FORMULATION AND EVALUATION OF BIODEGRADABLE IMPLANTABLE

DRUG DELIVERY SYSTEM OF CLINDAMYCIN HYDROCHLORIDE

Dissertation work submitted to

The Tamilnadu Dr.M.G.R.Medical University, Chennai

In partial Fulfillment for the award of degree of

MASTER OF PHARMACY

IN

PHARMACEUTICS

Submitted by

S.BEETHA ROHINI

Reg .No.26106301

Under the Guidance of

Dr.S.UMADEVI

M.Pharm., Ph.D.,

Professor and Head

April 2012

DEPARTMENT OF PHARMACEUTICS
RVS COLLEGE OF PHARMACEUTICAL SCIENCES
Sulur, Coimbatore.
 CERTIFICATE

This is to certify that the research project work entitled “ Formulation and Evaluation of

Biodegradable Implantable Drug Delivery System of Clindamycin Hydrochloride ” is a bonafide

work of Ms.S.BEETHA ROHINI (Reg.No.26106301) carried out in the Department of

Pharmaceutics, RVS College of Pharmaceutical Sciences, Sulur, Coimbatore, in Partial fulfilment

of the requirements for the award of degree in Master of Pharmacy in Pharmaceutics of The

Tamilnadu Dr.M.G.R.Medical University, Chennai and completed the work under the guidance

and supervision of Dr.S.UMADEVI during the academic year 2011-2012 This work is original and

contributory.

Place : Coimbatore Dr.R.VENKATANARAYANAN

Date : M.Pharm.,Ph.D

Principal

R.V.S. College of Pharmaceutical Sciences

Sulur, Coimbatore.
 CERTIFICATE

This is to certify that the research project work entitled “ Formulation and Evaluation of

Biodegradable Implantable Drug Delivery System of Clindamycin Hydrochloride” is a bonafide

work of Ms.S.BEETHA ROHINI (Reg.No.26106301) carried out in the Department of

Pharmaceutics, RVS College of Pharmaceutical Sciences, Sulur, Coimbatore in Partial fulfilment

of the requirements for the award of degree in Master of Pharmacy in Pharmaceutics of The

Tamilnadu Dr.M.G.R.Medical University, Chennai, under my supervision and guidance to my

fullest satisfaction. This work is original and contributory.

Place : Coimbatore Dr.S.UMADEVI

Date : M.Pharm.,Ph.D

Professor and Head

Department of Pharmaceutics

R.V.S. College of Pharmaceutical Sciences

Sulur, Coimbatore.
 DECLARATION

I hereby declare that this dissertation work entitled “ Formulation and Evaluation of Biodegradable

Implantable Drug Delivery System of Clindamycin Hydrochloride” was carried out by me in the

Department of Pharmaceutics at R.V.S.College of Pharmaceutical Sciences under the guidance, of

Dr.S.UMADEVI, Professor and Head, Department of Pharmaceutics in R.V.S.College of

Pharmaceutical Sciences, Sulur, Coimbatore . This work is original and contributory.

Place : Coimbatore S.BEETHA ROHINI

Date : ( Reg.No.26106301)
 ACKNOWLEDGEMENT

It gives me immense pleasure to convey my deep sense of gratitude and heartfelt thanks to my
guide Dr.S.Umadevi, Professor and HOD, Department of Pharmaceutics, RVS college of
Pharmaceutical Sciences, Sulur, Coimbatore for her help, motivation, suggestions,guidance,
encouragement and the confidence that she has shown in me throughout the course of my
work.

I sincerely thank Dr.R.Venkatanarayanan, Professor and Principal, RVS college of

Pharmaceutical Sciences, Sulur, Coimbatore, for his inspirations and for being a great
facilitator.

I express my sincere gratitude to my teachers Mr.Barish, Mr.Akelesh, Mrs.Ramya, Dr.Sam

Solomon, Mr.Kumar Nallasivam, Mr.Sivakumar for their meticulous guidance and
encouragement provided to me for the completion of my dissertation work.

I express my sincere thanks to Ms.Sivasankari, Lab.assitant, Department of pharmaceutics

other teaching faculty for her timely help.

I thank Mr.Sendhurpandi, Librarian, Mr.Kannan, Mrs.Stella Mary and Mr.Mohan,

Asst.Librarian, RVS college of Pharmaceutical Sciences, Sulur, Coimbatore for providing me
library facilities.

My heartfelt thanks to my friends Gaurav, Sudharsan, Dipak, Eldho, Atul, Ravichandran,

Subhojit, Sreenivas, Venkatesh for their support, honest opinions and diligence kept me
lively.
My sincere thanks to all my juniors far too numerous to mention individually.

I acknowledge the service extended by Dr.G.Geetha, Professor,Department of

Pharmaceutical analysis, PSG College of pharmacy, Coimbatore and Dr.S.Kamatchiammal,
Scientist, National Environmental Engineering Research Institute, Chennai for their timely
support for doing my project.
I am very thankful to A to Z Pharmaceuticals, Chennai, for genours gift sample of
clindamycin hydrochloride.

The most overwhelming enthusiasm, goodwill, love and affection have generously come from
my Parents, K.Subramanian and R.Manjula and Sister, S.Achutha Priya.

Finally I thank all, who have directly or indirectly helped in the successful completion of my
dissertation.

Date: S.BEETHA ROHINI

Place: Coimbatore (Reg.No.26106301)
 TABLE OF CONTENTS

S.NO CONTENTS PAGE NO

1 Introduction 1

2 Review of literature 17

3 Aim and Objective 30

4 Plan of Work 31

5 Materials and Methods 32

6 Experimental details 36

7 Result and Discussion 43

8 Summary and Conclusion 88

9 Bibliography 90
 LIST OF TABLES

TABLE
TITLE PAGE NO
NO.

2.1 Characteristics of Clindamycin HCl 17

Physicochemical and biopharmaceutics parameters of

2.2 19
Clindamycin Hydrochloride

5.1 Materials used in the formulation 32

5.2 Equipments 32

5.3 Polymer ratios used in the formulation 33

5.4 Formulation chart of Clindamycin hydrochloride implants 35

6.1 Allowable limit for weight variation 38

7.0 Selection of polymer 44

Preparation of standard curve of Clindamycin hydrochloride in

7.1 45
0.1N HCl

Preparation of standard curve of Clindamycin hydrochloride in pH

7.2 7.4 buffer 46

IR spectral data of pure drug alone and formulation containing

7.3 47
Clindamycin HCl

7.4 Weight uniformity of the Clindamycin HCl implant 51

7.5 Thickness of the Clindamycin HCl implant 52

7.6 Content uniformity of the Clindamycin HCl 53

7.7 % Moisture loss of the Clindamycin HCl implants 53

7.8 Surface pH of the Clindamycin HCl implant 54

In-vitro release data of Clindamycin HCl implants of different

7.9 55
formulations

7.10 Kinetics data of invitro drug release for F1 57

7.11 Kinetics data of invitro drug release for F2 58

7.12 Kinetics data of invitro drug release for F3 59

 7.13 Kinetics data of invitro drug release for F4 60

7.14 Kinetics data of invitro drug release for F5 61

7.15 Kinetics data of invitro drug release for F6 62

7.16 Kinetics data of invitro drug release for F7 63

7.17 Kinetics data of invitro drug release for F8 67

7.18 Kinetics data of invitro drug release for F9 68

7.19 Comparative kinetics for Zero-order drug release kinetics 69

7.20 Comparative kinetics for First-order kinetics 71

7.21 Comparative kinetics for Higuchi release kinetics 73

Comparative kinetics for Koresmeyer-peppas drug release

7.22 75
kinetics

7.23 Comparative kinetics for Hixson-Crowell drug release kinetics 77

Stability studies data of the optimized formulation of

7.24 79
Clindamycin implants

7.25 Minimum inhibitory concentration of Clindamycin HCl 80

7.26 Diameter of zone of inhibition of Clindamycin implants 84

LIST OF FIGURES

PAGE
FIGURE NO TITLE
NO.
Matrix system showing diffusion of the drug across the
1.1 9
polymer
Reservoir systems showing diffusion of the drug across the
1.2 10
polymer
2.1 Structure of Clindamycin Hydrochloride 17
2.2 Mechanism pathway of Clindamycin hydrochloride 18
5.1 Method of preparation of Clindamycin HCl implant 34
7.1 λmax of Clindamycin HCl in 0.1N HCl 43
7.2 λmax of Clindamycin HCl in pH 7.4 phosphate buffer 44
7.3 Standard curve for Clindamycin HCl in 0.1N HCl 45
7.4 Standard curve for Clindamycin HCl in pH 7.4 buffer 46
7.5 IR Spectrum of pure Clindamycin Hydrochloride 48
IR Spectrum of Clindamycin Hydrochloride with gelatin and
7.6 sodium alginate
49
7.7 Thermogram of pure Clindamycin hydrochloride 50
Thermogram of Clindamycin HCl with gelatin and sodium
7.8 50
alginate
7.9 In-vitro drug release of the formulation F1, F2 and F3 55
7.10 In-vitro drug release of the formulation F4, F5 and F6 56
7.11 In-vitro drug release of the formulation F7, F8 and F9 56
7.12 Zero-order release kinetics for the formulation F7 64

7.13 First-order release kinetics for the formulation F7 64

7.14 Higuchi release kinetics for the formulation F7 65
7.15 Koresmeyer-peppas release kinetics for the formulation F7 65
7.16 Hixson-Crowell release kinetics for the formulation F7 66
Comparative kinetics of Zero-order for the formulation F1, F2
7.17 69
and F3
Comparative kinetics of Zero-order for the formulation F4, F5
7.18 70
and F6
Comparative kinetics of Zero-order for the formulation F7, F8
7.19 70
and F9
Comparative kinetics of First-order for the formulation F1, F2
7.20 71
and F3
Comparative kinetics of First-order for the formulation F4, F5
7.21 71
and F6
Comparative kinetics of First-order for the formulation F7, F8
7.22 72
and F9
Comparative kinetics of Higuchi for the formulation F1, F2
7.23 73
and F3
Comparative kinetics of Higuchi for the formulation F4, F5
7.24 74
and F6
Comparative kinetics of Higuchi for the formulation F7, F8
7.25 74
and F9
Comparative kinetics of Koresmeyer-peppas for the
7.27 76
formulation F4, F5 and F6

Comparative kinetics of Koresmeyer-peppas for the

7.28 76
formulation F7, F8 and F9
 Comparative kinetics of Hixson-Crowell for the formulation
7.29 77
F1, F2 and F3

Comparative kinetics of Hixson-Crowell for the formulation

7.30 78
F4, F5 and F6

Comparative kinetics of Hixson-Crowell for the formulation

7.31 78
F7, F8 and F9

7.32 MIC of Clindamycin implant in Salmonella 80

7.33 MIC of Clindamycin implant in Salmonella paratyphi A 81
7.34 MIC of Clindamycin implant in Salmonella paratyphi B 81
7.35 MIC of Clindamycin implant in Enterobacter aerogens 82
7.36 MIC of Clindamycin implant in Staphylococcus aureus 82
7.37 MIC of Clindamycin implant in Proteus mirabilis 83
7.38 MIC of Clindamycin implant in Klebsiella pneumoniae 83

Disc diffusion zone for Staphylococcus aureus using

7.39 85
Clindamycin pad

Disc diffusion zone for Enterobacter aerogens using

7.40 85
Clindamycin pad

Agar well diffusion method in Staphylococcus aureus using

7.41 86
Clindamycin liquid

Agar well diffusion method in Staphylococcus aureus using

7.42 86
Clindamycin liquid

Agar well diffusion method in Enterobacter aerogens using

7.43 87
Clindamycin liquid

Agar well diffusion method in Enterobacter aerogens using

7.44 87
Clindamycin liquid

LIST OF ABBREVIATIONS
Abbreviations used Meaning
PEG Polyethylene glycol
FT-IR Fourier transform infrared
DSC Differential scanning calorimeter
LB Luria bertani
K0 Zero order rate constant
K1 First order rate constant
KH Higuchi rate constant
Kkp Koresmeyer-peppas rate constant
KHC Hixson-Crowell rate constant
MIC Minimum inhibitory concentration
HPMC Hydroxy propyl methyl cellulose
MC Methyl cellulose
EC Ethyl cellulose

ABSTRACT
The purpose of this study is to formulate implant containing Clindamycin hydrochloride that
could be used in the treatment of periodontitis. The implants were formulated by using
biodegradable polymer, gelatin and sodium alginate with PEG 400 as a plasticizer. The drug
and polymer compatability in implants were studied by FT-IR and DSC. There was no
interaction between the drug and polymer. The implant was evaluated for physicochemical
properties such as weight uniformity, thickness, content uniformity, %moisture loss and
surface pH. The result of physicochemical properties was uniform for all the formulations.
The in-vitro results showed that increase in the polymer concentration (70:30) prolong the
drug release upto 24hrs. Optimized formulation F7 release 84.90% of drug at the end of 24 th
hr and considered as a best formulation. The release mechanism for invitro release was
studied by using various mathematical models. The ‘n’ value for the koresmeyer-peppas
equation was in the range of 0.87-0.98 indicating the anamolous behaviour (non-fickian
release). In-vitro antibacterial activity was carried out in Staphylococcus aureus and
Enterobacter aerogen had an inhibitory effect after 24hrs of incubation. The stability studies
were carried out at room temperature, dark place and direct sunlight which does not shows
any significant change after one month.
 Introduction

1. INTRODUCTION
Novel drug delivery system (NDDS) has gained a considerable attention from the last
few decades. In the form of NDDS, an existing drug molecule can get a new life, thereby
increasing the market value, competitiveness and novelty in drug delivery. Implantable drug
delivery system (IDDS) is an example of such systems available for therapeutic use.

Historically the subcutaneous implantation of drug pellets is known to be the first

biomedical approach aiming to achieve the prolonged and continuous administration of
drugs. This first generation of IDDS was produced by compressing drug crystals, with or
without a small fraction of pharmaceutical excipients into tiny, cylindrical solid pellets that
could be readily implanted into subcutaneous tissue1.

