed by UV spectrophotometer (SHIMATZU 1700) at 227 nm against
blanks prepared in the same concentration of HP-β-cyclodextrin in water so as to cancel
any absorbance that may be exhibited by the HP-β-CD. Shaking was continued until 3
consecutive estimations were equivalent. The solubility experiment was conducted in
triplicate. The apparent stability constant (Kc) according the hypothesis of 1:1
stoichiometric ratio of complexes was calculated from the phase-solubility diagrams
using the following equation1.
K1:1 = Slope / So (1- Slope)
The slope is obtained from the initial straight-line portion of the plot of gliclazide
concentration against HP-β-CD concentration, and So is equilibrium solubility of
gliclazide in water.
Thin layer chromatography (T L C).
The stability study of the drug in the formulation was confirmed by thin layer
chromatography analysis. The TLC studies were carried out on Aluminium preparative
sheets using Methanol: Trimethylamine: water: Acetronitrile (20:65.9:15) as developing
solvent (mobile phase) and dil, sulphuric acid as spraying solution. The standard TLC
plates are used. The plates were spotted with pure gliclazide in methanol at about 2 cm
above from the bottom as standard. The sample (Gliclazide +HP-β-cyclodextrin) in
methanol were spotted adjacent to the pure gliclazide spot at a distance of 2 cm, the plate
was kept in an enclosed chamber saturated previously with mobile phase solvent system.
The solvent was allowed to rise on the plate to a sufficient level (⅔). The distance
travelled by solvent front was noted. The distance travelled by the solute was determined.
The Rf value was calculated for both the standard and sample, using the following
formula.
Rf Value = Distance travelled by solute / Distance travelled by mobile
solvent.
Rf value of Gliclazide= 0.781
Rf value of Gliclazide-HPβ-CD=0.842
IR Spectral Analysis:
The compatibility between drug and the formulation components were confirmed by
IR Spectral studies. The IR Spectra were recorded using mulling agent KBr pellets. The
IR spectrum of gliclazide and gliclazide-HP-β-CD is shown in Fig.7&8. The IR
spectroscopy was conducted using a Shimadzu FTIR 8400 spectrophotometer and the
spectrum was recorded in the wavelength region of 4000 to 400 cm-1. The procedure
consists of dispersing a sample (pure drug alone and drug-CD in different ratio of mM
complexes) in KBR and compressing in to disc / film by applying a pressure of 8 Tunes
for 5 min hydraulic press. The pellet was placed in the light and the spectrum was
obtained.
Differential Scanning Calorimetry (DSC):
DSC thermograms of the gliclazide, HP-β-cyclodextrin and solid complex
prepared by kneading method and physical mixtures were recorded on NETZSCH DSC
204 METTLER STARe Model. Samples (2-5 mg) were sealed in to aluminum pans and
scanned at a heating rate of 100c min-1 over a temperature range 30-3000c under a
nitrogen gas stream. The DSC thermograms are shown in fig.9&10.
X-ray Diffractometry:
X-ray powder diffraction patterns were recorded using a Phillips model powder
diffractometer with monochromatized Cu-Kα radiation. The solid inclusion complexes of
gliclazide HP-β-CD prepared by kneading method and physical mixtures were scanned at
room temperature in the continuous scan mode over the 50-500 2θ range with 0.1 2θ step
size and with counting time of 0.6 sec. The X-ray diffractograms are shown in
figs.11&12.
Preparation of Gliclazide-HP-β-CD Complex.
Kneading Method:
HP-β-cyclodextrin (1 mM) and distilled water (1.5 ml) were mixed together in a
mortar so as to obtain a homogeneous paste. Gliclazide (2 mM) was then added slowly.
The mixture was then kneaded for 45 min. During this process, an appropriate quantity of
water was added to the mixture in order to maintain a suitable consistency. The paste was
then dried in oven at 700C for 1-2 hours. The dried complex was milled and passed
through sieve no. 100. The same procedure was used to prepare a formulation of
gliclazide-HP-β-CD complexes in different mM ratios.
Physical mixture:
Gliclazide with HP-β-CD in different molar ratios (1:2M) were mixed in a mortar
for about one hour with constant trituration, passed through sieve No. 80 and stored in
desiccators over fused calcium chloride. The same procedure was used to prepare a
formulation of gliclazide-HP-β-CD complexes in different mM ratios.
Estimation of Drug Content.
The gliclazide content in the inclusion complex was estimated by UV
spectrophotometric (SHIMADZU 1700) method. The method was validated for linearity,
accuracy and precision. A sample of gliclazide-HP-β-CD complex equivalent to 100 mg
was dissolved with 25 ml methanol in a 100 ml volumetric flask, and the volume was
adjusted up to 100ml by using phosphate buffer of pH 7.4. The solution was filtered
through Wattman filter paper. The filtrate was assayed for drug content by measuring the
absorbance at 227 nm after suitable dilution, against phosphate buffer of pH 7.4 as blank.
Then the amount of gliclazide in the complex was calculated as % yield (% yield =
practical yield / theoretical yield x 100), mean drug content and weight equivalent to 100
mg of drug is estimated. The same procedure was used to estimate drug content of
gliclazide-HP-β-CD complexes in different mM ratios.
IN-VITRO Drug release from inclusion complex.
Drug release was studied by using USP-Thermo Lab eight station dissolution test
apparatus in phosphate buffer solution of pH 7.4. The test sample of drug-HP-β-CD
complex (100 mg equivalent to pure drug in complex) was tightened in a muslin bag with
a paddle stirrer, which rotates at a speed of 50 rpm, the temperature of water bath, was
maintained 370C ± 0.50C throughout the experiment. 5 ml aliquot of dissolution medium
was withdrawn at a specific time intervals and replaced with 5 ml fresh medium of
phosphate buffer solution of pH 7.4 to maintain sink condition. The withdrawn sample
was filtered through wattman filter paper, after suitable dilutions with phosphate buffer
solution of pH 7.4 the absorbance was determined by using UV spectrophotometer
(SHIMADZU 1700) at 227 nm against blank (phosphate buffer solution of pH 7.4). The
absorbance was recorded. The release of pure drug was also studied to compare with
release of drug from complexes. All studies were conducted in triplicate; the average data
obtained were computed for further calculations.
Formulation of Gliclazide-HP-β-CD tablets.
Gliclazide-HP-β-CD Tablets were prepared by two methods, wet granulation and
direct compression. In wet granulation method, the weighed quantities of gliclazide, HP-
β-CD ,MCC and ½ portion of potato starch (dry) were mixed in geometric ratios in
mortar, to which alcohol : water (1:1 ratio)containing 0.5% PVP were added and mixed
to get a lumps, the lumps were passed through sieve no 12, to get granules. These
granules were dried at 600c for 2-4 hours in a oven until they dry. To the dried granules,
remaining ½ portion of potato starch (dry), talc and magnesium stearate were added and
passed through sieve no 14. These granules were punched in to tablets (8 mm punch) by
using Rimek mini press 10 station rotary tablet punching machine. In direct compression
method, drug and all other ingredients were mixed in geometric ratio in mortar, and
directly compressed to get desired tablets.
Table No. 9. Formulae of Tablets.

