“Formulation and in vitro evaluation of orally administered

Gastro-retentive Floating tablets of Simvastatin”

By

SHIVA PRASAD BHAT

Dissertation Submitted to the

Rajiv Gandhi University of Health Sciences,
Bangalore,
Karnataka

In partial fulfillment
of the requirements for the degree of

MASTER OF PHARMACY
IN
“PHARMACEUTICS”

Under the guidance of

Dr. C.S.R.LAKSHMI

Department of Pharmaceutics
Nargund college of Pharmacy
Bangalore-560085

FEBRUARY-2011
 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE

DECLARATION BY THE CANDIDATE

I hereby declare that the matter embodied in the dissertation entitled

“Formulation and in vitro evaluation of orally administered gastro-

retentive floating tablets of Simvastatin” is a bonafide and genuine

research work carried out by me under the guidance of Dr. C.S.R.LAKSHMI

Department of Pharmaceutics, Nargund College of Pharmacy,

Bangalore-85. The work embodied in this thesis is original and has not been

submitted the basis for the award of degree, diploma, associate ship (or)

fellowship of any other university (or) institution.

Date:

Place: Bangalore SHIVA PRASAD BHAT

 NARGUND COLLEGE OF PHARMACY
BANGALORE-85

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “Formulation and in vitro

evaluation of orally administered gastro-retentive floating tablets of

Simvastatin” is a bonafide research work carried out by Mr. Shiva Prasad

Bhat submitted in partial fulfillment for the award of the degree of “Master of

Pharmacy” in pharmaceutics by the Rajiv Gandhi University of health sciences,

Karnataka, Bangalore.

Date: Dr. C.S.R.Lakshmi

Department of Pharmaceutics,
Place: Bangalore-85 Nargund College of Pharmacy,
Bangalore – 85
 NARGUND COLLEGE OF PHARMACY
BANGALORE-85

CERTIFICATE BY THE CO-GUIDE

This is to certify that the dissertation entitled “Formulation and in vitro

evaluation of orally administered gastro-retentive floating tablets of

Simvastatin” is a bonafide research work carried out by Mr. Shiva Prasad

Bhat submitted in partial fulfillment for the award of the degree of “Master of

Pharmacy” in pharmaceutics by the Rajiv Gandhi University of health sciences,

Karnataka, Bangalore.

Date: Mr. Raghunandan.H.V

Sr. Manager-Q.A
Place: Bangalore-85 Biocon Limited
Bangalore – 560100
 NARGUND COLLEGE OF PHARMACY
BANGALORE-85

ENDORSEMENT BY THE HEAD OF THE DEPARTMENT

This is to certify that the dissertation entitled “Formulation and in vitro

evaluation of orally administered gastro-retentive floating tablets of
simvastatin” is a bonafide research work carried out by Mr. Shiva Prasad

Bhat submitted in partial fulfillment for the award of the degree of “Master of
pharmacy” in Pharmaceutics by the Rajiv Gandhi University of Health Sciences,
Karnataka, Bangalore. This work was carried out by him in the library and
laboratories of Nargund College of Pharmacy, Bangalore under the guidance of
Dr.C.S.R.Lakshmi Department of Pharmaceutics, Nargund College of Pharmacy.

Date: Dr. C.S.R. LAKSHMI

Professor and HOD,
Place: Bangalore 85. Department of Pharmaceutics,
Nargund College of Pharmacy,
Bangalore- 85
 NARGUND COLLEGE OF PHARMACY
BANGALORE-85

ENDORSEMENT BY THE PRINCIPAL / HEAD OF THE

INSTITUTION

This is to certify that the dissertation “Formulation and in vitro evaluation

of orally administered gastro-retentive floating tablets of simvastatin” is a
bonafide research work carried out by Mr.Shiva Prasad Bhat submitted in
partial fulfillment for the award of the degree of “Master of pharmacy” in
Pharmaceutics by the Rajiv Gandhi University of Health Sciences, Karnataka,
Bangalore. This work was carried out by him in the library and laboratories of
Nargund College of Pharmacy, Bangalore under the guidance of
Dr.C.S.R.Lakshmi Department of Pharmaceutics, Nargund College of Pharmacy.

Date: Dr. L.V.G. NARGUND

Principal,
Place: Bangalore-85. Nargund College of Pharmacy,
Bangalore - 85
 COPYRIGHT

DECLARATION BY THE CANDIDATE

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

Karnataka shall have the rights to preserve, use and disseminate this

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

purpose.