In 1861 Lafarge first introduced the concept of implantable systems for sustained drug
administration. The concept was later used to produce solid implants containing steroid
hormones-initiating the use of pure drug with no added excipient. Sterile tablets consisting of
the highly purified drug, usually compressed without excipient intended for subcutaneous
implantation in body tissue. The device thus prepared had a high degree of hardness and
virtually zero porosity. Since water did not penetrate the matrix drug release occurred
principally by surface dissolution. Due to the inherent poor solubility of steroid drugs this
method provided a good form of depot medication2.

The implantable therapeutic systems are mainly approached for

• Long term
• Continuous drug administration and
• Controlled release

Over the years a number of approaches have been developed to achieve the controlled
administration of biologically active agents via implantation (or insertion) in tissues. These
approaches are outlined as follows1.

I. Controlled drug delivery by diffusion process

A. Polymer membrane permeation controlled systems containing
1. Non porous membrane
2. Microporous membrane
3. Semipermeable membrane

B. Matrix diffusion controlled systems containing

1. Lipophilic polymers
2. Hydrophilic swellable polymers

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 1

 Introduction

3. Porous polymers
C. Microreservoir dissolution controlled systems containing
1. Hydrophilic reservoir/ lipophilic matrix
2. Lipophilic reservoir/ hydrophilic matrix
II. Controlled drug delivery by activation process
A. Osmotic pressure activated
B. Vapour pressure activated
C. Magnetically activated
D. Phonophoresis activated
E. Hydration activated
F. Hydrolysis activated
III. Controlled drug delivery by feedback regulated process
A. Bioerosion regulated drug delivery
B. Bioresponsive drug delivery

Most of the approaches listed above can be adopted to fabricate the systems for
controlled release of biologically active agents. Polymers of both non-biodegradable and
biodegradable types can be used depending on the requirement.

Biodegradable polymers:

Biodegradable systems have gained much popularity over non-degradable delivery

system, as they are eventually absorbed or metabolized and excreted by the body. This
alleviates the need for surgical removal of the implant after the conclusion of therapy
increasing patient compliance.

Non-biodegradable polymers:

These are inert in the environment use and serve essentially as a rate limiting barrier
to the transport and release of drug from the device. The major disadvantage is the implants
have to be removed surgically once the conclusion of the therapy from the site of
implantation since they are non- biodegradable.

1.1 Polymers used in the implants3

Carbochain polymers

Polyethylene

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 2

 Introduction

Polypropylene

Polytetrafluoroethylene

Poly-α-cyanacrylates

Heterochain polymers

Poly (DL-lactide co-glycolide)

Polyurethanes

Polylactic acid

Polyorthoester

Collagen

Gellan

Gelatin

Mucopolysaccharides

1.2 Ideal requirements of implantable drug delivery systems4

• Environmentally stable
• Biocompatible
• Sterile
• Biostable
• Improve patient compliance by reducing the frequency of drug administration over the
entire period of treatment.
• Release the drug in a rate-controlled manner that leads to enhanced effectiveness and
reduction in side effects.
• Readily retrievable by medical personnel to terminate medication.
• Easy to manufacture and relatively inexpensive.

1.3 Advantages of the implantable drug delivery system4

• Improved efficiency
• Very effective
• Small dose is sufficient to elicit the action
• Reduced side effects
• On-spot delivery
• Convenient therapy
• Plasma drug levels are continuously maintained in a therapeutically desirable range

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 3

 Introduction

• Harmful side effects from systemic administration can be reduced or eliminated by

local administration from a controlled release system.
• Continuous small amounts of drug may be less painful than several large doses.
• Patient compliance is improved.

1.4 MECHANISM OF DRUG RELEASE FROM IMPLANTABLE DEVICES2

Drug release from most implantable devices is controlled by any one of six different
mechanisms discussed below.
1.4.1 Diffusion controlled
These devices are based on Fick’s law of diffusion which states that the rate of transfer of
a diffusing substance through unit area of a section. In this case the rate of release is
controlled by diffusion of drug through a polymeric membrane. Diffusion-controlled devices
can be further classified into membrane-permeation controlled, matrix-controlled and micro
reservoir-dissolution controlled.

Membrane-permeation controlled
In membrane-permeation controlled devices the drug reservoir is surrounded by a
membrane and because of the presence of the two distinct drug-reservoir and membrane
phases these are known as heterogeneous devices. When the device containing a highly
hydrophilic drug is placed in aqueous dissolution medium, water penetrates the coating and
dissolves the drug and the concentrated drug solution diffuse out through the polymeric
membrane. The release rate of the drug is controlled by the diffusion rate of drug solution
through a spherical membrane permeation controlled system with saturated reservoir is given
by equation.
dM 4 πDk ( C 1C 2 ) ab
=
dt ba

dM
Where, dt is related to the drug concentration in the matrix and the rate of polymer

erosion
D is the diffusivity of drug unit thickness of polymer
k is the partition coefficient (ratio of solubility of drug in the polymer divided by the
solubility of drug in the surrounding medium) of drug across the polymer membrane
C1 is the concentration of drug inside the sphere
C2 is the concentration of drug in the surroundings
a is the inner radius of the coat and
Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 4
 Introduction

b is the outer radius of the coat.

Matrix controlled
In matrix-controlled devices the drug is uniformly distributed throughout the polymer
and hence these are known as homogenous devices. In the presence of dissolution medium
drug at the surface dissolves first and is released in the dissolution medium. In many cases
the dissolved drug creates a depletion boundary separating the empty or drug-depleted
polymer from the drug loaded polymer matrix. The drug release rate is controlled by the
diffusivity barrier provided by at the empty matrixes which increase in thickness with time.
For a matrix system that is exposed to the dissolution medium on all the sides the surface area
of the inward-moving depletion boundary decrease resulting in a decrease in drug release
rate which depends on the device geometry.

Micro reservoir dissolution-controlled
In these devices the drug reservoir is made of a suspension of solid drug particles in
an aqueous solution of a water miscible polymer forming millions of microscopic drug
reservoirs in a polymer matrix the device is coated with a rate-controlling membrane to
further modify the drug release.
.
1.4.2 Chemically controlled
Chemically controlled drug delivery systems regulate the drug release rate by a
chemical reaction with the polymer. The principal advantage is that in contrast to a
nonbioerodible system the polymer is dissolved and absorbed by the body. However the fate
of these polymeric products in the body must be carefully observed and rigorous testing is
required to confirm the safety of the polymer. The two predominant mechanisms for
chemically controlling drug release are bioerosion and pendent chain.

Bioerosion
The bioerosion or biodegradation systems involve breakdown of the polymer into
small water soluble molecules. Bioerosion-controlled devices are matrix controlled with
uniform drug distribution inside the polymer. As the polymer is broken down water comes in
contact with the drug leading to its dissolution and release. Depending on water-soluble
components water may penetrate throughout the device or come in contact only with the
surface. In the former case polymer erosion starts throughout the matrix: these devices are

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 5

 Introduction

known as bulk eroding. On the other hand if the polymer is hydrophobic and water does not
penetrate inside the device, erosion only on the surface; these devices can be called surface
eroding. The drug rate from a surface eroding polymeric matrix with uniform drug
distribution is given by eq.
dM
=ks
dt

Where, K is a constant,
dM
dt is related to the drug concentration in the matrix and the rate of polymer

erosion
S is the surface area of the system.

Pendent chain
The other mechanism for chemically controlled release of drug is known as the
pendent-chain system where the drug is attached to the polymer backbone by a labile
chemical linkage. In the presence of water or enzymes the labile linkage breaks the drug. The
pendent chain may be water soluble or insoluble; a water backbone may serve as a drug
carrier to a specific cell or organ where the drug is released by metabolism. Insoluble pendent
chains serve as a depot from which the drug slowly released.

1.4.3 Solvent activated

Solvent-activated system release active agents because of controlled penetration of a
solvent into the device; they can be controlled by swelling or osmotic pressure.

Swelling controlled
Swelling- controlled systems are similar to matrix-type devices except that the
dispersed drug is immobilized inside a glassy polymer and therefore there is no diffusion of
drug. When this device is placed in water the outer polymer region begins to swell, resulting
in relaxation of the polymer chains. This allows the locked drug to diffuse outward. Therefore
two fronts are observed: one moving inward, separating the polymer in the glassy state from
the rubbery state and the second moving outward separating the swollen rubbery polymer
from the surrounding aqueous medium. The drug release is determined by the rate relaxation
of the chains that unlock the drug.

Osmotically controlled

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 6

 Introduction

In osmotically controlled system an osmotically active agent such as water soluble

salt is placed inside a rigid semi permeable housing, which is separated from the drug
compartment by a movable partition. The semi permeable housing draws water inside by
osmosis, leading to an increase in volume and exertion of pressure on the movable partition.
The partition, in turn pushes the drug out of the compartment through a delivery orifice or
cannula. Thus, the drug delivery rate is controlled by the mass movement of water across the
permeable membrane.

1.4.4 Externally regulated

These systems have the important advantage that the drug-delivery rate can be
externally increased on demand ever after the device has been implanted. Four predominant
techniques have been evaluated with externally modulated implant: magnetically controlled,
ultrasonically activated, thermally activated and electrically controlled.

Magnetically controlled
In magnetically controlled drug-delivery systems the drug and magnetic beads are
uniformly dispersed inside semi elastic polymer matrix made of a nonbiodegradable polymer
such as ethylene-vinyl acetate copolymer (EV Ac). When the device is placed in dissolution
medium the drug release follow matrix diffusion control. However, when the device is placed
in a magnetic field, the magnetic beads attempt to a align with the applied magnetic field
including a torque on the magnet and a slight rearrangement of the polymer. In an oscillating
magnetic field, the beads tend to oscillate compressing and expanding the polymer in the
process.

Ultrasonically activated
In these systems the drug is uniformly distributed inside a polymer and an external
ultrasonic field is applied to activate drug release. They have been evaluated for both non
biodegradable polymers (EVAc) and biodegradable polymers [polyesters, polynanhydrides,
polyglycolides, polylactides and sebacic acid]. In the case of biodegradable polymers
application of ultrasound increases the drug release as well as the polymer degradation rate.
In both the biodegradable and nonbiodegradable polymer systems the drug release rate was
controlled by the intensity, frequency and duration of the ultrasound.

Thermally activated
A series of thermosensitive hydrogels that show significant swelling changes in water
in response to temperature have been prepared and evaluated. These polymers responded to

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 7

 Introduction

temperature change based on the Flory-Huggins theory that a change in temperature affects
hydrogen bonding which in turn, affects swelling. A linear correlation is observed between
the diffusion coefficient for entrapped drug and polymer swelling.

Electrically controlled
Electrically controlled systems provide drug release by the action of an applied
electric field on a rate-limiting barrier membrance or a solute thus modulating its transport
across it. Grimshaw reported four different mechanisms for the transport of proteins and
neutral solutes across hydrogel membranes:
• Electrically and chemically induced swelling of a membrane to alter the effective pore
size and permeability
• Electrophoretic augmentation of solute flux within a membrane
• Electroosmotic augmentation of solute flux within the membrane and
• Electrostatic partitioning of charged solutes into charged membrane.

1.4.5 Self-regulated
These are biofeedback-controlled system, where the drug release rate is dependant on
the body’s need for the drug at a given time. From a therapeutic viewpoint these systems may
come close to duplicating the release from a gland such as the pancreas. A variety of
mechanisms have been employed to obtain self-regulated delivery.

Ionic strength and pH responsive
These devices take advantage of the fact that polymers containing weakly acidic or
basic side groups develop a charge in alkaline or acidic pH respectively. In a cross-linked
water-insoluble polymer, this results in water uptake and corresponding swelling of the
polymeric membrane with opening of molecular pores and increased drug release rate.

Glucose responsive
Glucose Oxidase catalyses a reaction between glucose and oxygen in the body fluids
to form gluconic acid, which reduces the pH of the microenvironment. The insulin-release
systems based on glucose Oxidase utilize this drop in pH to trigger an increased release.

Urea responsive
The device of disk containing hydrocortisone incorporated into a biodegradable
polymer with pH dependent degradation. This disk is coated with a hydrogen containing
immobilized urease. In physiological- buffer base line hydrocortisone is released due to the
hydrolysis of the polymer and diffusion of drug. In the prevalence of urea the enzyme urease
increases the pH of microenvironment by converting urea into ammonium bicarbonate and

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 8

 Introduction

ammonium hydroxide.This increase in pH results in results in increased hydrolysis of the

biodegradable polymer and increased hydrocortisone release.

1.5 NON-DEGRADABLE AND BIODEGRADABLE IMPLANT SYSTEMS

1.5.1 Non-degradable implant systems

Figure 1.1: Matrix system showing diffusion of the drug across the polymer

There are several types of nondegradable implantable drug delivery systems available in
the market place today, but the nondegradable matrix system and reservoir systems are the
two most common forms.
In the polymeric matrix system, the drug is dispersed homogeneously, inside the
matrix material. Slow diffusion of the drug through the polymeric matrix material provides
sustained release of the drug from the delivery system.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 9

 Introduction

Figure 1.2: Reservoir systems showing diffusion of the drug across the polymer

The reservoir-type consists of a compact drug core surrounded by a permeable nondegradable

membrane whose thickness and permeability properties can control the diffusion of the drug
into the body5. The release kinetics of drug from this system suggest that if the concentration
of the drug within the reservoir is in constant equilibrium with the inner surface of the
enclosed membrane, the driving force for diffusional release of the agent is constant and zero-
order release kinetics of the drug from the delivery system is obtained. This system is
nondegradable.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 10

 Introduction

1.5.2 Bio degradable implant systems

Biodegradable systems have gained much popularity over nondegradable delivery
systems. The major advantages of biodegradable systems include the fact that the inert
polymers, used for the fabrication of the delivery system, are eventually absorbed or excreted
by the body. This alleviates the need for surgical removal of the implant after the conclusion
of therapy thereby increasing patient acceptance and compliance6.
However, developing biodegradable systems is a more complicated task than
formulating nondegradable systems. When fabricating new biodegradable systems, many
variables must be taken into consideration. For instance, the degradation kinetics of the
polymer, in vivo, must remain at a constant rate to maintain sustained release of the drug.
Many factors can affect the rate of degradation of the polymer in the body. Alterations in
body pH or temperature can cause a transient increase or decrease in the degradation rate of
the system. The surface area of the delivery system also plays an important role in its
degradation7. As the system is eroded, the surface area of the implantable system decreases.