Gliclazide : 60mg
HP β-CD : 120mg
MCC : 60mg
Potato Starch (Dry) : 30mg
Talc : 15mg
Mag, Stearate : 15mg
Estimation of drug content from tablets.
The gliclazide content in the tablets were estimated by UV spectrophotometric
(SHIMADZU 1700) method. The method was validated for linearity, accuracy and
precision. Five gliclazide-HP-β-CD tablets (wet granulation) weighed and were crushed
in to powder. The Tablet powder equivalent to 100mg of gliclazide was dissolved with 25
ml methanol in 100 ml volumetric flask, and the volume was adjusted up to 100ml by
using phosphate buffer of pH 7.4. The solution was frequently shaken for 1hr, and
filtered through Wattman filter paper. Then, the filtrate was assayed for drug content by
measuring the absorbance at 227 nm after suitable dilutions, against phosphate buffer of
pH 7.4 as blank. The amount of gliclazide in the tablet was calculated as % yield (%
yield = practical yield / theoretical yield x 100), mean drug content and weight equivalent
to 100 mg of drug is estimated. The same procedure was used to estimate drug content of
gliclazide-HP-β-CD tablets prepared by direct compression method.
IN-VITRO Drug release from Gliclazide-HP-β-CD tablets.
Drug release was studied by using USP-24 Electrolab eight station dissolution test
apparatus in phosphate buffer solution of pH 7.4. A tablet of gliclazide-HP-β-CD
(formulated by wet granulation method) was placed in a basket, which rotates at a speed
of 50 rpm; the temperature of water bath was maintained 370C ± 0.50C throughout the
experiment. A 5 ml aliquot of dissolution medium was withdrawn at a specific time
intervals and replaced with 5 ml fresh medium of phosphate buffer solution of pH 7.4 to
maintain sink condition. The withdrawn sample was filtered through wattman filter
paper, after suitable dilutions with phosphate buffer solution of pH 7.4 the absorbance
was determined by using UV spectrophotometer (SHIMADZU 1700) at 227 nm against
blank (phosphate buffer solution of pH 7.4). The absorbance was recorded. Same
procedure was used to estimate the drug content in gliclazide-HP-β-CD tablet formulated
by direct compression method. All studies were conducted in triplicate; the average data
obtained were computed for further calculation ns.
Evaluation of Gliclazide-HP-β-CD tablets.
Weight variation of tablets was determined by weighing 20 tablets individually in
a electronic weighing machine, calculating the average weight, and comparing the
individual tablets weights to the average.
Hardness of tablets was tested by using Monsanto hardness tester.
Friability of tablets was determined in Roche Friabilator (Electrolab). Preweighed
tablets were placed in a friabilator, which is then operated for 100 revolutions. The tablets
were dusted and reweighed.
Disintegration of the tablets was determined by using phosphate buffer solution of
pH 7.4 in Disintegration test machine.
Stability studies of Gliclazide-HP-β-CD tablets.
Stability studies of the tablets are carried out according to ICH guidelines. In the
present study, as the tablets developed are solid dosage forms, a storage condition of 400c
± 20c; 75% RH ± 5% RH for 3 months was used for accelerated testing.
RESULTS
Concentration
Sl No (mcg/ml) Absorbance
1
0 0
2
10 0.13
3
20 0.231
4
30 0.324
5
40 0.436
6
50 0.558
Table No.10. Calibration curve data of Gliclazide in phosphate buffer pH 7.4
Standard Calibration Curve
0.6
0.5
Absorbance
0.4
0.3
0.2
0.1
0
0 10 20 30 40 50 60
Concentration (mcg/ml)
Figure No. 5. Standard Calibration Curve for Gliclazide in phosphate buffer pH 7.4
Fluid Solubility(mg/ml)
Conc.(%) of added solvent/surfactant
0 0.5 %(SD) 1.0 %(SD) 2.0 %(SD) 3.0 %(SD) 4.0 %(SD) 5.0 %(SD)
Water 0.086±0.005 - - - - - -
Water+Alcohol 0.123±0.003 0.197±0.005 0.318±0.003 0.533±0.004 0.780±0.006 0.998±0.003
Water+Glycerine - 0.114±0.006 0.158±0.005 0.232±0.004 0.302±0.005 0.321±0.061 0.412±0.005
Water+SLS 0.153±0.003 0.409±0.005 0.785±0.013 1.106±0.010 1.357±0.005 1.537±0.011
Table No.11. Solubility (mg/ml) of gliclazide in various fluids
pH 4 pH 6 pH 7.4 pH 8 pH 9
Solubility
3.168 6.174 6.058 0.097 0.096
(mg/ml)
Solubility
3.181 6.185 6.052 0.096 0.085
(mg/ml)
Solubility
3.168 6.181 6.054 0.011 0.087
(mg/ml)
3.172 6.8 6.055 0.101 0.089