Date:

Place: Bangalore SHIVA PRASAD BHAT

© Rajiv Gandhi University of Health Sciences, Karnataka.

Dedicated To
my
Beloved Family
&
My friends
 ACKNOWLEDGMENT

The work on this project has been an inspiring, often exciting, sometimes challenging, but

always interesting and an enjoyable experience. On the occasion of presenting this thesis, it is

my privilege to express my sincere thanks to my research guide Dr.C.S.R.Lakshmi madam,

Department of Pharmaceutics, Nargund College of Pharmacy, who has provided excellent

guidance, valuable advices, and shared intelligent thoughts, criticisms and inculcated discipline.

I am highly indebted to her for her valuable presence even in her busy schedule, which helped

me to complete this work successfully.

Many thanks to God. It is he who has blessed me with the people whose names I feel privileged

to mention here.

I express my deep gratitude to Dr. L.V.G. Nargund, Director & Principal Nargund College of

Pharmacy, for his enduring support. He has been generous with providing facilities to carry

out this work.

I thank specially to Prof. C.R. MahendraSetty, Asst.Prof. Harish, Asst.Prof. Puranik,

Asst.Prof. Rama Bukka, Sr. Lecturer Jayanthi A, Asst.Prof. Ritu Vivek Kimbahune,

Asst.Prof. Preethi Karawa and all teaching and non-teaching staff for their great anticipation

during my research work.

Behind every success there are lots of efforts, but efforts are fruitful due to hands making the

passage smoother. I cannot forget Mr. Raghunandan H.V,senior manager Q.A Biocon.

Mr.Harsha Jinadatharay manager Q.A Biocon, Ms. Rajeshwari Vaidhyanathan,manager Q.C

Biocon. who guided me in every step and encouranged me, Mr.Guru Prasad and Mr.Mahesh

who helped me to get all the required materials, I would like to thanks Mutthu Krishna
sir,Pallavi madam vellu Sir,Viramani Sir, Shwetha,Anandraman sir, Basavaraj Sir, Gayatri,

Padmaja, Honnesh, Harish sir,Suresh sir and whole Q.A and Q.C team of Biocon.

I express loving thanks to my dearest friends in college Pavan, Rajesh, Naveen, Rohit Patel,

Hitesh Patel, Shakunthala, Vedha, Parveen, Nishit Doshi, Mayank Parekh, Pinkesh Patel,

Jitesh, Anup, Nitesh, Sagar, Sai and Avinash for their enduring support throughout the

research work.

‘Thanks is a small word to my father ( Shri Ramakanta Bhat ), mother (Umalakshmi),

Timmanna Bhat, Shantha Bhat,, Brother Sateesh Bhat veena Bhat, Sister Usha Kiran

Kameshwar, Kiran Kameshwar, Ganapathi Hosmane, Vijayalakshmi Hosmane, Parvathi Bhat,

Nirnajan Hosmane, Ganapathi.S.Hegde, Lalitha Hegde, Manasa Hegde, Ashwini Hegde.

Dakshayani who not only supported me but also inspired me during the course of my study.

I would like to thank my dear friends Suresh.M.V, Muruli, Sadiq, Santhosh Gowder, Sunil

and all my friends and well-wishers for their moral support and encouragement during my

study.

Loving thanks to my dearest friends, Arshad Ali, Praveen Kumar, Kiran, Anand, Rojen

,Chaithanya, Keerthi Kumar, Shri Ramesh,,Ramyashree, Nagaraj Hegde, Krishna Prasad, Shri

Krishna, Nanda and Navya.

I can’t forget Rupa Madam, Narmada madam, Lalitha madam, Manjunath sir who provided

me the Strong basic foundation in B.Pharm and encouraged me

My Sincere thanks to all!!!

Date:

Place: Bangalore Shiva Prasad Bhat

 ABBREVIATIONS

LIST OF ABBREVIATIONS

API Active Pharmaceutical ingredient

AR Analytical grade

USP United States Pharmacopoeia

Conc. Concentration

CPR Cumulative percentage release.