1.6 THERAPEUTIC APPLICATIONS2

• Ocular disease
Ocusert containing pilocarpine base and alginic acid in a drug reservoir surrounded by
a release-rate controlling ethylene-viny1 acetate membrane. The ocusert system provides an
initial burst followed by a near zero order delivery of pilocarpine at 20 or 40 µg/h for a period
of seven days.

• Contraception
Norplant a subdermal implant for long-term delivery of the contraceptive agent
levonorgestrel gas recently been approved for marketing by the FDA. The device consists of
six silicone membrane capsules each containing about 36 mg of levonorgestel. Cumulatively
the six capsules deliver about 70 µg/day at about 800 days.
• Dental allocation
Sustained-release fluoride delivery stannous fluoride was incorporated into different
dental cements. The device, about 8 mm long and containing 42 mg of fluoride in the core
was attached to the buccal surface of the maxillary first molar and designed to release 0.5 mg
of fluoride per day for 30 days.
• Immunization

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 11

 Introduction

The concept here is to provide pulsatile of continuous administration of the antigen

over a prolonged time period. For example, immunization efficiency of ethylene-vinyl acetate
copolymer pellets containing bovine serum albumin as model antigen.
• Cancer
Silicone rod implants similar to those used for delivery of levonorgestrone,
testosterone propionate or ethinyl estradiol were used in patients with prostate cancer.
Lupron depot is an implantation system providing one month depot release of
leuprolide acetate a synthetic analogue of the gonadotropin releasing hormone (GhRH). The
implant consists of biodegradable microspheres prepared from polylactic – glycolic
copolymer at 50:50 composition containing 10% leuprolide acetate for the treatment of
prostate cancer
• Narcotic antagonists
Naltrexone freebase and its hydrochloride or the pamolate acid salt has been prepared
in a variety of polymers and dosage forma for prolonged narcotic antagonist activity. Though
in vitro delivery of up to 50 day has been achieved by some of the systems in vivo duration of
release has been shorter.

1.7 DIFFERENT TYPES OF IMPLANTS

Brain implants8
Brain implants, often referred to as neural implants, are technological devices that
connect directly to a biological subject's brain- usually placed on the surface of the brain or
attached to the brain's cortex. A common purpose of modern brain implants and the focus of
much current research is establishing a biomedical prosthesis circumventing areas in the brain
that have become dysfunctional after a stroke or other head injuries. This includes sensory

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 12

 Introduction

substitution, e.g. in vision. Other brain implants are used in animal experiments simply to
record brain activity for scientific reasons. Some brain implants involve creating interfaces
between neural systems and computer chips.

Microchip implants9

A human microchip implant is an integrated circuit device or RFID (radiofrequency

identification) transponder encased in silicate glass and implanted in the body of a human
being. A subdermal implant typically contains a unique ID number that can be linked to
information contained in an external database, such as personal identification, medical
history, medications, allergies, and contact information.

Microdermal implant10

Micro dermal implants are a form of body modification which gives the anaesthetic
appearance of a transdermal implant, but without the complications of the much more
complicated surgery associated with transdermal implants. Microdermal implants can be
placed practically anywhere on the surface of the skin on the body.

Contraceptive implants11

Norplant is implanted under the skin in the upper arm of a woman, by creating a small
incision and inserting the capsules in a fan-like shape. Insertion of Norplant usually takes 15
minutes and the capsules can sometimes be seen under the skin, although usually they looks
like small veins.

Retinal implants12

A retinal implants is a biomedical implant technology that it meant to partially restore

useful vision to people who have lost due to a degenerative eye conditions such as retinitis
pigmentosa or macular degeneration. There are two types of retinal implants: epiretinal
implant (on the retina) and subretinal implant (behind the retina).

Dental implants13

A dental implant is a "root" device, usually made of titanium, used in dentistry to

support restorations that resemble a tooth or group of teeth to replace missing teeth. All dental
implants placed today are root-form endosseous implants, i.e., they appear similar to an
actual tooth root and are placed within the bone. The bone of the jaw accepts and

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 13

 Introduction

osseointegrates with the titanium post. Osseointegration refers to the fusion of the implant
surface with the surrounding bone. Dental implants will fuse with bone; however they lack
the periodontal ligament, so they will feel slightly different than natural teeth during chewing.

Dental implant is available as patches for the bacterial infections in order to prevent
the growth of micro-organisms.

DENTAL IMPLANTS

Dental implants can be used to support a number of dental prostheses, including

crowns, implant-supported bridges or dentures14. They can also be used as anchorage for
orthodontic tooth movement. The use of dental implants permits unidirectional tooth
movement without reciprocal action.

Dental implants are not susceptible to dental caries and other bacterial infections but
they can develop a condition called peri-implantitis. This is an inflammatory condition of the
mucosa and/or bone around the implant which may result in bone loss and eventual loss of
the implant. The condition is usually, but not always, associated with a chronic infection.
Peri-implantitis is more likely to occur in heavy smokers, patients with diabetes, patients with
poor oral hygiene and cases where the mucosa around the implant is thin15.

Dental diseases may affect the teeth or the gums or other tissues and parts of the
mouth. Dental diseases can cause much more serious problems than a toothache; they can
affect our ability to chew, smile, or speak properly. Their severity may range from a simple
apthous ulcer, to a common tooth cavity, or up to a deadly oral cancer. These are among the
most common diseases in humans and include dental caries, gingivitis, periodontitis and
many more oral conditions16.

1.9 PERIODONTAL DISEASES17

Periodontal diseases are generally divided into two groups

• Gingivitis , which causes lesions (inflammatory abnormalities) that affect the gums.
• Periodontitis , which damages the bone and connective tissue that supports the teeth.

A periodontal disease is caused by bacteria. Even in healthy mouth, the sulcus is teeming
with bacteria, but they tend to be harmless varieties. Periodontal diseases usually develops

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 14

 Introduction

because of two events in the oral cavity: an increase in bacteria quantity and a change in
balance of bacterial types from harmless to disease-causing bacteria.

Periodontitis

Periodontitis occurs when the gum tissues separate from the tooth and sulcus, forming
periodontal pockets. Periodontitis is characterized by:

• Gum inflammation, with redness and bleeding

• Deep pockets (greater than 3 mm in depth) that form between the gum and the tooth.
• Loose teeth, caused by loss of connective tissue structures and bone.

Periodontal treatment approaches can basically be categorized as:

• Non-surgical approaches- Scaling and root planning, which may include the use of
topical or systemic antibiotics.
• Surgical approaches- Periodontal surgical techniques include flap surgery (periodontal
reduction), bone grafts and guided tissue regeneration.
• Restorative procedures- Crown lengthening is an example of a restorative procedure
that may be performed for cosmetic reasons or to improve function. For patients who
have already lost teeth to advanced periodontitis, dental implants are another options.

Non- Surgical treatment

Scaling and root planning is a deep cleaning to remove bacterial plaque and calculus
(tartar). It is the cornerstone of periodontal disease treatment and the first procedure a dentist
will use. Scaling involves scraping tartar from the above and below the gum line. Root
planning smoothes the root surfaces of the teeth.

At the time of scaling and root planning, the antibiotics are recommended because of
the risk of developing antibiotic-resistant infections. Antibiotics for periodontal disease come
in various forms. They may be taken as a prescription mouthwash rinse, or placed topically as
dissolving gels, threads or microchips into the periodontal pockets.

Nonsurgical periodontal therapy is used to delay repopulation of pathogenic

microorganisms by controlling the supragingival bacterial plaque and by disrupting or
removing the subgingival gram-negative flora.

The clinical outcome of periodontal treatment is improved if specific microbial

pathogens are eradicated from the tissues18. Because local scaling and root planning alone

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 15

 Introduction

cannot achieve this predictably, mechanical treatment has been combined with the delivery of
either topical or systemic antimicrobial therapy19-21. Agent used in this situation include
amoxicillin, clindamycin, metronidazole, tetracycline and doxycycline. Some antibiotics have
been shown to have anti-inflammatory properties that are independent of their antimicrobial
activities22, 23.

In addition to a direct antibacterial effect on ribosomal nits, clindamycin has a number

of unique pharmacologic features that enhance its clinical efficacy. Clindamycin is the only
proven antibiotic that reduces the adherence of bacteria to the epithelial cell of mucosal
surfaces and inhibits the expression of virulence factors.

Clindamycin is known to have a very favourable spectrum of activity against

anaerobic infections. Its antimicrobial spectrum also includes gram-positive cocci, gram-
positive and gram-negative anaerobes and certain protozoa. Clindamycin has been considered
a suitable antimicrobial for the management of periodontal infection. Clindamycin in gel
form have been used in the treatment of periodontal diseases24. When it was given in gel form
its bioavailablity reduces and number of doses increases. Normally clindamycin half-life is 2-
3 hrs25. In the present study, in order to increase its half-life as well as to reduce the dose,
implant has been developed by using the biodegradable polymers.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 16

 Review of Literature

2. REVIEW OF LITERATURE

2.1 CLINDAMYCIN24

Clindamycin is a lincosamide antibiotic which inhibits the growth of the microorganisms.

Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin, a substance
produced by the chlorination of linocomycin. It has a potency equivalent to not less than
800µg of clindamycin (C18H33ClN2O5S) per mg.

Table 2.1: Characteristics of Clindamycin Hydrochloride

Generic name Clindamycin Hydrochloride

Synonyms Anti-clindamycin, Cleocin, Dalacin
Chemical name L-threo-α-D-galacto-octopryanoside methyl
7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-
propyl-2-pyrrolidinyl)-carbonyl)amino]-1-
thio-(2S-trans) monohydrochloride
Molecular formula C18H33ClN2O5S.HCl
Molecular weight 461.45
Appearance Yellow, amorphous solid

Figure 2.1 Clindamycin Hydrochloride

Mechanism of action

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 17

 Review of Literature

Clindamycin has a bacteriostatic effect. It is a bacterial protein synthesis inhibitor by

inhibiting ribosomal translocation26. It binds to 50S rRNA of the bacterial ribosome subunit 27.
It also inhibit the binding of amino-acyl transfer RNA or the translocation of messenger RNA
Clindamycin contains a basic pyrrolidene ring attached to a sugar group through an amide
bond. The replacement of the hydroxyl group in lincomycin to a chloride atom increases the
lipophilicity and therefore clindamycin shows a better absorption and penetration into
bacterial cells.

Figure 2.2: Mechanism pathway of Clindamycin hydrochloride28, 29

Indication 25

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 18

 Review of Literature

It is used for the treatment of serious infections caused by susceptible anaerobic bacteria,
including Bacteroides spp., Peptostreptococcus, anaerobic Streptococci, Clostridium spp.,
and microaerophilic Streptococci. It may be useful in polymicrobic infections such as intra-
abdominal or pelvic infections, osteomyelitis, diabetic foot ulcers, aspiration pneumonia and
dental infections. It can also be used to treat MSSA (Methicillin sensitive Staphylococcus
aureus) and respiratory infections caused by S. pneumoniae and S. pyogenes in patients who
are intolerant to other indicated antibiotics or who are infected with resistant organism. It may
be used vaginally to treat vaginosis caused by Gardnerella vaginosa. Clindamycin reduces
the toxin producing effects of S. aureus and S. pyogenes and as such, may be particularly
useful for treating necrotizing fasciitis.

Table 2.2: Physicochemical and biopharmaceutics parameters of Clindamycin Hydrochloride25

Physicochemical parameters
Storage Store at controlled room temperature 20ºC to
25ºC (68º to 77ºF)
Solubility Soluble in water, pyridine, ethanol and DMF
(N,N-dimethlyformamide)
Melting point 142ºC
Biopharmaceutical parameters
Bioavailability 90% (Oral), 4-5%(Topical)
Absorption Rapidly absorbed after oral administration
with peak serum concentrations observed
after about 45 minutes. Absorption of an oral
dose is virtually complete (90%)
Protein Binding 92-94%
Metabolism Hepatic
Half life 2-3Hrs
Excretion Excreted in the urine and in the feces; the
remainder is excreted as bioinactive
metabolites

Adverse reaction30

Gastrointestinal - Abdominal pain, nausea, vomiting, diarrhea, colitis, esophagitis

and esophageal ulcer.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 19

 Review of Literature

Hypersensitivity Reactions - Maculopapular rash and urticaria have been observed

during drug therapy. Rare instances of erythema multiforme, some resembling Stevens-
Johnson syndrome, have been associated with clindamycin.
Liver - Jaundice and abnormalities in liver function tests have been observed during
clindamycin therapy.
Skin and Mucous Membranes - Pruritus, vaginitis and rare instances of exfoliative
and vesiculobullous dermatitis have been reported. Rare cases of toxic epidermal necrolysis
have been reported during post-marketing surveillance.
Hematopoietic - Transient neutropenia (leukopenia) and eosinophilia have been
reported. Reports of agranulocytosis and thrombocytopenia have been made.
Renal - Although no direct relationship of clindamycin to renal damage has been
established, renal dysfunction as evidenced by azotemia, oliguria and/or proteinuria has been
observed in rare instances.
Musculoskeletal - Rare instances of polyarthritis have been reported.
Nervous System - Dysgeusia has been reported during post-marketing surveillance.

Interactions

Erthyromycin - Antagonistic effect

Kaolin/ Pectin - Decreased GI absorption of clindamycin
Hormonal contraceptives- Decreased contraceptive efficacy
Neuromuscular blockers - Enhanced neuromuscular blockade
Uses

• Acne
• Bacterial vaginosis
• As prophylaxis in bacterial endocarditis
• Other serious anaerobic infection

Dosage form

Capsule 75mg, 150mg, 300mg

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 20

 Review of Literature

Gel, topical 1% 30gm, 60gm or 40ml, 75ml

Granules for oral solution 75mg/5ml (100ml)

I.V 300mg (50ml), 600mg (50ml), 900mg (50ml)

Lotion 1% 60ml

Solution, topical 1% 30ml, 60ml

Vaginal suppository 100mg

Dosage

For Severe infection caused by sensitive organisms

Adults: 300 to 450mg p.o q 6hrs pr 1.2 to 2.7ml/day i.m or i.v two to four
equally divided doses

Children: 16 to 20mg/kg/day (Hydrochloride) in 3 to 4 equally divided doses or

13 to 25mg/kg/day p.o (Palmitate HCl) in 3 to 4 equally divided doses.