Average
0.165 0.278 0.256 0.102 0.113

(±SD)
Table No. 12. Effect of pH on solubility of glicazide.
HP-B-CD Drug Dissolved
Sl No (Mm) (Mm)
1 0 0
2 1 0.03
3 3 0.08
4 6 0.14
5 9 0.23
6 12 0.32
7 15 0.41
Table No.13. Phase Solubility Study Profile of gliclazide with HP β-CD
Phase Solubility Study of Gliclazide-HP-B-CD
0.45
Conc of Gliclazide (Mm)
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
0 2 4 6 8 10 12 14 16
Conc of HP-B-CD (Mm)
Figure.No.6. Phase Solubility Study Profile of Gliclazide with HP β-CD
Figure No.7. IR Profile of Gliclazide and its HP β-CD inclusion complexes
Infrared Spectra of inclusion complex

1st I.R. spectra is Glicazide drug, GZ
2nd I.R. spectra is HP-β-CD drug, (HP-β-CD)
3rd I.R. Spectra is Glicazide: HP-β-CD (1:0.5) G1
4th I.R. Spectra is Glicazide: HP-β-CD (1:1) G2
5th I.R spectra is Glicazide: HP-β-CD (1:1.5) G3
6th I.R. spectra is Glicazide: HP-β-CD (1:1.5) G4
7th I.R. spectra is Glicazide: HP-β-CD (1:2) G5
Figure No.8. IR spectra of Gliclazide and its HP β-CD Physical Mixture.
1st I.R. spectra is Glicazide drug

2nd I.R. spectra is HP-β-CD drug
3rd I.R. Spectra is Glicazide: HP-β-CD (1:0.5) GP1
4th I.R. Spectra is Glicazide: HP-β-CD (1:1) GP2
5th I.R spectra is Glicazide: HP-β-CD (1:1.5) GP3
6th I.R. spectra is Glicazide: HP-β-CD (1:1.5) GP4
7th I.R. spectra is Glicazide: HP-β-CD (1:2) GP5
Figure No.9. DSC Profile of Gliclazide and its HP β-CD Inclusion complexes
1st DSC spectra is Glicazide drug

2nd DSC spectra is HP-β-CD drug
3rd DSC Spectra is Glicazide: HP-β-CD (1:0.5) G1
4th DSC Spectra is Glicazide: HP-β-CD (1:1) G2
5th DSC spectra is Glicazide: HP-β-CD (1:1.5) G3
6th DSC spectra is Glicazide: HP-β-CD (1:1.5) G4
7th DSC spectra is Glicazide: HP-β-CD (1:2) G5
Figure No.10. DSC Profile of Gliclazide and its HP β-CD Physical Mixture.
1st DSC spectra is Glicazide drug

2nd DSC spectra is HP-β-CD drug
3rd DSC Spectra is Glicazide: HP-β-CD (1:0.5) GP1
4th DSC Spectra is Glicazide: HP-β-CD (1:1) GP2
5th DSC spectra is Glicazide: HP-β-CD (1:1.5) GP3
6th DSC spectra is Glicazide: HP-β-CD (1:1.5) GP4
7th DSC spectra is Glicazide: HP-β-CD (1:2) GP5
Figure No.11. XRD Profile of Gliclazide and its HP β-CD Inclusion complexes.
1st XRD spectra is Glicazide drug

2nd XRD spectra is HP-β-CD drug
3rd XRD Spectra is Glicazide: HP-β-CD (1:0.5) G1
4th XRD Spectra is Glicazide: HP-β-CD (1:1) G2
5th XRD spectra is Glicazide: HP-β-CD (1:1.5) G3
6th XRD spectra is Glicazide: HP-β-CD (1:1.5) G4
7th XRD spectra is Glicazide: HP-β-CD (1:2) G5
Figure No.12. XRD Profile of Gliclazide and its HP β-CD Physical Mixture.
1st XRD spectra is Glicazide drug