VLDL Very Low Density Lipoprotein

HDL High Density Lipoprotein
LDL Low Density Lipoprotein
FFA Free Fatty Acid
PUFA Poly Unsaturated Fatty Acids
CVD Coronary Vascular Disease
CHD Congestive Heart Disease
CR-GRDF Controlled Release-Gastro Retentive Dosage Form
MMC Migrating Myoelectric Complex
GRDF Gastro Retentive Dosage Form
HBS Hydrodynamically Balanced System
GR Gastro Retentive
PVA Poly Vinyl Alcohol
BDDS Bioadhesive Drug Delivery System
FDDS Floating Drug Delivery System
HPMC Hydroxy Propyl Methyl Cellulose
DSC Differential Scanning Calorimetry

FTIR Fourier transform infrared spectroscopy

HPLC High Pressure Liquid Chromatography

gm Gram

GIT Gastro intestinal tract

HCl Hydrochloric acid

SLS Sodium Lauryl Sulphate

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 ABBREVIATIONS

Hrs Hours

IP Indian Pharmacopoeia

DCP Dicalcium Phosphate

BD bulk density

Sec Seconds

mg Milligram

ml Milliliter

pH Negative logarithm of hydrogen ion concentration

RH Relative Humidity

SD Standard Deviation

TBD Tapped bulk density

t½ Time required to reduce half of the initial concentration.

USP United States of pharmacopoeia

UV Ultra Violet

g Microgram

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 Abstract

Gastroretentive effervescent floating tablet of simvastatin were formulated using

different grades of hydroxypropyl methylcellulose (HPMC K4M, HPMC K15M, HPMC

K100M). In vitro release, floating lag time and duration of floating of the fabricated

tablets were investigated. Gastroretentive effervescent floating tablets containing 20mg of

simvastatin were developed using HPMC K4M, HPMC K15M, HPMC K100M with

different drug to polymer ratio, mixture of 10%sodium bicarbonate, 2.5% citric acid

anhydrous as gas generating agents, dicalcium phosphate and lactose as fillers. Citric acid

was also used as an antioxidant. Tablets were prepared by direct compression method.

The formulation was optimized to get 85% drug release at the end of 12hrs and to get

optimum floating lag time and buoyancy. The resulting formulations produced robust

tablets with optimum hardness, consistent uniformity in weight and low friability. The

formulation with HPMC K4M in the drug –polymer ratio of 1:3 showed 85.830% drug

release at the end of 12hours, maintained integrity of tablets and also have optimum

floating lag time. Tablets of all the batches floated for more than 12hrs. The results of

dissolution studies indicated that the formulation F2 (HPMC K4M 1:3 ratio) is the most

successful of the study. A decrease in release rate of the drug was observed on increasing

polymer ratio and also by increasing viscosity grades of the polymer (HPMC). The

optimized formula F2 was fitted to various kinetic models and the result showed that F2

batch followed Zero order kinetics. The mechanism of drug release from F2 batch was

anamolous non-fickian diffusion pattern.

Key words: Simvastatin, direct compression, HPMC K4M, HPMC K15M, HPMC

K100M
 CONTENTS

LIST OF CONTENTS

Sl. no CONTENTS Page no

1 Introduction 1-26

2 Objective 27-28

3 Review of literature 29-59

4 Methodology 60-84

5 Results 85-124

6 Discussion 125-131

7 Conclusion 132-133

8 Summary 134-135

9 Bibliography 136-141

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 TABLES

LIST OF TABLES
Sl.No Tables Page no.,
1 Lipid Profile 3
2 Commonly used drugs in formulation of gastroretentive dosage 25
form
3 Marketed products of Floating drug delivery systems 26
4 List of excipients 60
5 List of equipments 61
6 Standard calibration curve of Simvastatin in pH 1.2(0.1N HCl with 65
0.5%SLS)
7 Optical characteristics and precision of the proposed method at 66
pH1.2
8 Standard calibration curve of simvastatin in acetonitrile 67
9 Optical characteristics and precision of the proposed method in 67
acetonitrile
10 Binary mixture composition 69
11 Compatibility study testing plan 69
12 HPLC gradient program 71
13 Preliminary trial formulae 73
14 Floating tablets with various formulae 74
15 Comparison between angle of repose and flow property 75
16 Limits in Hausner’s ratio 76
17 Compressibility index 77
18 Tablet weight variation 78
19 Interpretation of diffusion mechanisms from polymeric films 82
20 FTIR peaks of Simvastatin 86
21 Peak temperature and enthalpy values of simvastatin in various 91
drug-excipient mixture
22 Isothermal stress testing 101
23 Pre-compression parameters 102
24 Post-compression parameters 103
25 Floating lag time 104
26 In vitro drug release studies of floating tablet of simvastatin 105
containing HPMC K4M
27 In vitro drug release studies of floating tablet of simvastatin 106
containing HPMC K15M
28 In vitro drug release studies of floating tablet of simvastatin 107
containing HPMC K100M
29 Kinetic modeling of Simvastatin formulation: F2 108
30 Kinetic modeling of Simvastatin formulation: F3 110
31 Kinetic modeling of Simvastatin formulation: F6 112
32 Kinetic modeling of Simvastatin formulation: F7 114
33 Kinetic modeling of Simvastatin formulation: F9 116
34 Correlation coefficients of different mathematical models for 118
formulation