Neonates younger than 1 month: 15 to 20mg/kg/day i.m or i.v in 3 to 4 equally

divided doses.

Acute pelvic inflammatory disease

Adults: 900mg i.v q 8hrs (given with gentamicin)

Acne vulgaris
Adults and children older than age 12. Apply a thin film of topical gel, lotion or
solution locally to affected area b.i.d.

For prevention of endocarditis:
Adults: 300 mg orally 1 hour before surgical procedure; then 150 mg 6 hours after
initial dose.
Children: 10 mg/kg (not to exceed adult dose) orally 1 hour before surgical
procedure; then 5 mg/kg 6 hours after initial dose.

2.2 POLYMER PROFILE

2.2.1 GELATIN31

Gelatin is a generic term for a mixture of purified protein fractions obtained either by
partial acid hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin) of

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 21

 Review of Literature

animal collagen. The protein fractions consist almost entirely of amino acids joined together
by amide linkages to form linear polymers.

Synonyms: Byco; Cryogel; Gelatine, Instagel, Solugel

Molecular weight: 15 000- 2 50 000

Functional categories: Coating agent, film former, gelling agent, suspending agent, tablet
binder, viscosity-increasing agent

Pharmaceutical Specifications

Test Ph Eur 2005

pH 3.8-7.6

Loss of drying 15%

Isoelectric point 6.0-9.5 (Type A), 4.7-5.6 (Type B)

Typical properties

Acidity/alkalinity: For a 1%w/v aqueous solution at 25ºC

pH = 3.8-6.0 (Type A)

pH = 5.0-7.4 (Type B)

Density

1.325 g/cm3 for type A

1.283 g/cm3 for type B

Isoelectric point

7-9 for type A

4.7-5.3 for type B

Moisture content: 9-11%

Solubility:

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 22

 Review of Literature

Practically insoluble in acetone, chloroform, ethanol (95%), ether and methanol. Soluble
in glycerine, acids and alkalis, although strong acids or alkalis cause precipitation. Gelatine is
soluble in hot water, forms a jelly or gel on cooling at 35-40ºC.

Application in pharmaceutical formulation or technology

Gelatin is used as a biodegradable matrix material in an implantable delivery system.

Gelatin is also used for the microencapsulation of drugs, preparation of pastes, pastilles,
pessaries and suppositories. In addition, it is used as a tablet binder and coating agent and as a
viscosity for solutions and semisolids.

2.2.2 SODIUM ALGINATE32

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 23

 Review of Literature

Sodium alginate consists of sodium salt of alginic acid, which is a mixture of polyuronic
acids composed of residues of D-mannuronic acid and L-guluronic acid.

Synonyms: Algin, E401, Kelcosol, Keltone, Protanal, Sodium polymannuronate

Functional category: Stabilizing agent, suspending agent, tablet and capsule disintegrant,
tablet binder, viscosity-increasing agent.

Pharmaceutical specifications

Test USPNF 23

Microbial limits 200/g

Loss of drying 15.0%

Ash 18.0-27.0%

Assay 90.8-106.0%

Typical properties

Acidity/alkalinity: pH~7.2 for a 1%w/v aqueous solution

Solubility:

Practically insoluble in ethanol (95%), ether, chloroform, and ethanol/water. Slowly soluble
in water and forms a viscous colloidal solution.

Viscosity (dynamic):

Typically, a 1%w/v aqueous solution at 20ºC, will have a viscosity of 20-400 mPas (20-400
cP). Viscosity may vary depending upon concentration, pH, temperature or the presence of
metal ions.

Applications in pharmaceutical formulation or technology

Sodium alginate is used in tablet formulations as a binder and disintegrant, it has been used as
a diluents in capsule formulations. Sodium alginate has also been used in the preparation of
sustained release oral formulations, since it can delay the dissolution of a drug from tablets,
capsules and aqueous suspensions.

2.3 REVIEW OF LITERATURE

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 24

 Review of Literature

H.A.Khan et al 33, Tamsulosin biodegradable PLGA in-situ implant was formulated and the
invitro release study was performed. The effect of drug loading and the effect of excipients on
the release pattern were studied. This system is prepared by dissolving a biodegradable
polymer DL-poly (lactide-co-glycolide) 70K in biocompatible solvent, dimethyl sulfoxide.
Two types of implants were prepared such as implants containing tamsulosin hydrochloride
and tamsulosin hydrochloride with biocompatible excipients such as tween 20, tween 60,
span 20, span 80, chremophore EL or chremophore RH 40. In vitro dissolution studies were
performed in static condition using phosphate buffer (pH 7.4) to observe the release of drugs
from these implants for 10 days. Formulation containing only tamsulosin hydrochloride
showed that the release rate of drug was 64.51%, 70.64%, 74.08%, 76.12% and 80.05%. It
can be concluded that the release rate of drug increases with increasing drug concentrations.
The other formulation containing tamsulosin with excipients showed that the release rate was
74.70%, 75.14%, 60.03%, 63.83%, 70.82% and 76.43% against same conc. of drug (8.7% of
drug) but different excipients such as tween 20, tween 60, span 20, span 80, chremophore EL
and cremophore RH 40 respectively. It can be concluded that excipient lowers the release rate
of the drug and may prolong the activity and overall release kinetics.

Heba A Gad et al34, In Situ implants containing Doxycycline hydrochloride and/or

Secnidazole was formulated to treat the periodontitis by direct periodontal intrapocket
administration. Biodegradable polymers [poly (lactide) (PLA) and poly (lactide-co-glycolide)
(PLGA)], each polymer in two concentrations 25%w/w, 35%w/w were used to formulate the
in-situ implants. The rheological behaviour, in vitro drug release and the antimicrobial
activity of the prepared implants were evaluated. Increasing the concentration of each
polymer increases the viscosity and decreases the percent of the drug released after 24hrs.
PLA implants showed a slower drug release rate than PLGA implants in which the implants
composed of 25% PLGA showed the fastest drug release.

Ananta Choudhury et al35, Buccoadhesive film of Ciprofloxacin hydrochloride was

developed and in-vitro parameter was studied. Films were formulated using different
concentration of hydroxypropyl methyl cellulose and polyvinyl alcohol. The prepared films
were subjected to different evaluation like weight determination, thickness, surface pH,
folding endurance, swelling index, mucoadhesive time, mucoadhesive strength, drug content,
in-vitro drug release study, ex-vivo release study and release kinetic behavior. From the result

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 25

 Review of Literature

it was conclude that all prepared films having desire flexibility and mucoadhesive properties,
along with that they shows good in-vitro and ex-vivo drug release performance. Drug release
from the films follows desire sustained release phenomenon as needed in buccoadhesive drug
delivery.

M.G.Ahmed et al36, Chitosan strips containing Gatifloxacin (10%, 20% and 30% to the
weight of polymer) were prepared by solution casting method using 1% v/v acetic acid in
water. The strips containing 30% gatifloxacin were cross-linked by exposing to the vapours
of 2% v/v glutaraldehyde in water intended to extend the release. The prepared films were
evaluated for their thickness, content uniformity, weight variation, tensile strength, hardness
and in-vitro dissolution. Macroscopical features revealed that drug was dissolved in the
polymer matrix rather than dispersing. The average weight and thickness of both the
crosslinked and uncross-linked strips were uniform. There was a reduction in the tensile
strength and increase in hardness when the films were cross-linked. Static dissolution studies
showed a burst release initially followed by a progressive fall in the release of the drug and
extended upto 19 days once the strip was cross-linked. Release kinetics of gatifloxacin from
chitosan strips followed the higuchi’s diffusional model and also showed zero order release
profile.

Manoj kumar et al37, Periodontal films containing metronidazole were prepared by solvent
casting technique using ethyl cellulose, hydroxyl propyle cellulose and eudragit RL-100 with
dibutyl phthalate and polyethylene glycol 400. The films were evaluated for their thickness
uniformity, folding endurance, weight uniformity, content uniformity, tensile strength and
surface pH. Data of in-vitro release from films were fit to different equations and kinetic
models to explain release kinetics. Hixon-crowell, Higuchi and Korsmeyer-Peppas models
were used to fit the in-vitro release data. Formulation with high concentration of ethyl
cellulose released 94.18% of the drug at the end of 120hrs and was more sustained with first
order release kinetics. From the result, it was concluded that metronidazole could be
incorporated in a slow release device for the treatment of peridontitis.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 26

 Review of Literature

N.Udupa et al38, Dental implants of doxycycline hydrochloride and tinidazole were

formulated using a biodegradable carrier poly (ε-caprolactone), for the treatment of
peridontitis. The in-vitro drug release pattern and stability of these devices were studied. The
formulations showed an initial burst release followed by more sustained release of the drugs
throughout the period of study (42 days). The stability of the drug were shown a marked
improvement by formulating them in polymer matrix.

Varinder kumar et al39, Mucoadhesive buccal patches containing venlafaxine were prepared
using the solvent casting method. Chitosan and pectin were used as bioadhesive polymer at
different ratios. The patches were evaluated for their physical characteristics like mass
variation, drug content uniformity, folding endurance, surface pH, and in vitro drug release,
in vitro buccal permeation study, ex vivo bioadhesion strength and ex vivo mucoadhesion
time. Patches exhibited controlled release and releases the entire contents with a period of 10
hrs. Incorporation of PVP K-30 generally enhances the release rate. Swelling index was
proportional to the concentration of chitosan. Drug with 1:4 (chitosan:pectin) polymer
showed satisfactory bioadhesive strength of 17.53 ± 0.47 g, and ex vivo mucoadhesion time
of 10.32hrs. The surface pH of all batches was within ± 0.4 units and thus no mucosal
irritation is expected. Patches containing 1:4 of chitosan and pectin had higher bioadhesive
strength with sustained drug release as compared to patches with other ratios of polymer. The
optimized patch demonstrated good in vitro and ex vivo results.

G.L.Prabushankar et al40, Levofloxacin dental films for periodontitis were formulated by

solvent casting technique using ethyl cellulose and other copolymers in chloroform:
dichloromethane (1:1) solvent with dibutyl phthalate and PEG 400. The films were evaluated
for their thickness uniformity, folding endurance, weight uniformity, content uniformity,
tensile strength, surface pH, and in vitro antibacterial activity. In vitro release from films was
fit to different equations and kinetic models to reveal release kinetics. The R2 values are
higher for Higuchi’s model compared to Hixson Crowell cube root law for all the films and
the release from all the films followed diffusion rate. Formulation with eudragit RL-100
released 99.74% of drug at the end of tenth day and was considered as best formulation. . In
vitro antibacterial activity was carried out on S. aureus and E.coli was found to be effectively
higher in 48hrs and then decline at 96hrs.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 27

 Review of Literature

V.S. Mastiholimath et al41, Ornidazole dental implants for the treatment of periodontal
diseases was prepared by using solvent casting technique using hydroxyl propyl cellulose,
hydroxyl methyl cellulose, eudragit RL-100 and ethyl cellulose with dibutyl phthalate . The
physicochemical parameters like thickness, weight variation, content uniformity and release
characteristic were evaluated. The drug release was initially high on day one to achieve
immediate therapeutic level of drug in periodontal pocket followed by marked fall in release
by day two with progressive moderate release profile to maintain therapeutic level following
anomalous transport mechanism. Formulation with ethyl cellulose released 97.07% of drug at
the end of 120hrs and was considered as best formulation. In vitro antibacterial activity was
carried out on Streptococcus mutans and had an inhibitory effect upto 96hrs.

Rao.K.Purushotham et al42, Diclofenac sodium biodegradable drug implant for speedy

fracture healing was formulated in varied ratios of gelatin and sodium alginate 70:30, 80:20
and 90:10% w/w by heating and congealing method. The implants were evaluated for content
uniformity, thickness, weight variation, IR and invitro release studies. The implants gave
uniform result for thickness, weight variation and drug content. From the invitro release
studies, it was concluded that subdermal implants containing 90:10%w/w gelatin: sodium
alginate were found to produce the most satisfactory drug release of 98.41% in 144 hours.

M.G.Ahmed et al43, Chitosan based Ciprofloxacin and Diclofenac film for peridontitis
therapy was prepared by solvent casting method. Some of the drug loaded films were
crosslinked with 2% glutaraldehyde for 2 and 4hrs. The films were evaluated for their
physicochemical properties including weight variation, thickness, tensile strength, invitro
release and antibacterial activity. Mean weight and thickness data showed that the different
films were uniform. Tensile strength was maximum for drug-free films and minimum for
films containing the highest amount of drug. In vitro drug release data indicate that the films
showed an initial burst release followed by sustained release for upto 7 days for
uncrosslinked films (87-95%) and 21 days for crosslinked films (70-78%). Films stored at
refrigerated conditions exhibited slower degradation rate. The drug loaded films that were
crosslinked for 4hrs had inhibitory effect on S. mutans for up to 24 days.

Sujatha et al44, Sparfloxacin dental implants for the treatment of Periodontal diseases was
prepared by using solvent casting technique using hydroxyl propyl cellulose, hydroxyl methyl

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 28

 Review of Literature

cellulose, eudragit RL-100 and ethyl cellulose with dibutyl phthalate. The drug release was
initially high on day one to achieve immediate therapeutic level of drug in periodontal pocket
followed by marked fall in release by day two with progressive moderate release profile to
maintain therapeutic level following anamolous transport mechanism. Formulation F4
released 90.24% of drug at the end of 120hr and was considered as best formulation. In vitro
antibacterial activity was carried out on Streptococcus mutans.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 29

 Aim and Objective

3. AIM AND OBJECTIVE

The goal of drug delivery system is to provide a therapeutic amount of drug to the

targeting site in the body to achieve promptly and then maintain the desired drug

concentration.

Our system of interest is to develop Clindamycin hydrochloride Implantable drug

delivery system. This drug has low half-life of 2-3 hrs, in order to increase its half-life,

implants were developed.

Present research work is to design and evaluate the biodegradable implantable drug

delivery system of Clindamycin hydrochloride for periodontal diseases.

Thus objective of my work is to formulate and evaluate the implants of Clindamycin

hydrochloride in different ratios of drug and polymer, gelatin and sodium alginate and to

study the drug release and anti-microbial activity.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 30

 Plan of Work

4. PLAN OF WORK

Selection of drug and polymer

Preformulation study

Formulation of Clindamycin hydrochloride implant in different drug:polymer ratio

using gelatin and sodium alginate.