2nd XRD spectra is HP-β-CD drug
3rd XRD Spectra is Glicazide: HP-β-CD (1:0.5) GP1
4th XRD Spectra is Glicazide: HP-β-CD (1:1) GP2
5th XRD spectra is Glicazide: HP-β-CD (1:1.5) GP3
6th XRD spectra is Glicazide: HP-β-CD (1:1.5) GP4
7th XRD spectra is Glicazide: HP-β-CD (1:2) GP5
Sample. G1 G2 G3 G4 G5
1 95.13 95.18 96.41 97.38 97.07
2 94.86 93.78 95.79 96.81 98.15
3 96.04 96.26 96.19 97.03 98.43
AVG mg 95.34 95.07 96.13 97.07 97.88
std dev+- 0.62 1.24 0.31 0.29 0.72
c.v. (%) 0.006 0.013 0.0032 0.0029 0.00733
Table No.14. Drug Content Profile of Gliclazide HP-β-CD inclusion Complexes
G1 = Gliclazide: HP-β-CD (1:0.5)
G2 = Gliclazide: HP-β-CD (1:1)
G4 = Gliclazide: HP-β-CD (1:2)
Sample. GP1 GP2 GP3 GP4 GP5
82.97
1 81.3 81.25 82.1 82.46
2 81.56 81.98 82.23 82.67 83.45
3 81.78 82.1 82.46 82.89 83.78
AVG mg 81.54 81.77 82.26 82.67 83.4
std dev+- 0.24 0.46 0.18 0.22 0.41
c.v. (%) 0.003 0.006 0.002 0.003 0.005
Table No.15. Drug Content Profile of Gliclazide HP-β-CD Physical Mixtures
GP1 = Gliclazide: HP-β-CD (1:0.5)
GP2 = Gliclazide: HP-β-CD (1:1)
GP4 = Gliclazide: HP-β-CD (1:2)
Time (min)
Gliclzide Pure G 1(± Stdv) G 2 (± Stdv) G 3 (± Stdv) G 4 (± Stdv) G5 (± Stdv)
(± Stdv)
0 0 0 0 0 0 0
5 10.56 (±0.147) 20.34(±0.132) 27.74(±0.143) 33.29(±0.126) 37.60(±0.167) 40.64(±0.145)
10 12.71( ± .134) 60.55(±0.145) 66.01(±0.147) 70.49(±0.167) 77.58(±0.143) 79.18(±0.153)
20 17.37(±0.123) 71.71(±0.156) 76.41(±0.135) 82.89(±0.187) 85.06(±0.189) 86.21(±0.156)
30 22.64(±0.167) 79.03(±0.154) 84.58(±.0176) 86.21(±0.198) 89.84(±0.145) 89.05(±0.176)
40 24.96±(0.135) 84.11(±0.165) 87.51(±0.132) 89.29(±0.187) 91.92(±0.154) 91.97(±0.176)
50 27.19(±0.123) 86.19(±0.145) 88.36(±0.126) 90.37(±0.176) 92.15(±0.165) 93.21(±0.134)
60 37.19(±0.123) 96.19(±0.145) 98.36(±0.126) 98.37(±0.176) 98.15(±0.165) 98.21(±0.134)
Table No.16. Percentage of drug release Profile of Gliclazide inclusion complex with
HP-β-CD
(Kneading Method)
G 1 = Gliclazide-HP-β-CD Inclusion Complex
Time Gliclazide GP1(± Stdv) GP2(± Stdv) GP3(± Stdv) GP4(± Stdv) GP5(± Stdv)
(min) pure(± Stdv)
0 0 0 0 0 0 0
5 10.56(±0.107) 15.19(±0.127) 19.87(±0.184) 22.48(±0.105) 29.34(±0.132) 31.29(±0.122)
10 12.71(±0.167) 39.47(±0.148) 40.45(±0.159) 42.72(±0.195) 45.61(±0.162) 47.83(±0.153)
20 17.37(±0.187) 45.54(±0.187) 47.91(±0.187) 50.86(±0.187) 53.74(±0.187) 54.67(±0.187)
30 22.64(±0.184) 50.71(±0.163) 51.04(±0.129) 54.84(±0.141) 55.27(±0.127) 58.54(±0.137)
40 24.96(±0.129) 53.02(±0.169) 54.37(±0.149) 56.52(±0.150) 59.81(±0.138) 60.69(±0.169)
50 27.19(±0.149) 56.11(±0.139) 59.52(±0.166) 60.94(±0.181) 61.54(±0.167) 62.15(±0.148)
60 29.93(±0.178) 58.19(±0.162) 61.21(±0.158) 62.61(±0.138) 63.04(±0.139) 64.21(±0.128)
Table No.17. Percentage of drug release Profile of Gliclazide complex with HP-β-CD
(Physical Mixture)
GP 1 = Gliclazide-HP-β-CD Physical Mixture
Dissolution Profile
100
GP
P e r c e n ta g e o f D r u g
80
G1
R e le a s e d
60 G2
40 G3
G4
20 G5
0
0 10 20 30 40 50 60
Time (min)
Figure No.13. Dissolution Rate Data Profile graph of Gliclazide and its Inclusion
Complex (Kneading Method)
GP = Gliclazide Pure
Dissolution Profile
100
80 GP
GP2
R e le a s e d
60
GP3
40 GP4
20 GP5
0
0 10 20 30 40 50 60
Time (min)
Figure No.14. Dissolution Rate Data Profile graph of Gliclazide and its Complex
(Physical Mixture)
GP = Gliclazide Pure
CORRELATION COEFFECIENT
Formulations Zero order Equation First order Equation

Regression coefficient (R2) Regression coefficient (R2)
GP 0.8965 0.9126
G1 0.6815 0.8347
G2 0.6661 0.376
G3 0.6305 0.8466
G4 0.5846 0.6178
G5 0.59 0.8756
GP1 0.7336 0.7234
GP2 0.7477 0.844
GP3 0.7302 0.8169
GP4 0.6595 0.7486
GP5 0.6488 0.7603
Table No.18. Correlation Coefficients (R2) Values in the analysis of Glicazide HP-β-CD
Dissolution data profile as per Zero order and First order of physical and inclusion
complexes
100
Percentage of Drug Remaind
90
80
GP
70
G1
60
G2
50
G3
40
G4
30
20 G5
10
0
0 10 20 30 40 50 60
Time (min)
Figure No. 15. % Drug Remained Profile of Glaclazide HPβ-CD Inclusion complex.
100
Percentage of Drug Remaind
90
80
GP
70
GP1
60
GP2
50
GP3
40
GP4
30
20 GP5
10
0
0 10 20 30 40 50 60
Time (min)
Figure No. 16. % Drug Remained Profile of Glaclazide HPβ-CD Physical
Mixture
2
Dissolution profile
1.8
1.6
log cum % drug rem ain
1.4 G1
1.2 G2
1 G3
0.8 G4
0.6 G5
0.4 Linear (G1)