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 TABLES

35 Swelling and erosion index of formulation F2 118

36 Swelling and erosion index of formulation F3 119
37 Swelling and erosion index of formulation F6 120
38 Swelling and erosion index of formulation F7 121
39 Swelling and erosion index of formulation F9 122
40 Stability studies 124

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 FIGURES

LIST OF FIGURES
Sl. No Figures Page.
No
1 Standard curve of Simvastatin in pH1.2(0.1N HCl with 0.5%SLS) 67
2 Standard curve of Simvastatin in acetonitrile 69
3 FTIR peaks of Simvastatin 85
4 DSC thermogram of pure drug Simvastatin 87
5 DSC thermogram of mixtures of drug and HPMC K4M 87
6 DSC thermogram of mixtures of drug and HPMC K15M 88
7 DSC thermogram of mixtures of drug and HPMC K100M 88
8 DSC thermogram of mixtures of drug and Citric acid anhydrous 89
9 DSC thermogram of mixtures of drug and sodium bicarbonate 89
10 DSC thermogram of mixtures of drug and lactose 90
11 DSC thermogram of mixtures of drug and Dicalcium phosphate 90
12 Dsc thermogram of mixtures of drug and Magnesium stearate 91
13 HPLC standard run of Simvastatin 92
0
14 HPLC peak of Simvastatin API (25 C) 92
15 HPLC peak of Simvastatin in Simvastatin and HPMC K4M mixture 93
(250C)
16 HPLC peak of Simvastatin in Simvastatin and HPMC K15M 93
mixture(250C)
17 HPLC peak of Simvastatin in Simvastatin and HPMC K100M mixture 94
(250C)
18 HPLC peak of Simvastatin in Simvastatin and Citric acid mixture 94
(250C)
19 HPLC peak of Simvastatin in Simvastatin and sodium bicarbonate 95
(250C)
20 HPLC peak of Simvastatin in Simvastatin and lactose (250C) 95
21 HPLC peak of Simvastatin in Simvastatin and Dicalcium phosphate 96
mixture (250C)
22 HPLC peak of Simvastatin in Simvastatin and magnesium 96
stearate(250C)
23 HPLC peak of Simvastatin API (400C/75%RH) 97
24 HPLC peak of Simvastatin in Simvastatin and HPMC K4M 97
mixture(400C/75%RH)
25 HPLC peak of Simvastatin in Simvastatin and HPMC K15M 98
mixture(400C/75%RH)
26 HPLC peak of Simvastatin in Simvastatin and HPMC K100M 98
mixture(400C/75%RH)

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 FIGURES

27 HPLC peak of Simvastatin in Simvastatin and citric acid 99

mixture(400C/75%RH)
28 HPLC peak of Simvastatin in Simvastatin and sodium bicarbonate 99
mixture(400C/75%RH)
29 HPLC peak of Simvastatin in Simvastatin and lactose 100
mixture(400C/75%RH)
30 HPLC peak of Simvastatin in Simvastatin and Dicalcium phosphate 100
mixture(400C/75%RH)
31 HPLC peak of Simvastatin in Simvastatin and magnesium stearate 101
mixture(400C/75%RH)
32 Dissolution profile of Simvastatin with HPMC K4M 105
33 Dissolution profile of Simvastatin with HPMC K15M 106
34 Dissolution profile of Simvastatin with HPMC K100M 107
35 Zero plot of formulation F2 108
36 First order plot of formulation F2 109
37 Higuchi plot of formulation F2 109
38 Korsmeyer-Peppas plot of formulation F2 109
39 Zero plot of formulation F3 110
40 First order plot of formulation F3 111
41 Higuchi plot of formulation F3 111
42 Korsmeyer-Peppas plot of formulation F3 111
43 Zero plot of formulation F6 112
44 First order plot of formulation F6 113
45 Higuchi plot of formulation F6 113
46 Korsmeyer-Peppas plot of formulation F6 113
47 Zero plot of formulation F7 114
48 First order plot of formulation F7 115
49 Higuchi plot of formulation F7 115
50 Korsmeyer-Peppas plot of formulation F7 115
51 Zero plot of formulation F9 116
52 First order plot of formulation F9 117
53 Higuchi plot of formulation F9 117
54 Korsmeyer-Peppas plot of formulation F9 117
55 Swelling index of formulation F2 119
56 Erosion index of formulation F2 119
57 Swelling index of formulation F3 120
58 Erosion index of formulation F3 120
59 Swelling index of formulation F6 121