Construction of standard graph of pure drug Clindamycin hydrochloride in 0.1N HCl

and Phosphate buffer pH 7.4.

Infra red spectroscopy and differential scanning calorimeter analysis for identifying

the interaction between the drug and polymer.

Physicochemical parameters
Weight uniformity test
Thickness
Drug content uniformity
Percentage moisture loss
Surface pH

Invitro drug release studies

Stability studies

Antimicrobial activity.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 31

 Materials and Methods

5.MATERIALS AND METHODS

Table 5.1: Materials used in the formulation

Materials Source
Clindamycin HCl A to Z Pharmaceuticals Private Ltd, Chennai.
Gelatin Sd fine – chem. Ltd, Mumbai.
Sodium alginate Sd fine – chem. Ltd, Mumbai.
PEG 400 Himedia Laboratories Pvt. Ltd, Mumbai.
Potassium dihydrogen Spectrum reagents and chemicals Pvt.Ltd,
phosphate Cochin.
Disodium hydrogen phosphate Sd fine – chem. Ltd, Mumbai.
Luria Bertani broth Himedia Laboratories Pvt. Ltd, Mumbai.
Luria Bertani agar Himedia Laboratories Pvt. Ltd, Mumbai.
Table 5.2: Equipments

S.N Equipment Manufacturer

o
1 IR Shimadzu, Japan
2 Digital balance Essae Teraoka Ltd, India
3 UV-Visible Lab India, Mumbai.
4 Screw gauge Micrometer, Chennai.
5 Mechanical stirrer Remi Motor Ltd, Mumbai
6 Differential scanning TA instrument, US.
calorimeter
7 Laminar air flow Klenzaids, Mumbai.
chamber

FORMULATION OF CLINDAMYCIN HCl

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 32

 Materials and Methods

The formulae for the preparation of Clindamycin HCl implants were given in the table 6.
Gelatin and Sodium alginate were used as a polymer.

Aqueous solution of gelatin and sodium alginate combination were prepared by dissolving
them in distilled water by stirring at a water bath at 60ºC. A solution of drug was added to the
above aqueous solution. The resultant solution was poured on a glass petridish and allowed to
dry at room temperature for 3 days. After drying they were stored at room temperature for
further use.

The concentration of polymers (gelatin and sodium alginate) was varied i.e., 500 mg, 750 mg
and 1000 mg. In that different concentration of polymers, each had different ratios of gelatin
and sodium alginate 70:30, 80:20 and 90:10 as shown in table 5.

Table 5.3: Polymer ratios used in the formulation

Polymer 500mg
F1 (70:30) F2 (80:20) F3 (90:10)
Gelatin (mg) 350 400 450
Sodium alginate (mg) 150 100 50
Polymer 750mg
F4 (70:30) F5 (80:20) F6 (90:10)
Gelatin (mg) 525 600 675
Sodium alginate (mg) 225 150 75
Polymer 1000mg
F7 (70:30) F8 (80:20) F9 (90:10)
Gelatin (mg) 700 800 900
Sodium alginate (mg) 300 200 100

Preparation of implants

Soak gelatin in 15ml of distilled water

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 33

 Materials and Methods

Hydration, 30minutes

Add sodium alginate to the gelatin

solution

Add PEG 400 Heat at 60°C at a water bath

Stir the solution until it get dissolved

Addition Dissolve the drug in

10ml of distilled water

Pour the resultant solution in the glass

petridish

Drying 3 days at room temperature

Store the dried implant for further

studies

Figure 5.1: Method of preparation of Clindamycin HCl implant

Table 5.4: Formulation chart of Clindamycin hydrochloride implants

Ingredients Formulation code

F1 F2 F3 F4 F5 F6 F7 F8 F9

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 34

 Materials and Methods

Clindamycin
hydrochloride (mg) 250 250 250 250 250 250 250 250 250

Gelatin (mg) 350 400 450 525 600 675 700 800 900

Sodium alginate (mg) 150 100 50 225 150 75 300 200 100

PEG 400 (ml) 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15

Distilled water (ml) 25 25 25 25 25 25 25 25 25

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 35

 Experimental Details

6. EVALUATION

6.1 PRELIMINARY SCREENING

Drug

i)Melting point

Melting point of the sample was determined by using capillary method.

ii)FTIR spectrum

FTIR spectrum of the drug was obtained by preparation of pellets using anhydrous KBr
between 4000 cm-1 and 500 cm-1.

iii)UV scanning

a) Scanning of Clindamycin Hydrochloride in 0.1N HCl

100mg of drug was dissolved in 100ml of 0.1N HCl. 1ml and 5ml of solution was
pipette and made upto 100ml with the 0.1N HCl to obtain 10 and 50mg/ml of
Clindamycin HCl. Scanning was done in the range 200 to 400nm to obtain λmax.
b) Scanning of Clindamycin Hydrochloride in pH 7.4 phosphate buffer
100mg of drug was dissolved in 100ml of pH 7.4 phosphate buffer. 1ml and 5ml of
solution was pipette and made upto 100ml with the pH 7.4 phosphate buffer to obtain
10 and 50mg/ml of Clindamycin HCl. Scanning was done in the range 200 to 400nm
to obtain λmax.

Polymer

The following polymers were chosen for the formulation of implants.

• HPMC
• MC
• EC
• Gelatin
• Sodium alginate
The trial formulation of implant was done with those polymers and the polymer has
been selected. The selected polymer was tested for the compatability studies by using
IR and DSC analysis.

6.2 ANALYTICAL METHODS

Construction of standard curve by UV method

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 36

 Experimental Details

Preparation of stock solution

100 mg of Clindamycin hydrochloride was accurately weighed and dissolved in 0.1 N HCl.
The volume was made up with the same to produce 100 ml of stock solution having
concentration of 1 mg/ml. From this 10 ml was pipette out and made up to 100 ml using 0.1
N HCl having concentration of 100 µg/ml.

Preparation of the working standard

Working standard solutions having concentration of 10 to 60 µg/ml were prepared by

appropriately diluting the stock solution with 0.1 N HCl. The absorbance of each working
standard was measured at 210 nm in UV spectrophotometer using 0.1 N HCl as a reagent
blank.

6.3 DRUG-POLYMER COMPATILIBILITY

6.3.1 IR analysis

Pure drug and polymers were subjected to IR studies. About 2 mg of pure drug/combination
of drug-polymer were triturated with KBr (Potassium bromide) to form a pellet. The mixture
was placed in the sample holder and was analyzed by infrared to study the interference of
polymers with the drug.

6.3.2 DSC analysis

DSC analysis was done to ascertain the compatibility of drug with the excipients.It was
performed on a DSC Q10 V 9.0, differential scanning calorimeter with a thermal analyzer.
About 2.3 mg of the powered sample was placed in a sealed aluminium pan, before heating
under nitrogen flow (20ml/min) at a scanning rate of 10ºC min-1,from 134.98ºC to 148.56ºC.
An empty aluminum pan was used as reference.

6.4 PHYSICOCHEMICAL PARAMETERS

The implants were evaluated for

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 37

 Experimental Details

Weight uniformity test

Thickness of the implants

Content uniformity

Percentage of moisture content

Surface pH

6.4.1 Weight uniformity test45, 46

The weight uniformity test was carried out by weighing 10 patches cut from different places
of same formulation and their individual weights were determined by using the digital
balance and the average weight was calculated.

Table 6.1: Allowable limit for weight variation

Average weight (mg) Maximum % difference allowed

130 or less 10
130-324 7.5
More than 324 5

6.4.2 Thickness of film42

Film thickness of 10 strips was measured with the help of screw gauge. The strip was placed
between the two jaws and the thickness was measured. The mean value was calculated.

6.4.3 Content uniformity

The drug content of the prepared implants was estimated using following method. Implant
containing Clindamycin HCl was taken in 100 ml standard volumetric flask. To this pH 7.4
phosphate buffer solution was added and made upto volume. The flask was kept overnight.
The solution was filtered and 5 ml of this filtrate was pipetted out into a 100 ml standard
volumetric flask and made upto the volume with pH 7.4 phosphate buffer solution and the
absorbance was determined at 210 nm.

6.4.4 Percentage moisture loss47

The percentage moisture loss was carried out to check integrity of the film at dry conditions.
Implant was weighed and kept in a desicator containing anhydrous calcium chloride. After
three days, the implants were taken out and reweighed; the % moisture loss was calculated
using the formula.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 38

 Experimental Details

Moisture loss=( Intial weightFinal weight/ Initialweight) ×100

6.4.5 Surface pH40

Implant was allowed to swell for 1 hour on the surface of the agar plate, prepared by
dissolving 2% w/v agar in warmed distilled water under stirring and then pouring the solution
into the petridish to gelling/solidify at room temperature. The surface pH was measured by
means of pH paper placed on the surface of the swollen film. The mean of 3 readings was
recorded.

6.5 IN-VITRO DRUG RELEASE STUDIES

The in-vitro release of Clindamycin HCl from the implant was carried out in small test tubes
containing 10 ml of pH 7.4 phosphate buffer. The test tubes were sealed with the aluminium
foil and kept at 37ºC. The sample was withdrawn and replaced with the fresh pH 7.4
phosphate buffer solution for every 1 hour upto 12th hour. Again the sample was withdrawn at
24th hour. The concentration of drug in the withdrawn solution was measured at 210 nm.

In-vitro drug release kinetic studies48-51

The results of in-vitro release profiles obtained for all the formulations were plotted in modes
of data treatment as follows,

1. Cumulative % drug released versus time (Zero order kinetic model)

2. Log cumulative % drug remaining versus time (First order kinetic model)
3. Cumulative % drug release versus square root of time (Higuchi plot)
4. Log cumulative % drug release versus log T (Koresmeyer-peppas model)
5. Cube root of drug % remaining versus time (Hixson-Crowell model)

Zero Order Kinetics: Zero order release would be predicted by the following equation.

At = A0-K0t

Where, At = Drug released at time ‘t’, A0 = Initial drug concentration

K0 = Zero order rate constant( h-1)

First Order kinetics: First order release would be predicted by the following equation

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 39

 Experimental Details

Log C = Log C0 – Kt/2.303

Where, C = Amount of drug remained at time‘t’, C0 = Initial amount of drug

K= First order rate constant (h-1)

When the data is plotted as log cumulative percent drug remaining versus time it yields a
straight line , indicating that the release follows first order kinetics. The constant ‘K’ can
be obtained by multiplying 2.303 with a slope values.

Higuchi Model: In this plot, amount of drug release versus square root of time is plotted.
The linearity of regression co-efficient determines whether it is being followed or not.

Q= KHt1/2

Where, Q = Amount of drug release at time ‘t’, KH =Higuchi rate constant

Koresmeyer-peppas model: In order to understand the mode of release of drug from

swellable matrices. The data were fitted to the following peppas law equation

Mt/M = Ktn

Where, Mt/M = Fraction of drug release at time ‘t’

K = Constant incorporating the structural and geometrical characteristics of the

drug/ polymer system

n = Diffusion exponent related to the mechanism of the release

when the data is plotted as log of drug released versus log time, a straight line is obtained
with the slope equal to ‘n’ and the value of ‘K’ can be obtained from y-intercept. For
fickian release n=0.5 while 0.5<n<1.0 indicates anomalous (Non-fickian) transport and
n=1 indicates case II diffusion leading to zero-order release.

Hixson-Crowell model: Data obtained from the invitro release studies were plotted cube
root of % remaining versus time.

W01/3- Wt1/3 = Kt

Where, Wo = Initial amount of drug release at time‘t’,

Wt = Remaining amount of drug at time‘t’

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 40

 Experimental Details

K = Constant incorporating the surface-volume relation.

6.6 STABILITY STUDIES OF THE OPTIMIZED FORMULATION

Stability is defined as the ability of particular drug or dosage form in a specific container to
remain with its physical, chemical, therapeutic and toxicological specifications. The
optimized formulation was selected for the stability studies.

The purpose of stability testing is to provide evidence on how quality of a drug substance or
drug product varies with time under the influence of a variety of environmental factors such
as temperature, humidity and light and enables recommended storage conditions, re-test
periods and shelf-lives to be determined. In the present study, stability study is carried out for
the optimized formulation sealed and packed in aluminium foil at room temperature in dark
place and exposure to direct sunlight for one month.

6.7 ANTIMICROBIAL ACTIVITY

6.7.1 Minimum inhibitory concentration52

Add 100 µl of Clindamycin solution (100 µg/100 µl) to the first tube. Add 4.0 ml of sterile
LB broth to the first tube and add 2.0ml to all other tubes.Transfer 2.0 ml of Luria Bretani
broth from the first tube to the second tube. Using a separate pipette, mix the contents of this
tube and transfer 2.0 ml to the third tube. Continue dilutions in this manner to tube number 4.
Remove 2.0 ml from tube 4 and discard it. The fifth tube, which serves as a control, receives
no Clindamycin. Add 20 µl of the bacterial culture to each of the tubes. Incubate all tubes at
37oC for overnight. Finally read the turbidity using spectrophotometry at 600 nm.

6.7.2 Disc-diffusion method52

Luria Bertani agar medium were prepared and the test micro-organisms were inoculated by
the spread plate method. Filter paper disc were soaked with 2, 4 and 6µg of the Clindamycin
implant and placed in the prepared agar plates. Each disc was pressed down to ensure
complete contact with the agar surface and distributed evenly so that they are no closer than
24mm from each other, center to center. The agar plates were then incubated at 37°C. After
16 to 18hrs of incubation, each plate was examined. The resulting zones of inhibition were
uniformly circular with a confluent lawn of growth. The diameter of the zone of complete
inhibition was measured.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 41

 Experimental Details

6.7.3 Agar well diffusion method52

Petriplates containing 20ml Luria Bertani agar medium were seeded with 24hrs culture of
bacterial strains. Wells were cut and 2.5, 25, 50, 100 and 200µg of the liquid clindamycin
implant were added. The plates were then incubated at 37°C for 24hrs. The antibacterial
activity was assayed by measuring the diameter of the inhibition zone formed around the
well.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 42

 Result and Discussion

7. RESULT AND DISCUSSION

7.1 PRELIMINARY SCREENING

Drug

i)Melting point

Melting point was found to be 141.8°C. This complies with melting point reported in USP.

ii)FTIR

The obtained IR spectrum of the sample shows all the prominent and primary peaks and
confirms Clindamycin HCl.

iii)UV scanning

a) Scanning of Clindamycin Hydrochloride in 0.1N HCl

The prepared solution of Clindamycin HCl in 0.1N HCl was scanned in UV
spectrophotometer and λmax was found to be 210nm.
b) Scanning of Clindamycin Hydrochloride in pH 7.4 phosphate buffer
The prepared solution of Clindamycin HCl in pH 7.4 phosphate buffer was scanned in
UV spectrophotometer and λmax was found to be 210nm.