Linear (G2)
0.2
Linear (G3)
0
Linear (G4)
0 10 20 30 40 50 60 70
Linear (G5)
Time(min)
Figure No. 17. Log % Drug Remained Profile of Glaclazide HPβ-CD Inclusion complex.
2.5
GP1
2
log cum % drug remain
GP2
GP3
1.5 GP4
GP5
1 Linear (GP1)
Linear (GP2)
Linear (GP3)
0.5
Linear (GP4)
Linear (GP5)
0
0 10 20 30 40 50 60 70
Time (min)
Figure No. 18. Log % Drug Remained Profile of Glaclazide HPβ-CD Physical Mixture.
DE Increase in
Formulations T 50% T 80% T 90% (30%) K1 (min-1) K1 (Folds)
GP - - - 13.62 0.005
G1 8.12 32.12 - 55.60 0.030 5.98
G2 7.24 27.12 - 60.10 0.023 4.6
G3 6.48 15.48 45.12 65.16 0.039 7.8
G4 6.24 11 30.48 68.98 0.042 8.6
G5 6 10.24 29.48 70.30 0.048 9.6
GP1 28.24 - - 36.03 0.012 2.4
GP2 26 - - 37.90 0.014 2.8
GP3 18.36 - - 40.52 0.014 2.8
GP4 14 - - 43.58 0.012 2.4
GP5 11.48 - - 45.09 0.014 2.8
Table No.19. Dissolution Parameter Profile of Gliclazide- HP-β-CD Inclusion
complexes and Physical Mixtures.
GZ TAB W GZ TAB D GZ TAB 1W GZ TAB D
Time (min) (± Stdv) (± Stdv) (± Stdv) (± Stdv)
0 0 0 0 0
5 12.18(±0.134) 14.49(±0.168) 47.25(±0.134) 52.05(±0.123)
10 15.53(±0.187) 18.62(±0.145) 68.68(±0.186) 74.27(±0.167)
20 20.87(±0.145) 23.21(±0.137) 79.37(±0.119) 83.58(±0.129)
30 24.06(±0.167) 26.35(±0.147) 86.41(±0.187) 91.46(±0.148)
40 27.12(±0.148) 29.12(±0.146) 89.16(±0.178) 95.17(±0.128)
50 29.03(±0.167) 32.98(±0.138) 93.59(±0.187) 97.09(±0.128)
60 30.91(±0.187) 34.48(±0.149) 95.87(±0.170) 98.21(±0.193)
Table No.20. Percentage of drug release Profile of Gliclazide- HP-β-CD Tablets.
GZ TAB W = Gliclazide Tablet (without HP-β-CD) by Wet Granulation method
GZ TAB D = Gliclazide Tablet (without HP-β-CD) by Direct compression method
GZ TAB 1 W = Gliclazide-HP-β-CD Tablet by Wet Granulation method
GZ TAB 2 D = Gliclazide-HP-β-CD Tablet by Direct compression method.
100
90
80
70
GZ TAB W
60
GZ TAB D
50
GZ TAB 1 W
40
GZ TAB 2 D
30
20
10
0
0 10 20 30 40 50 60
Figure No.19. Dissolution Rate Data Profile graph of Gliclazide- HP-β-CD Tablets
CORRELATION COEFFECIENT
Formulations Zero order Equation First order Equation

Regression coefficient (R2) Regression coefficient (R2)
GZ TAB W 0.8431 0.8797
GZ TAB D 0.8292 0.8860
GZ TAB1 W 0.6624 0.9584
GZ TAB 2 D 0.3038 0.9743
Table No.21. Correlation Coefficients (R2) Values in the analysis of Glicazide HP-β-CD
Tablets Dissolution data profile as per Zero order and First order
100
90
80
GZ TAB W
70
GZ TAB D
% Drug remain
60 GZ TAB 1 W
GZ TAB 2 D
50
Linear (GZ TAB W )
40 Linear (GZ TAB D )
Linear (GZ TAB 1 W )
30
Linear (GZ TAB 2 D )
20
10
0
0 10 20 30 40 50 60
Time(min)
Figure No. 20. % Drug Remained Profile of Glaclazide HPβ-CD Tablets.
2
1.8 GZ TAB W
Log cum % drug remain
1.6 GZ TAB D
1.4 GZ TAB W 1
1.2 GZ TAB 2D
1
Linear (GZ TAB W)
0.8
Linear (GZ TAB D)
0.6
Linear (GZ TAB W 1)
0.4
Linear (GZ TAB 2D)
0.2
0
0 10 20 30 40 50 60
Time(min)
Figure No. 21. Log % Drug Remained Profile of Glaclazide HPβ-CD Tablets.
Increase in
Formulation T 50% T 80% T 90% DE (30%) K1 (min-1) K1 (Folds)
23.3 37.2 46.2 10.07
GZ TAB W 1.001 -
17.8 31.2 42.6 12.71
GZ TABD 1.086 2.987
15.9 19.6 30.8 65.90
GZ TAB 1W 2.781 2.778
13.2 17.5 27.6 70.34
GZ TAB 2D 0.951 0.875
Table No.22. Dissolution Parameter Profile of Gliclazide- HP-β-CD Tablets
Formulation Hardness Hardness Hardness Avg. Hardness Std. Dev.
GZ Tabw 5.12(±0.132) 5.8(±0.132) 5.3(±0.132) 5.41(±0.132) 0.356
GZ Tab D 4.98(±0.132) 5.02(±0.132) 5.03(±0.132) 5.01(±0.132) 0.026
GZ Tab1w 5.03(±0.132) 5.12(±0.132) 5.09(±0.132) 5.08(±0.132) 0.045
GZ Tab 2D 4.97(±0.132) 5.06(±0.132) 5.12(±0.132) 5.05(±0.132) 0.075
Table No.23. Hardness Profile of Gliclazide-HP-β-CD Tablets.
Formulation Time(min) Time(min) Time(min) Avg. Time Std. Dev.
GZ Tabw 4.98 4.93 4.89 4.93 0.04

GZ Tab D
4.56 5.59 4.52 4.89 0.60
GZ Tab1w
4.79 4.76 4.71 4.75 0.04
GZ Tab 2D
4.26 4.21 4.29 4.25 0.04
Table No.24. Disintegration Time Profile of Gliclazide HP-β-CD Tablets.
Formulation Initial wt Weight lost % friability
GZ Tabw 1.537(±0.162) 0.009(±0.156) 0.455(±0.187)
GZ Tab D 1.502(±0.149) 0.004(±0.158) 0.226(±0.136)
GZ Tab1w 1.457(±0.176) 0.005(±0.137) 0.343(±0.187)
GZ Tab 2D 1.431(±0.165) 0.002(±0.149) 0.139(±0.129)
Table No.25. Friability Percentage Profile of Gliclazide-HP-β-CD Tablets
Average %Deviation
Average Deviation Wt from Avg,
Formulation Weight(gm) Wt(±) Wt(±)
GZ Tabw 0.301 ±0.004 ±0.842
GZ Tab D 0.303 ±0.005 ±0.928
GZ Tab1w 0.301 ±0.004 ±0.938
GZ Tab 2D 0.301 ±0.003 ±0.906
Table No.26. Weight Variation Profile of Gliclazide HP-β-CD Tablets.
Sample GZ TAB W GZ TAB D GZ TAB 1 W GZ TAB 2 D
1 98.08 99.22 99.76 99.79
2 99.34 99.58 99.44 99.01
3 99.47 99.29 98.89 99.58

AVG
mg 98.96 99.36 99.36 99.46
std
dev± 0.77 0.19 0.44 0.40
c.v.
(%) 0.007 0.001 0.004 0.004
Table No.27. Drug Content Profile of Gliclazide HP-β-CD Tablets after Stability Test.
GZ TAB W GZ TAB D GZ TAB 1 GZ TAB 2D

Time min (± Stdv) (± Stdv) W(± Stdv) (± Stdv)
0 0 0 0 0
5 11.83(±0.168) 14.1(±0.187) 46.86(±0.130) 51.64(±0.141)
10 15.16(±0.176) 18.19(±0.189) 68.22(±0.167) 73.82(±0.139)
20 20.48(±0.158) 22.92(±0.167) 79.02(±0.120) 83.19(±0.187)
30 23.74(±0.156) 26.04(±0.167) 86.02(±0.183) 91.05(±0.189)
40 26.74(±0.138) 28.71(±0.187) 88.71(±0.165) 94.78(±0.174)
50 28.58(±0.145) 32.59(±0.187) 93.18(±0.175) 96.68(±0.148)
60 30.5(±0.138) 34.09(±0.176) 95.45(±0.187) 97.8(±0.136)
Table No.28. Percentage of drug release Profile of Gliclazide- HP-β-CD Tablets
After Stability Study
Dissolution Profile
100
80
GZ TAB W
R ele ase d
60 GZ TAB D
40 GZ TAB 1 W
GZ TAB 2 D
20
0
0 10 20 30 40 50 60
Time (min)
Figure No.22. Dissolution Rate Data Profile graph of Gliclazide- HP-β-CD Tablets
After Stability Study.
Formulation Hardness Hardness Hardness Avg. Hardness Std. Dev.
GZ Tab w 5.09(±0.112) 5.69(±0.136) 5.19(±0.128) 5.32 0.32
GZ Tab D 4.76(±0.148) 5.01(±0.187) 4.89(±0.128) 4.88 0.13
GZ Tab1w 4.92(±0.148) 5.03(±0.137) 4.97(±0.176) 4.97 0.06
GZ Tab 2D 4.75(±0.167) 4.90(±0.186) 5.02(±0.138) 4.89 0.14
Table No.29. Hardness Profile of Gliclazide-HP-β-CD Tablets after stability test.
Formulation Time(min) Time(min) Time(min) Avg. Time Std. Dev.
GZ Tabw 5.06 4.98 4.97 5.00 0.05