Figure 7.1: λmax of Clindamycin HCl in 0.1N HCl

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 43

 Result and Discussion

Figure 7.2: λmax of Clindamycin HCl in pH 7.4 phosphate buffer

Polymer

The implant had formulated with the selected polymers and the results was shown in the
following table 7.1

Table 7: Selection of polymer

Trials Inference
Drug+EC No implant was formed
Drug+EC+HPMC No implant was formed
Drug+MC No implant was formed
Drug+gelatin No implant was formed
Drug+sodium alginate No implant was formed
Drug+gelatin+sodium alginate Implant was formed

From the obtained result, implant was not formed with some polymer due to the solubility
nature of the polymers. It was not soluble with the drug during the formulations. Gelatin and
sodium alginate was soluble in the drug solution. The trial with gelatin and sodium alginate
was done by using different ratios and 70:30, 80:20, 90:10 were selected for the formulations.
Further, compatibility study was done by using IR and DSC analysis.

7.2 ANALYTICAL METHOD

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 44

 Result and Discussion

7.2.1 Standard curve of Clindamycin HCl in 0.1N HCl

Beer’s law was found to be obeyed in the concentration range of 10-60 µg/ml with slope
value of 0.005 and correlation coefficient was found to be R 2=0.992. The absorbance values
of the working solution in 0.1 N HCl are shown in table no.7.1

Table 7.1: Preparation of standard curve of Clindamycin hydrochloride in 0.1N HCl

Concentration(µg/ml Absorbance
)
10 0.049
20 0.103
30 0.154
40 0.221
50 0.240
60 0.303

Figure 7.3: Standard curve for Clindamycin HCl in 0.1N HCl

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 45

 Result and Discussion

Absorbance

7.2.2 Standard curve of Clindamycin HCl in pH 7.4 buffer

Using the same method calibration curve is plotted in pH 7.4 phosphate buffer. Beer’s law
was found to be obeyed in the concentration range of 10-60 µg/ml with slope value of 0.007
and correlation coefficient was found to be R2=0.995. The absorbance values of the working
solutions in pH 7.4 phosphate buffer are shown in table no.7.2

Table 7.2: Preparation of standard curve of Clindamycin hydrochloride in pH 7.4 buffer

Concentration(µg/ml) Absorbance
10 0.089
20 0.147
30 0.218
40 0.298
50 0.358
60 0.415
Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 46
 Result and Discussion

Figure 7.4: Standard curve for Clindamycin HCl in pH 7.4 buffer

Standard graph of Clindamycin HCl in pH 7.4

7.3 DRUG-POLYMER COMPATABILITY

7.3.1 IR analysis

Clindamycin HCl and formulation was subjected for IR spectroscopic analysis, to ascertain whether
there is any interaction between the drug and polymers used. The IR spectra obtained are given in
figure 7.5 & 7.6 .The characteristic peak of the pure drug were compared with the peaks obtained for
formulation and are given in the table 10. From the data, it was observed that similar characteristic
peaks at 3379.4, 2959.87, 1451.48, 1683.91, 1255.7, 1081.14 and 714.65cm-1 for Clindamycin
implants. It appears that there is no chemical interaction between the drug and polymer.

Table 7.3: IR spectral data of pure drug alone and formulation containing Clindamycin HCl

Group Frequency of pure drug (cm-1) Frequency of formulation (cm-1)

N-H Streching 2947.33 2959.87
C-H bending 1447.62 1451.48
N-H stretching 3375.54 3379.4
C=O stretching 1679.09 1683.91
C-Cl stretching 793.73 714.65
C-C stretching 1251.84 1255.7
C-O stretching 1093.67 1081.14

Hence it can be concluded that the drug is in free state and there is no interaction between drug and
polymers used.

7.3.2 DSC analysis

In order to investigate the possible interactions between the drug and polymers used, differential
scanning calorimetric study as carried out. DSC thermogram of the formulation was compared with
the pure drug. The DSC thermograms obtained are reported in Figure 7.7 & 7.8. The pure
Clindamycin HCl displayed a sharp endothermic peak at 144.21°C corresponding to the melting

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 47

 Result and Discussion

point of the drug and a similar peak was also observed in the formulation. From the DSC
thermograms it was observed that the decomposition temperature of the pure drug and the formulation
remained the same. Hence it can be concluded that there was no significant interaction between drug
and the polymers used.
Figure 7.5: IR Spectrum of pure Clindamycin Hydrochloride

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 48

 Result and Discussion

Figure 7.6: IR Spectrum of Clindamycin Hydrochloride with

gelatin and sodium alginate

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 49

 Result and Discussion

Figure 7.7: Thermogram of pure Clindamycin hydrochloride

Figure 7.8: Thermogram of Clindamycin HCl with gelatin and sodium alginate

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 50

 Result and Discussion

7.4 PHYSICOCHEMICAL PARAMETERS

7.4.1 Weight uniformity test

Table 7.4: Weight uniformity of the Clindamycin HCl implant

Formulation code Weight of implants(mg)

F1 0.017±0.001
F2 0.020±0.002
F3 0.021±0.002
F4 0.025±0.002
F5 0.027±0.002
F6 0.026±0.002
F7 0.033±0.003
F8 0.029±0.003
F9 0.032±0.003
n=10

Drug loaded films were tested for uniformity of weight. The weight was found to be uniform
in the prepared batches.

7.4.2 Thickness of the implants

Table 7.5: Thickness of the Clindamycin HCl implant

Formulation code Thickness (mm)

F1 0.114±0.0156
F2 0.1±0.01
F3 0.131±0.0074

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 51

 Result and Discussion

F4 0.142±0.0104
F5 0.134±0.0112
F6 0.133±0.011
F7 0.169±0.015
F8 0.16±0.0132
F9 0.159±0.0132
n=10

Drug loaded implants were tested for thickness. From the result it was inferred that F1 has
least thickness where as the F7 has a highest thickness since it contain highest concentration
of polymer in the ratio 70:30, 700mg and 300mg of gelatin and sodium alginate respectively.

7.4.3 Content uniformity

Table 7.6: Content uniformity of the Clindamycin HCl

Formulation Trial I (mg) Trial II (mg) Trial III (mg) Average (mg)
code
F1 10.53 11.56 11.33 11.14±0.40
F2 11.50 11.53 11.30 11.44±0.09
F3 11.50 11.60 11.43 11.51±0.06
F4 11.01 11.46 11.21 11.22±0.15
F5 11.37 10.07 11.05 10.83±0.50
F6 9.93 11.50 11.40 10.94±0.67
F7 11.54 11.51 11.44 11.49±0.04
F8 11.43 11.45 11.53 11.47±0.12
F9 11.48 11.50 11.43 11.47±0.11

The test for content uniformity was carried out to ascertain that the drug is uniformly
distributed into formulation.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 52

 Result and Discussion

7.4.4 Percentage moisture loss

Table 7.7: % Moisture loss of the Clindamycin HCl implants

Formulation code Trial I Trial II Average

F1 28% 37.5% 32.75%
F2 50% 42.85% 46.42%
F3 25% 31.80% 28.4%
F4 26.47% 33.33% 29.9%
F5 25.71% 16.13% 20.92%
F6 16.6% 21.62% 19.11%
F7 20% 17.64% 18.82%
F8 19.35% 22.85% 21.1%
F9 21.73% 16.66% 19.19%

From the result it was inferred that F2 has highest moisture loss whereas F7 has lowest
moisture loss. If gelatin concentration increases moisture loss decreases, since gelatin has low
moisture content.

7.4.5 Surface pH

Table 7.8: Surface pH of the Clindamycin HCl implant

Formulation Trial I Trial II Trial III Average

code
F1 6 6 6 6
F2 6 6 6 6
F3 6 6 6 6
F4 7 6 7 6.6
F5 7 6 6 6.3
F6 7 7 6 6.6
F7 7 6 7 6.6
F8 6 7 7 6.6
F9 7 7 6 6.6

The surface pH of all formulations was within the range of 6-7 which is close to the neutral
pH and hence no irritation was expected.

7.4 INVITRO DRUG RELEASE STUDIES

The invitro result of all formulations was carried out in Phosphate buffer pH 7.4. The results
are shown in the table 7.9

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 53

 Result and Discussion

Table 7.9: In-vitro release data of Clindamycin HCl implants of different formulations

Time Formulation code

F1 F2 F3 F4 F5 F6 F7 F8 F9
in hrs
1 22.84 23.40 23.96 20.46 22.68 23.20 20.12 21.38 22.06
2 26.01 27.13 28.61 24.41 27.89 30.20 23.01 24.20 24.79
3 44.20 44.76 48.01 26.29 29.41 33.58 32.62 37.61 38.24
4 49.17 54.02 56.27 31.34 34.22 37.63 41.86 43.81 45.43
5 55.11 59.45 63.48 37.85 39.82 41.00 49.43 53.62 55.75
6 59.63 63.52 66.95 43.04 47.61 51.72 54.18 59.56 59.76
7 71.50 75.35 79.67 50.82 54.28 57.47 59.74 62.24 63.69
8 79.87 80.12 81.88 57.63 62.08 63.46 61.64 67.37 68.52
9 85.29 87.45 91.52 62.68 65.85 69.87 68.47 74.97 76.91
10 96.21 97.71 98.23 73.67 76.43 78.57 72.68 78.79 80.20
11 - - - 79.53 81.44 82.72 75.53 81.50 83.91
12 - - - 91.14 92.98 94.38 79.78 82.62 85.13
24 - - - 94.71 96.41 97.27 84.90 87.73 89.77
%drug release

Figure 7.9: In-vitro drug release of the formulation F1, F2 and F3

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 54

 Result and Discussion

%drug release

Figure 7.10: In-vitro drug release of the formulation F4, F5 and F6

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 55

 Result and Discussion

%drug release

Figure 7.11: In-vitro drug release of the formulation F7, F8 and F9

From the obtained results, the F1, F2, F3 formulations release the drug 96.21, 97.71, 98.23
respectively at 10th hour due to the presence of low polymer concentration.

In the F4, F5, F6 formulation the release of the drug was 94.71, 96.41, 97.27 respectively at
24th hour because the polymer concentration is increased when compared with the F1-F3
formulations.

The polymer concentration again increased to sustain the drug release in the formulations F7,
F8, F9 and its release rate was found to be 84.90, 87.73, 89.77 respectively. By increasing the
polymer concentration , the drug release can be sustained.

In-vitro drug release kinetics

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 56

 Result and Discussion

7.5.1 Formulation No.1

Table 7.10: Kinetics data of invitro drug release for F1

Time log T Square Cumulativ Log %drug Log Cube root

in root of e %drug cumulativ remaining %drug of drug
hrs T release e %drug remaining %
release remainin
g
0 0 0 0 0 0 0 0
1 0 1 22.84 1.358 77.16 1.887 4.327
2 0.301 1.414 26.01 1.415 73.99 1.867 4.198
0
3 0.477 1.732 44.20 1.645 55.80 1.746 3.821
1
4 0.602 2 49.17 1.691 50.83 1.706 3.704
0
5 0.698 2.236 55.11 1.741 44.89 1.652 3.553
9
6 0.778 2.449 59.63 1.775 40.37 1.606 3.430
1
7 0.845 2.645 71.50 1.854 28.50 1.454 3.054
0
8 0.903 2.828 79.87 1.902 20.13 1.303 20.720
0
9 0.954 3 85.29 1.930 14.71 1.167 2.450
2
10 1 3.162 96.21 1.983 3.79 0.578 1.559
11 1.041 3.316 - - - - -
3
12 1.079 3.464 - - - - -
1
24 1.380 4.898 - - - - -
2

7.5.2 Formulation No: 2

Table 7.11: Kinetics data of invitro drug release for the F2

Time log T Square Cumulativ Log %drug Log Cube

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 57

 Result and Discussion

in root of e %drug cumulativ remainin %drug root of

hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 23.40 1.369 76.60 1.884 4.246
2 0.301 1.414 27.13 1.433 72.87 1.862 4.176
0
3 0.477 1.732 44.76 1.650 55.24 1.742 3.808
1
4 0.602 2 54.02 1.732 45.98 1.662 3.582
0
5 0.698 2.236 59.45 1.774 40.55 1.607 3.435
9
6 0.778 2.449 63.52 1.802 36.48 1.562 3.316
1
7 0.845 2.645 75.35 1.877 24.65 1.391 2.910
0
8 0.903 2.828 80.12 1.903 19.88 1.298 2.708
0
9 0.954 3 87.45 1.941 12.55 1.098 2.323
2
10 1 3.162 97.71 1.989 2.29 0.359 1.318
11 1.041 3.316 - - - - -
3
12 1.079 3.464 - - - - -
1
24 1.380 4.898 - - - - -
2

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 58

 Result and Discussion

7.5.3 Formulation No: 3

Table 7.12: Kinetics data of invitro drug release for the F3

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of
hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 23.96 1.379 76.04 1.881 4.236
2 0.301 1.414 28.61 1.456 71.39 1.853 4.148
0
3 0.477 1.732 48.01 1.681 51.99 1.715 3.732
1
4 0.602 2 56.27 1.750 43.73 1.640 3.523
0
5 0.698 2.236 63.48 1.802 36.52 1.562 3.317
9
6 0.778 2.449 66.95 1.825 33.05 1.519 3.209
1
7 0.845 2.645 79.67 1.901 20.33 1.308 2.729
0
8 0.903 2.828 81.88 1.913 18.12 1.258 2.626
0
9 0.954 3 91.52 1.961 8.48 0.928 2.039
2
10 1 3.162 98.23 1.992 1.77 0.247 1.209
11 1.041 3.316 - - - - -
3
12 1.079 3.464 - - - - -
1
24 1.380 4.898 - - - - -
2