GZ Tab D
4.62 5.64 4.61 4.95 0.59
GZ Tab1w
4.86 4.83 4.84 4.84 0.02
GZ Tab 2D
4.32 4.32 4.36 4.33 0.02
Table No.30. Disintegration Time Profile of Gliclazide HP-β-CD Tablets after stability
test.
Formulation Initial wt Weight lost % friability
GZ Tabw 1.532(±0.102) 0.008(±0.147) 0.457
GZ Tab D 1.495(±0.192) 0.004(±0.136) 0.228
GZ Tab1w 1.448(±0.132) 0.004(±0.187) 0.344
GZ Tab 2D 1.423(±0.148) 0.003(±0.128) 0.141
Table No.31. Friability Percentage Profile of Gliclazide-HP-β-CD Tablets after stability
test.
Average %Deviation
Average Deviation Wt from Avg,
Formulation Weight(gm) Wt(±) Wt(±)
GZ Tabw 0.300 ±0.005 ±0.886
GZ Tab D 0.301 ±0.006 ±0.960
GZ Tab1w 0.300 ±0.004 ±0.972
GZ Tab 2D 0.300 ±0.004 ±0.930
Table No.32. Weight Variation Profile of Gliclazide HP-β-CD Tablets after Stability
Study.
SUMMARY AND CONCLUSION
Low RSD values ensured reproducibility of the method. No interference
from excipients used was observed. Thus method was found suitable for the
estimation of Gliclazide content in dissolution fluids. The calibration curve shown
in fig.no.5 and data table no.10 was used for the purpose.
The melting point of gliclazide, gliclazide-HP-β-CD complexes and
physical mixtures found to be in between 3190c to 3250c.
The solubility of gliclazide is increasing as the concentration of
solvent/surfactant increases. Solubility is more in a blend of water+SLS than the
alcohol and glycerine with water, also showing more solubility in pH 6 then the
other pH. Data is given in table no.11&12.
The phase solubility diagrams for the complex formation between
gliclazide HP β-CD shown in table no.13 and figure no.6. The aqueous solubility
of the gliclazide was increased linearly as a function of the concentration of HP β-
CD. The aqueous solubility diagrams of gliclazide HP β-CD complexes can be
classified as AL type according to Higuchi and Connors. Because the straight line
had a slope < 1 in each case, the increase in solubility was due to the formation of
a 1:1 M complex in solution with HP β-CD.
The apparent stability constant (Kc) in each case was calculated from the
slope of the corresponding linear plot of the phase solubility diagram according to
the equation, Kc = Slope/ So (1-Slope), where So is the solubility of the drug in the
absence of solubilizer. The estimated Kc values of gliclazide with HP β-CD
complexe are 256.3 M-1. The values of Kc indicated that all the complexes formed
between gliclazide and HP-β-CDs are quite stable.
The Rf values were found to be 0.738 and 0.869 for pure gliclazide,
gliclazide-HP-β-CD complex respectively, indicating that the spots of the sample
were indeed that of the unchanged gliclazide. As the Rf values of gliclazide,
gliclazide HP-β-CD complex coinciding and as no other spots were observed it
can be concluded that gliclazide and HP-β-CD are compatible without any
chemical change or reaction.
The IR spectra of gliclazide, gliclazide-HP-β-CD inclusion complex and
physical mixtures are shown in figure no.7&8 respectively. The IR spectral
observations indicated no interaction between gliclazide and HP-β-CD complexes.
The DSC thermograms of gliclazide HP β-CD inclusion complex and
physical mixtures are shown in figure no.9&10. The DSC curve of HP β-CD
showed broad endothermic peaks. In the thermograms of gliclazide HP β-CD, the
intensity (or height) of the endothermic peak was reduced indicating interaction of
gliclazide with HP-β-CD and absence of crystalline drug and its complete
complexation with HP-β-CD.
XRD patterns of gliclazide and complexes with HP-β-CD are shown in
figure no.11&12. The diffraction peaks were much reduced in the case of
glicazide HP-β-CD complexes. The disappearance of gliclazide crystalline peaks
confirmed the stronger drug amorphization and entrapment in HP β-CD.
Low C.V. values in the percent drug content ensured uniformity of drug
content in all batches. The coefficient of variation (C.V.) in the percent drug
content was found to be less than 1.0 percent in all the batches prepared, and given
in table no.14&15.
Solid inclusion complexes of Gliclazide-HP-β-CD in 1:0.5, 1:1, 1:1.5, 1:2
and 1:2.5 ratios were prepared by kneading method and physical mixture. The
dissolution rate of gliclazide from CDs complex and physical mixture system was
studied using phosphate buffer solution of pH 7.4 as a dissolution fluid. The result
is given in table no. 16&17and shown figure no.13&14.
The dissolution of gliclazide was higher from all the gliclazide HP-β-
cyclodextrin complexes prepared when compared to gliclazide HP-β-cyclodextrin
physical mixture and pure gliclazide drug. The gliclazide HP-β-cyclodextrin
physical mixture showing more dissolution than the pure gliclazide drug. The
dissolution data were fitted into mathematical models such as zero order and first
order models to assess the kinetics and mechanism of dissolution are given in
figures no.15-18. The dissolution data obeyed first order kinetic model. The
correlation coefficient (r2) values observed in the analysis of dissolution data as
per the above models are given in table no.18. All the ‘r2’ values were greater
indicating that the dissolution of gliclazide from all the complexes obeyed first
order model. The corresponding dissolution rate was calculated from the slopes of
the linear plots.
Dissolution efficiency (DE30) values were calculated as per Khan. T50 (time
taken for 50% dissolution), T80 (time taken for 80% dissolution) and T90 (%)
values were recorded from the dissolution profiles. The dissolution parameters are
summarized in table no.19.
The K1 and DE30values were increased as the proportion of CD in the
complex system was increased in each batch. The increase in K1 (no. of folds)
with CD systems is shown in table no.19. Gliclazide HP-β-CD complexes gave
higher enhancement in the dissolution rate and efficiency when compared to
Gliclazide HP-β-CD physical mixture.
The gliclazide tablets prepared with HP-β-CD by wet granulation and direct
compression methods. The physical characteristics like size, shape, thickness and
appearance of all series of tablets prepared were found good.
The dissolution rate of gliclazide tablets prepared with HP-β-CD by various
methods was studied using phosphate buffer solution of pH 7.4 as the dissolution
fluid. The results are given in table no.20 and shown in figure no.19.
The dissolution of gliclazide tablets prepared with HP-β-CD was higher
when compared with gliclazide tablets prepared without HP-β-CD. The dissolution
data were fitted into various models such as zero order and first order model are
given in figure no.20&21. The correlation coefficient (R2) values observed in the
analysis of dissolution data as per the above models are given in table no.21. All
the R2 values indicating that the dissolution of gliclazide from the tablets prepared
obeyed first order model. The dissolution rates were calculated from the slope of
the linear plots.
Dissolution efficiency (DE30) values are calculated as per Khan. T50, T80
and T90 values were recorded from the dissolution profiles. The dissolution
parameters are given in table no.22. The increase in K1 and K1 no. of folds of all
the tablets of gliclazide prepared with HP-β-CD found when compared with
tablets of glicazide prepared without HP-β-CD and shown in table no.22.
The hardness of the gliclazide tablets is 5.01- 5.41 kg/cm2. The
disintegration time of tablets is in between 4.25- 4.93 min. The friability
percentage and weight variation of all the tablets are found within the standard
limits, the data is given in table no.23-26.
The tablets prepared in the present investigation were tested for their
stability by storing at 400c and 75% RH for a period of 3 months. The stored
products were evaluated for drug content, dissolution rate, weight variation,
friability, and hardness and disintegration tests. Drug content of all the series
tablets remained unaltered after storage for 3 months are given in table no.27. The
dissolution characteristics of all the series tablets remained unaltered during the
storage period are given in table no 28. And shown in figure no.22. Weight
variation, Friability percent of all series of tablets remains much unaltered after
storage for 3 months; hardness and disintegration of all the tablet remains intact
without much change in their characteristics after storage for 3 months in a
prescribed temperature and humidity are given in table no.29-32.
The present work has been undertaken with an overall objective of studying
the complexation of gliclazide, BCS class II drugs with hydroxypropyl-β-
cyclodextrin to evaluate the feasibility of enhancing their solubility, dissolution
rate, bioavailability and therapeutic efficacy. The feasibility of formulating the CD
complexes into tablets with enhanced dissolution rate characteristics was also
investigated.
Complexation of gliclazide with hydroxypropyl-β-cyclodextrin was
investigated by solubility in different pH and blend of solvent/surfactants in
different concentration with water and phase solubility study. The effect of
hydroxypropyl-β-cyclodextrin on the solubility of gliclazide was also derived from
phase solubility studies. Solid inclusion complexes of gliclazide-HP-β-CD were
prepared by kneading method and physical mixture employing different ratios of
gliclazide-HP-β-CD. The inclusion complexes prepared by kneading and physical
methods were evaluated and characterized by TLC, IR, XRD and DSC studies.
Kinetics and mechanism of drug dissolution from the inclusion complexes were
evaluated by studying dissolution of solid inclusion complexes. Selected
gliclazide-HP-β-CD complexes were formulated in to tablets by wet granulation
and direct compression methods and the resulting tables were evaluated for
dissolution rate and other physical properties of tablets. Gliclazide-HP-β-CD
tablets were also subjected to stability evaluation as per ICH guidelines.
From the results obtained the following conclusions are drawn.
¾ The phase solubility diagram of gliclazide was of type AL with HP β-CD.
¾ The phase solubility studies indicated the formation of gliclazide- HP β-CD
inclusion complexes at a 1:1 M ratio in solustion. The complexes formed
were quite stable.
¾ The aqueous solubility of gliclazide was increased linearly as a function of
concentration of the HP β-CD.
¾ Inclusion complex prepared by kneading method exhibited higher
solubilizing efficiency when compared with physical mixture of gliclazide-
HP β-CD.
¾ DSC and XRD indicated better drug inclusion in HP β-CD, and good drug
amorphization and entrapment in HP β-CD.
¾ IR spectral studies indicated no chemical interaction between the
gliclazide- HP β-CD.
¾ The compatibility test between gliclazide- HP β-CD done by TLC method
indicated that gliclazide- HP β-CD are compatible with out any chemical
change or reaction.
¾ Gliclazide- HP β-CD complexes exhibited higher rates of dissolution and
dissolution efficiency values than the uncomplexed gliclazide.
¾ Gliclazide- HP β-CD (1: 2.5) complex exhibited 9.6 fold increases in the
dissolution rate.
¾ Gliclazide- HP β-CD complexes could be formulated in compressed tablets
by wet granulation and direct compression methods. All the Gliclazide-
HP-β-CD tablets prepared fulfilled the official specifications of hardness,
friability and disintegration time and gave rapid dissolution of the contained
drug.
¾ All gliclazide- HP β-CD tablets exhibited higher rates of dissolution and
efficiency values than the tablets prepared without HP β-CD.
¾ The gliclazide-HP β-CD tablets prepared by direct compression gave a little
increased rate of dissolution and efficiency when compared to the tablets
prepared by wet granulation method.
¾ Cyclodextrin complexation (HP- β-CD) has markedly enhanced the
absorption rate gliclazide.
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Enhancement of Solubility and Dissolution of Gliclazide by

Complexation with Hydroxypropyl β-Cyclodextrin

Mr. Amit Tondare. B. Pharm.

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

Department of Industrial Pharmacy

DECLARATION BY THE CANDIDATE

I hereby declare that the matter embodied in the dissertation entitled

“Enhancement of Solubility and Dissolution of Gliclazide by Complexation with

Hydroxypropyl β-Cyclodextrin is a bonafide and genuine research work

Department of Industrial Pharmacy, Karnataka College of Pharmacy, Bidar.

Place: Bidar Amit Tondare

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “Enhancement of Solubility and

Dissolution of Gliclazide by Complexation with Hydroxypropyl β-Cyclodextrin” is a

bonafide research work done by Mr. Amit Tondare submitted in partial

fulfillment of the requirement for the degree of “Master of Pharmacy” in

Industrial Pharmacy of the “Rajiv Gandhi University of Health Sciences,

ENDORSEMENT BY THE PRINCIPAL & H.O.D.

This is to certify that the dissertation entitled Enhancement of Solubility

and Dissolution of Gliclazide by Complexation with Hydroxypropyl β-

Cyclodextrin is a bonafide research work done by Amit tondare Under the

Department of Industrial Pharmacy, Karnataka College of Pharmacy, Bidar.

I hereby declare that the Rajiv Gandhi University of Health Science,

dissertation / thesis in print or electronic format for academic / research

Place: Bidar TONDARE AMIT

@ Rajiv Gandhi University of Health Sciences, Karnataka

I take this privilege and pleasure to acknowledge the contributions of many

It is with pleasure of immense gratitude that I express my most cordial and

I am gratefully indebted to Prof. Sirse KrantiKumar, M. Pharm. PhD, the

I consider it as a great privilege to express my heartfelt gratitude and sincere

I extend my sincere thanks to Dr. Baswaraj Raga, Dr. Kashinath Naubade,

I take this opportunity to express my sincere thanks to teaching and non-

I would like to express my sincere thanks to Aditya,atul,varsha,Deepak and

I would like to express my sincere thanks to Deepak,basavraj,Kvamshi,

Words are not sufficient to express my deepest love and appreciation to my

Finally I consider this as an opportunity to express my gratitude to all the

Place: TONDARE AMIT.

Gliclazide is a second generation sulphonylurea oral hypoglycemic agent. It is

characterize inclusion complexes of Gliclzide with HP-β-CD. The phase solubility

CD by kneading method exhibited greatest enhancement in solubility and fastest

compression parameters like hardness, friability, weight variation, thickness, drug

content, in-vitro dissolution and FT-IR and DSC studies.

Key words: Gliclazide, β-CD, HP-β-CD, Physical method, Kneading method,

Abbreviations Complete Name

HP- β-CD Hydroxypropyl betacyclodextrin

rpm Rotations per minute

λmax Wavelength maximum

SR.NO CHAPTER PAGE NO.

8 SUMMARY, CONCLUSION 111

SR.NO CHAPTER PAGE NO.

8 SUMMARY, CONCLUSION 111

2 Physicochemical properties of cyclodextrin 3

3 CD-enhanced Solubility and Dissolution 12

4 CD Effect on Drug Stability 17

5 Modification of the Drug Release 30

10 Calibration curve data of Gliclazide 75

11 Solubility (mg/ml) of gliclazide in various fluids 76

12 Effect of pH on solubility of glicazide. 76

Phase Solubility Study Profile of gliclazide with HP β-CD

Drug Content Profile of Gliclazide HP-β-CD inclusion

Percentage of drug release Profile of Gliclazide inclusion

Percentage of drug release Profile of Gliclazide complex with

Correlation Coefficients (R2) Values in the analysis of