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 59

 Result and Discussion

7.5.4 Formulation No: 4

Table 7.13: Kinetics data of invitro drug release for the F4

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of
hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 20.46 1.310 79.54 1.900 4.300
2 0.301 1.414 24.41 1.387 75.59 1.878 4.228
0
3 0.477 1.732 26.29 1.419 73.71 1.867 4.192
1
4 0.602 2 31.34 1.496 68.66 1.836 4.094
0
5 0.698 2.236 37.85 1.578 62.15 1.793 3.961
9
6 0.778 2.449 43.04 1.633 56.96 1.755 3.847
1
7 0.845 2.645 50.82 1.706 49.18 1.691 3.663
0
8 0.903 2.828 57.63 1.760 42.37 1.627 3.486
0
9 0.954 3 62.68 1.797 37.32 1.571 3.341
2
10 1 3.162 73.67 1.867 26.33 1.420 2.974
11 1.041 3.316 79.53 1.900 20.47 1.311 2.735

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 60

 Result and Discussion

3
12 1.079 3.464 91.14 1.959 8.86 0.947 2.069
1
24 1.380 4.898 94.71 1.976 5.29 0.723 1.742
2

7.4.5 Formulation No: 5

Table 7.14: Kinetics data of the invitro drug release for F5

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of
hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 22.68 1.355 77.32 1.888 4.260
2 0.301 1.414 27.89 1.445 72.11 1.857 4.162
0
3 0.477 1.732 29.41 1.468 70.59 1.848 4.132
1
4 0.602 2 34.22 1.534 65.78 1.818 4.036
0
5 0.698 2.236 39.82 1.600 60.18 1.779 3.918
9
6 0.778 2.449 47.61 1.677 52.39 1.719 3.741
1

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 61

 Result and Discussion

7 0.845 2.645 54.28 1.734 45.72 1.660 3.575

0
8 0.903 2.828 6208 1.792 37.92 1.578 3.359
0
9 0.954 3 65.85 1.818 34.15 1.533 3.244
2
10 1 3.162 76.43 1.883 23.57 1.372 2.867
11 1.041 3.316 81.44 1.910 18.56 1.268 2.647
3
12 1.079 3.464 92.98 1.968 7.02 0.846 1.914
1
24 1.380 4.898 96.41 1.984 3.59 0.555 1.531
2

7.4.6 Formulation No: 6

Table 7.15: Kinetics data of the invitro drug release for the F6

Time log T Square Cumulativ Log %drug Log Cube root

in root of e %drug cumulativ remainin %drug of drug
hrs T release e %drug g remainin %
release g remaining
0 0 0 0 0 0 0 0
1 0 1 23.20 1.365 76.80 1.885 4.250
2 0.301 1.414 30.20 1.480 69.80 1.843 4.117
0
3 0.477 1.732 33.58 1.526 66.42 1.822 4.049

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 62

 Result and Discussion

1
4 0.602 2 37.63 1.575 62.37 1.794 3.965
0
5 0.698 2.236 41.00 1.612 59.00 1.770 3.892
9
6 0.778 2.449 51.72 1.713 48.28 1.683 3.641
1
7 0.845 2.645 57.47 1.759 42.53 1.628 3.490
0
8 0.903 2.828 63.46 1.802 36.54 1.562 3.318
0
9 0.954 3 69.87 1.844 30.13 1.478 3.111
2
10 1 3.162 78.57 1.895 21.43 1.331 2.777
11 1.041 3.316 82.72 1.917 17.28 1.237 2.585
3
12 1.079 3.464 94.38 1.974 5.62 0.749 1.777
1
24 1.380 4.898 97.27 1.987 2.73 0.430 1.397
2

7.5.7 Formulation No: 7

Table 7.16: Kinetics data of the invitro drug release for F7

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 63

 Result and Discussion

hrs T release e %drug g remainin drug %

release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 20.12 1.303 79.88 1.902 4.306
2 0.301 1.414 23.01 1.361 76.99 1.886 4.254
0
3 0.477 1.732 32.62 1.513 67.38 1.828 4.069
1
4 0.602 2 41.86 1.621 58.14 1.764 3.873
0
5 0.698 2.236 49.43 1.693 50.57 1.703 3.697
9
6 0.778 2.449 54.18 1.733 45.82 1.661 3.578
1
7 0.845 2.645 59.74 1.776 40.26 1.604 3.427
0
8 0.903 2.828 61.64 1.789 38.36 1.583 3.372
0
9 0.954 3 68.47 1.835 31.53 1.498 3.159
2
10 1 3.162 72.68 1.861 27.32 1.436 3.011
11 1.041 3.316 75.53 1.878 24.47 1.388 2.903
3
12 1.079 3.464 79.78 1.901 20.22 1.305 2.724
1
24 1.380 4.898 84.90 1.928 15.10 1.178 2.471
2
Cumulative %drug release

Figure 7.12: Zero-order release kinetics for the formulation F7

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 64

 Result and Discussion

Log cumulative% drug remaining

Figure 7.13: First-order release kinetics for the formulation F7

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 65

 Result and Discussion

Cumulative% drug release

Figure 7.14: Higuchi release kinetics for the formulation F7

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 66

 Result and Discussion

log cumulative %drug release

Figure 7.15: Koresmeyer-peppas release kinetics for the formulation F7

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 67

 Result and Discussion

Cube root of drug %remaining

Figure 7.16: Hixson-Crowell release kinetics for the formulation F7

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 68

 Result and Discussion

7.5.8 Formulation No: 8

Table 7.17: Kinetics data of the invitro drug release for F8

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of
hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 21.38 1.330 78.62 1.895 4.283
2 0.301 1.414 24.20 1.383 75.80 1.876 4.232
0
3 0.477 1.732 37.61 1.575 62.39 1.795 3.966
1
4 0.602 2 43.81 1.641 56.19 1.749 3.830
0
5 0.698 2.236 53.62 1.729 46.38 1.666 3.592
9
6 0.778 2.449 59.56 1.774 40.44 1.606 3.432
1
7 0.845 2.645 62.24 1.794 37.76 1.577 3.354
0
8 0.903 2.828 67.37 1.828 32.63 1.513 3.195
0
9 0.954 3 74.97 1.874 25.03 1.398 2.925
2
10 1 3.162 78.79 1.896 21.21 1.326 2.768
11 1.041 3.316 81.50 1.911 18.50 1.267 2.644
3
12 1.079 3.464 82.62 1.917 17.38 1.240 2.590

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 69

 Result and Discussion

1
24 1.380 4.898 87.73 1.943 12.27 1.088 2.306
2

7.5.9 Formulation No: 9

Table 7.18: Kinetics data of the invitro drug release for F9

Time log T Square Cumulativ Log %drug Log Cube

in root of e %drug cumulativ remainin %drug root of
hrs T release e %drug g remainin drug %
release g remainin
g
0 0 0 0 0 0 0 0
1 0 1 22.06 1.343 77.94 1.891 4.271
2 0.301 1.414 24.79 1.394 75.21 1.876 4.221
0
3 0.477 1.732 38.24 1.582 61.76 1.790 3.952
1
4 0.602 2 45.43 1.657 54.57 1.736 3.793
0
5 0.698 2.236 55.75 1.746 44.25 1.645 3.537
9
6 0.778 2.449 59.76 1.776 40.24 1.604 3.426
1
7 0.845 2.645 63.69 1.804 36.31 1.560 3.311
0

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 70

 Result and Discussion

8 0.903 2.828 68.52 1.835 31.48 1.498 3.157

0
9 0.954 3 76.91 1.885 23.09 1.363 2.847
2
10 1 3.162 80.20 1.904 19.80 1.296 2.705
11 1.041 3.316 83.91 1.923 16.09 1.266 2.524
3
12 1.079 3.464 85.13 1.930 14.87 1.172 2.459
1
24 1.380 4.898 89.77 1.953 10.23 1.009 2.170
2

From the various mathematical models, the in-vitro kinetics studies were performed for all
the formulations. The ‘n’ value was in the range 0.87-0.93. So that the prepared implant
undergo diffusion mechanism because it follows non-fickian or anamolous transport.

7.6 COMPARATIVE KINETICS OF ALL THE FORMULATIONS

The comparative kinetics value for zero-order, first-order, higuchi, koresmeyer-peppas and
Hixson-crowell are shown in the following tables and figures.

Table 7.19: Comparative kinetics for Zero-order drug release kinetics

Formulation Zero-Order Drug Release

code R2 K0
F1 0.973 10.09
F2 0.968 11.42
F3 0.959 12.81
F4 0.812 18.95
F5 0.801 21.81
F6 0.789 24.03

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 71

 Result and Discussion

F7 0.725 26.88
F8 0.696 28.75
F9 0.696 29.46

At = A0-K0t
Cumulative %drug release

Figure 7.17: Comparative kinetics of Zero-order for the formulation F1, F2 and F3

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 72

 Result and Discussion

Cumulative %drug release

Figure 7.18: Comparative kinetics of Zero-order for the formulation F4, F5 and F6

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 73

 Result and Discussion

Cumulative %drug release

Figure 7.19: Comparative kinetics of Zero-order for the formulation F7, F8 and F9

Table 7.20: Comparative kinetics for First-order kinetics

Formulation First-Order Drug Release

code R2 K1
F1 0.014 1.468
F2 0.030 1.482
F3 0.057 1.495
F4 0.098 1.656
F5 0.142 1.662

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 74

 Result and Discussion

F6 0.178 1.663
F7 0.005 1.534
F8 0.022 1.517
F9 0.038 1.519

Log C = Log C0 – Kt/2.303

Log cumulative% drug remaining

Figure 7.20: Comparative kinetics of First-order for the formulation F1, F2 and F3

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 75

 Result and Discussion

Log cumulative% drug remaining

Figure 7.21: Comparative kinetics of First-order for the formulation F4, F5 and F6

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 76

 Result and Discussion

Log cumulative% drug remaining

Figure 7.22: Comparative kinetics of First-order for the formulation F7, F8 and F9

Table 7.21: Comparative kinetics for Higuchi release kinetics

Formulation Higuchi Drug Release

code R2 KH
F1 0.965 0.048
F2 0.974 0.070
F3 0.979 0.093
F4 0.915 0.063
F5 0.923 0.071
F6 0.929 0.076
F7 0.932 0.026
F8 0.917 0.035
F9 0.917 0.041

Q=KHt1/2

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 77

 Result and Discussion

Cumulative% drug release

Figure 7.23: Comparative kinetics of Higuchi for the formulation F1, F2 and F3

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 78

 Result and Discussion

Cumulative% drug release

Figure 7.24: Comparative kinetics of Higuchi for the formulation F4, F5 and F6

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 79

 Result and Discussion

Cumulative% drug release

Figure 7.25: Comparative kinetics of Higuchi for the formulation F7, F8 and F9

Table 7.22: Comparative kinetics for Koresmeyer-peppas drug release kinetics

Formulation Koresmeyer-peppas Drug Release

code R2 Kkp
F1 0.648 0.829
F2 0.644 0.841
F3 0.640 0.855
F4 0.668 0.836
F5 0.641 0.876
F6 0.519 0.991
F7 0.636 0.883

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 80

 Result and Discussion

F8 0.625 0.908
F9 0.622 0.917

Mt/M = Ktn
Log cumulative %drug release

Figure 7.26: Comparative kinetics of Koresmeyer-peppas for the formulation F1, F2

and F3

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 81

 Result and Discussion

log cumulative %drug release

Figure 7.27: Comparative kinetics of Koresmeyer-peppas for the formulation F4, F5

and F6

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 82

 Result and Discussion

log cumulative %drug release

Figure 7.28: Comparative kinetics of Koresmeyer-peppas for the formulation F7, F8

and F9

Table 7.23: Comparative kinetics for Hixson-Crowell drug release kinetics

Formulation Hixson-Crowell Drug Release

code R2 KHC
F1 0.015 0.048
F2 0.033 0.070
F3 0.056 0.093
F4 0.100 0.063
F5 0.125 0.071
F6 0.143 0.076
F7 0.022 0.026
F8 0.038 0.035

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 83

 Result and Discussion

F9 0.054 0.041

W01/3- Wt1/3 = Kt
Cube root of drug %remaining

Figure 7.29: Comparative kinetics of Hixson-Crowell for the formulation F1, F2 and F3
Cube root of drug %remaining

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 84

 Result and Discussion

Figure 7.30: Comparative kinetics of Hixson-Crowell for the formulation F4, F5 and F6
Cube root of drug %remaining

Figure 7.31: Comparative kinetics of Hixson-Crowell for the formulation F7, F8 and F9

7.6 STABILITY STUDIES

Stability studies of the optimized formulations of Clindamycin implants was carried out to
determine the effect of formulation additives on the stability of the drug and also to determine
the physical stability of the formulations. The stability studies were carried out at room
temperature 29ºC, dark place and direct sunlight.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 85

 Result and Discussion

Stability studies showed after one month the significant changes in the physicochemical
parameters and drug release was shown in the table 31.

Table 7.24: Stability studies data of the optimized formulation of Clindamycin implants

Stability studies
th
0 day 30th day
Room Dark Direct Room Dark Direct
S.N Parameter
temp. place sunligh temp. place sunligh
o
29ºC t 29ºC t
1 Weight uniformity 0.032 0.028 0.026 0.030 0.025 0.020
2 Thickness 0.165 0.166 0.152 0.162 0.164 0.150
3 % Moisture loss 16.6% 19.01% 18.21% 16.05 18.89 17.65%
% %
4 Surface pH 7 6 7 7 6 7
5 Drug content 11.62 11.48 11.29 11.61 11.45 11.05
6 Drug release at 24th 85.96% 84.97% 85.69% 86.23 85.60 90.25%
hour % %

Stability studies were conducted on implants at room temperature, dark place and exposure to
direct sunlight for one month. The observed parameters reduced markedly after exposing to
direct sunlight and no significant change at room temperature, dark place. The stability of the
drug was improved by formulating them in polymer matrix.

7.7 ANTIMICROBIAL ACTIVITY

7.7.1 Minimum inhibitory concentration

The minimum inhibitory concentration was determined by using different concentration of

the Clindamycin implant in various micro-organisms.

Table 7.25: Minimum inhibitory concentration of Clindamycin HCl

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 86

 Result and Discussion

Organism Control 12.5 µg 25 µg 50 µg 100µg

name
Klebsiella 0.132 0.113 0.11 0.108 0.084
Salmo 0.15 0.114 0.092 0.087 0.069
SPA 0.143 0.121 0.108 0.097 0.081
SPB 0.138 0.098 0.092 0.085 0.061
Ent.bact 0.109 0.088 0.082 0.071 0.009
Pro mira 0.175 0.114 0.136 0.103 0.093
Staph 0.077 0.008 0.006 0.005 0.004
Kleb – Klebsiella pneumonia; Salmo- Salmonella; SPA- Salmonella typhi A; SPB-
Salmonella typhi B; Ent.bact-Enterobacter aerogens; Pro mira- Proteus mirabilis; Staph-
Staphylococcus aureus

Figure 7.32: MIC of Clindamycin implant in Salmonella

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 87

 Result and Discussion

Figure 7.33: MIC of Clindamycin implant in Salmonella paratyphi A

Figure 7.34: MIC of Clindamycin implant in Salmonella paratyphi B

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 88

 Result and Discussion

Figure 7.35: MIC of Clindamycin implant in Enterobacter aerogens

Figure 7.36: MIC of Clindamycin implant in Staphylococcus aureus

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 89

 Result and Discussion

Figure 7.37: MIC of Clindamycin implant in Proteus mirabilis

Figure 7.38: MIC of Clindamycin implant in Klebsiella pneumoniae

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 90

 Result and Discussion

7.7.2 Disc diffusion and agar well diffusion method

The diameter of zone of inhibition was measured and the value was shown in the table 7.26.

Table 7.26: Diameter of zone of inhibition of Clindamycin implants

AGAR WELL DIFFUSION DISC DIFFUSION METHOD

ORGANISM METHOD
NAME (ZONE SIZE) (ZONE SIZE)

12.5µ 25µ 50 µg 100 200 +ive 2 µg 4 µg 16 µg

g g µg µg Control
(2 µg)

Staphylococcus 6 mm 9mm 11mm 13mm 17 5 mm 6 mm 7mm 11mm

aureus mm

Enterobacter 4 mm 5mm 7 mm 10 16 1 mm 1.5m 3 5 mm

aerogens mm mm m mm

+ive control = Standard Clindamycin disc

After 24hrs of incubation, the diameter of zone of inhibition was measured and it was
compared with the standard drug diameter. It shows better antibacterial activity over those
micro-organisms. The zone of inhibition of Clindamycin implant by agar disc diffusion and
agar well diffusion method was shown in the following figures.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 91

 Result and Discussion

Figure 7.39: Disc diffusion zone for Staphylococcus aureus using Clindamycin
implant pad

Figure 7.40: Disc diffusion

zone for Enterobacter
aerogens using Clindamycin implant pad

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 92

 Result and Discussion

Figure 7.41: Agar well diffusion method in Staphylococcus aureus using

Clindamycin liquid

Figure 7.42: Agar well diffusion method in Staphylococcus aureus using

Clindamycin liquid

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 93

 Result and Discussion

Figure 7.43: Agar well diffusion method in Enterobacter aerogens using

Clindamycin liquid

Figure 7.44: Agar well diffusion method in Enterobacter aerogens using

Clindamycin liquid

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 94

 Summary and Conclusion

8. SUMMARY AND CONCLUSION

Development of implantable drug delivery system is triggered by the need to control the drug
release and for the localized therapy.

Clindamycin hydrochloride was incorporated in gelatin and sodium alginate polymer in

different concentrations. The various physicochemical parameters, drug release studies and
antimicrobial activity were performed for the developed implant.

The following conclusions were drawn from the results obtained.

In the preliminary screening, the drug undergo melting point determination, IR

analysis and UVscanning, the result obtained was complied with the USP standards.

From the FT-IR spectra, it was observed that similar characteristic was observed that
similar peaks appear for the drug and their formulation. Hence, it shows that there was
no chemical interaction between the drug and polymer used.

The DSC thermograms obtained for the pure drug and for the formulation showed no
significant shift in the endothermic peaks confirming the stability of the drug in the
formulation.

From the results of the weight uniformity and thickness, it can be inferred that all the
formulations exhibited uniform weight and thickness with low standard deviation
values.

All the formulations were found to obtain uniform quantity of drug as per content
uniformity studies indicating reproducibility of the technique.

For all the formulation, the percentage moisture showed maximum loss except F7
because of low concentration of gelatin undergo moisture loss in dry condition.

From the result of invitro release studies of the formulation F1 to F9, the formulation
F7 showed an sustained release at the end of 24 th hour due to the high concentration of
gelatin and sodium alginate, 700 and 300 mg respectively.

The ‘n’ values of various mathematical model fittings suggests that all the films
exhibit anamolous transport. It had concluded that the prepared implant undergo
diffusion mechanism

The antimicrobial activities were performed on Staphylococcus aureus and
Enterobacter aerogens, the zone of inhibition was observed by agar disc diffusion and
agar well diffusion method. From the results, the optimized implant shows better
activity over those micro-organisms.

The result of stability studies carried out on optimized formulation indicate that after
one month at room temperature, dark place and direct sunlight. The drug content

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 88

 Summary and Conclusion

reduced markedly after exposing sunlight and there was no significant change at room
temperature and dark place.

The future plan is to carry out the invitro-invivo correlation studies.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 89

 Bibliography

9. BIBLIOGRAPHY

1. Jain NK. Advances in controlled and novel drug delivery. New Delhi. CBS
publishers;2001:209-210.

2. Stuti Gupta, Ravindra P Singh, Rajendra K Songara, Nirav Rabadia, Gaurang Patel,
Vishal Virani. Implantable drug delivery system. Int J of Drug formulation and
Reasearch 2011, Mar-Apr;Vol 2(2):111-136.

3. Shtilman ML. New concepts in polymer science. Polymeric biomaterials: Part I-

Polymer implants. 171-202.

4. Rajgor N, Patel M, Bhaskar VH. Implantable drug delivery system. Systemic reviews
in pharmacy 2011; 2(2):91-95.

5. Banker R. Controlled release of biologically active agents, New York, John Wiley;
1987:40-56.

6. Zaheer S, Lehman J, Stevenson G. Capsular contracture around silicone implants: The

role of intraluminal antibiotics. Plast Reconstr Surg 1982;69:809-12.

7. Langer R. Implantable controlled release systems. Ihler GM editor. New York:

Pergamon press 1986:121-137.

8. Wikipedia.org/wiki/implant#brain implant

9. Wikipedia.org/wiki/implant#microchip implant

10. Wikipedia.org/wiki/implant#microdermal implant

11. Wikipedia.org/wiki/implant#contraceptive implant

12. Wikipedia.org/wiki/implant#retianl implant

13. Wikipedia.org/wiki/implant#dental implant

14. Ann MR, An KA, Choi JH, Sohn DS. Immediate loading with minidental implants in
the fully edentulous mandible. Implant Dent 2004; 13(4):367-372.

15. Fransson C, Wennstrom J, Tomasi C, Berglundh T. Extent of peri-implantitis-

associated bone loss,.Journal of clinical periodontology 2009;36(4):657-363.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 90

 Bibliography

16. Wikipedia.org/wiki/dental diseases and dental health problems

17. www.perio.org - American Academy of Periodontology

18. Mombelli A. Periodontitis as an infectious diseases: Specific features and their

implications. Oral Dis 2003;9(1): 6-10.

19. Haffajee AD, Socransky SS, Gunsolley JC. Systemic antiinfective periodontal
therapy. A systemic review. Ann periodontal 2003;8:115-81.

20. Mombelli A, Schmid B, Rutar A, Lang NP. Local antibiotic therapy guided by
microbiological diagnosis. J Clin Periodontol 2002;29:743-9.

21. Kulkarani GV, Lee WK, Aitken S, Birek P, McCulloch CA. A randomized, plaebo-
controlled trial of doxycycline:effect on the microflora of recurrent periodontitis
lesions in high risk patients. J Periodontol 1991; 62: 197-202.

22. Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and
biochemical results of the metalloproteinase inhibition with submicrobial doses of
doxycycline to prevent acute coronary syndromes. Arterioscler Thromb Vasc Biol
2004; 24:733-8.

23. Houri-Haddad Y, Karaka L, Stabhloz A, Soskolne A, Shapira L. Tetracycline

conditioning augments the in vivo inflammatory response induced by cementum
extracts. J Periodontol 2004; 75:388-92.

24. USP Pharmacoepia, 2002:437-438

25. www.drugbank.com/clindamycin

26. Clindamycin Univ. Of Michigan. Retrieved, July 31,2009.

27. Merck manual of diagnosis and therapy. Merck & Co, Nov 2005.

Retrieved 2007-20-01.

28. Dalacin C (2009).retrieved July 17,2009.

29. Song KS. Ribosomal protein synthesis inhibitors. Encyclopedia reference of

molecular pharmacology, Berlin, Gemany :S Offermanns and W Rosenthal Eds. 827-
833.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 91

 Bibliography

30. Pfizer Canada Inc, June 2008. TM Pfizer enterprises. 9-10.

31. Raymond C Rowe, Paul J Sheskey, Sian C Owen.Handbook of pharmaceutical

excipients, 5th edition.295-297.

32. Raymond C Rowe, Paul J Sheskey, Sian C Owen.Handbook of pharmaceutical

excipients, 5th edition. 656-657.

33. Elias-al-Mamun MD, Humaira Afreen Kahn, Irin Dewan, Reza-ul Jalil. Invitro study
of Tamsulosin release kinetics from biodegradable PLGA insitu implants. Pak J
Pharm Sci 2009,Oct;22(4):360-367.

34. Heba A Gad, Mohamed A El-Nabarawi, Abd El-HAdy. Formulation and evaluation of
PLA and PLGA insitu implants containing Secnidazole and/or Doxycycline for
treatment of periodontitis. AAPS Pharm Sci Tech 2008, Sep;9(3):878-883.

35. Ananta Choudary, Sujoy Das, Satish Dhangar, Sumit Kapasiya, Abhishak Kanango.
Development and characterization buccoadhesive film of Ciprofloxacin
hydrochloride, Int J of PharmTech Research 2010, Apr-June; 2(2):1050-1057.

36. Mohammed Gulzar Ahmed, Narayana Charyulu R, Kanthraj K, Harish NM,

Prabhakar Prabhu. Preparation and evaluation of periodontal strips of Gatifloxacin for
periodontal diseases. Int J of Pharma and Bio Sciences 2010, Jul-Sep;1(3):1-8.

37. Manoj Kumar, Prabhushankar GL, Sathesh babu PR. Formulation and in-vitro
evaluation of periodontal films containing Metronidazole. Int J of PharmTech
Research 2010, Oct-Dec;2(4):2188-2193.

38. Nagaraju R, Udupa N. Preparation and evaluation of dental implants containing

Doxycycline hydrochloride and Tinidazole in biodegradable carrier, Indian Journal of
Pharmaceutical Sciences 1998, Nov-Dec:405-06.

39. Varinder Kumar, Foziyah Zakir, Geeta Agarwal, Ankush Choudary. Formulation and
evaluation of buccal patches of Venlafaxine, IJPBS 2011, July-Sep; 1(3):170-182.

40. Prabhushankar GL, Gopalkrishna B, Manjunatha KM, Girisha CH. Formulation and
evaluation of Levofloxacin dental films for periodontitis, Int J of Phamacy and
Pharmaceutical Sciences 2010; 2(1):162-167.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 92

 Bibliography

41. Mastiholimath VS, Dandagi PM, Gadad AP, Patil MB, Manvi FV, Chandur VK.
Formulation and evaluation of Ornidazole dental implants for periodontitis. Int J of
Pharm Sci 2006; 68(1):68-71.

42. Rao K Purushotham, Jayabhaye SJ, Ravindra Kamble, Anil Bhandari, Pratima S.
Desigining of Diclofenac Sodium biodegradable drug implant for speedy fracture
healing. J of Chemical and Pharm Research 2010; 3(1):330-337.

43. Mohammed Gulzar Ahmed, Narayana Charyulu R, Harish NM, Prabhakar Prabhu.
Formulation of chitosan-based Ciprofloxacin and Diclofenac film for periodontitis
therapy 2009, Feb ;8(1):33-41.

44. Sujatha Muchalambe, Dandagi PM, Yogesh HS, Ravindra R, Gopalakrishna B.

Preparation and evaluation of Sparfloxacin dental implants for treatment of
periodontal diseases. Int J Ph Sci 2010, May-Aug ; 2(2):606-611.

45. Agarwal GP. Evaluation of free films.Indian drugs 1985; 23(1):45-47.

46. Kwan CK. Free films I: Apparatus and preliminary evaluation. Jr of Pharm Sci 1972;
61(1):106-1007.

47. Dhanraju MD, Shivakumar VR, Subhashree R, Bhaskar K. Bioadhesive ocuserts

matrix for ophthalmic administration of Ciprofloxacin HCl. Indian drugs 2002;39(4):
222-224.

48. Brazel CS, Peppas NA. Modelling of drug release from swellable polymers. Eur J
Pharm Biopharm 2000; 49: 47-58.

49. Gambhire MN, Ambade KW, Kurmi SD, Kadam VJ, Jadhav KR. Development and
invitro evaluation of an oral floating matrix tablet formulation of diltiazem
hydrochloride. AAPS Pharm Sci Tech 2007; 8(3):E1-9.

50. Young CR, Dietzsch C, Cerea M, Farrell T, Fegely KA, Siahboomi AR.
Physicochemical characterization and mechanism of release of theophylline from
melt-extruded dosage form based on methacrylic acid polymer. Int J Pharm 2005;
301: 112-120.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 93

 Bibliography

51. Suvakanta Dash, Padal Narasimha Murthy, Lilakanta Nath, Prasanth Chowdary.
Kinetic modelling on drug release from controlled drug delivery systems. Acta
Poloniae Pharmaceutica-Drug Research 2010; 67(3): 217-203.

52. Ericsson HM, Sherris JC. Antibiotic Sensitivity testing. Report of an international
collaborative study. Acta Pathol. Microbiol. Scand. Sect. 1971. B.217 :1-90.

Department of Pharmaceutics, RVS College of Pharmaceutical Sciences Page 94