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

 FIGURES

60 Erosion index of formulation F6 121

61 Swelling index of formulation F7 122
62 Erosion index of formulation F7 122
63 Swelling index of formulation F9 123
64 Erosion index of formulation F9 123

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85

Chapter-1 Introduction

1. INTRODUCTION

Obesity is defined as an excess of adipose tissue that imparts health risk; a body

weight of 20% excess over ideal weight for age, sex and height is considered a health

risk.11

Adults with a body mass index (BMI, calculated as weight in kg divided by height in

meter squared) between 25kg/m2 and 30kg/m2 are considered obese. Anyone who is

more than 100 pounds overweight or who has a BMI greater than or equal to 40 kg/m2

is considered morbidity obese.14

Causes, incidence and risk factors11, 14

Taking in more calories than burning, leads to being overweight and eventually

obesity. The body stores unused calories as fat. Obesity can be the result of:

Eating more food than your body can use

Drinking too much alcohol.

Not getting enough exercise/sedentary life style

Genetic predisposition to develop obesity

Secondary obesity may result following a number of underlying diseases such as

hyperthyroidism, cushing‟s disease, insullinoma and hypothalamic disorders.

Some antidepressants and antipsychotic medicines may also contribute to weight

gain and obesity.

People who are at higher risk for obesity include:14

Low income groups

Former smokers

People with chronic mental illness

People with disabilities

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 1

Chapter-1 Introduction

People with sedentary life style.

Complications14

Medical problems commonly resulting from untreated obesity and morbid obesity

include:

Type 2 diabetes and metabolic syndrome.

High blood pressure, coronary heart disease and stroke

Obstructive sleep apnea and other sleep disorders

Osteoarthritis

Cholelithiasis

HYPERLIPIDEMIA

Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis associated

condition, such as coronary heart diseases (CHD), ischemic cerebrovascular disease

and peripheral vascular disease. Although the incidence of these atherosclerosis-

related events has declined in United states, these conditions still account for the

majority of morbidity and mortality among middle aged and older adults.

Dyslipidemias, including hyperlipidemia (hypercholesterolemia) and low levels of

high –density-lipoprotein cholesterol (HDL-C), are major causes of increased

atherogenic risk, both genetic disorders and lifestyle (sedentary behaviour and diets

high in calories, saturated fat and cholesterol) contribute to the dyslipidemias seen in

developed countries around the world.12

Hyperlipidemia or hyperlipoprotienemia is the condition of abnormally elevated

levels of any or all lipids and/ or lipoproteins in the blood.16 It is the most common

form of dislipidemia. It is now well established that hypercholesterolemia has a

directly proportional relationship with atherosclerosis and IHD. The most important

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 2

Chapter-1 Introduction

evidence cited in support of this is the atherosclerotic plaques contain cholesterol and

cholesterol esters, largely derived from the lipoproteins in the blood.11

The major classes lipoprotein particles are chylomicrons, very-low density

lipoproteins (VLDL), low- density lipoproteins (LDL) and high-density liopoproteins

(HDL)11

Low-density lipoprotein (LDL) is richest in cholesterol and has the maximum

association with atherosclerosis.

Very-low-density lipoprotein (VLDL) carries much of the triglycerides and has

less marked effect than LDL

High-density lipoprotein (HDL) is protective „good cholesterol‟ against

atherosclerosis.11

Table no-1: Lipid Profile11

Sl.No classes Sites of Normal serum Role in

synthesis values atherosclerosis

1 HDL -C Liver, Intestine >40mg/dl protective

2 VLDL-C Intestine, Liver <160mg/dl Less marked

3 LDL-C Liver <130mg/dl maximum

4 Total cholesterol <200mg/dl

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 3

Chapter-1 Introduction

Classification of hyperlipidemia13

Hyperlipidemias may be either primary or secondary:

 Primary (Familial) hyperlipidemia: These are due to genetic defects in

lipoprotein metabolism and transport.

 Acquired (secondary) hyperlipidemia: These are due to some other diseases

(e.g. Diabetes mellitus, nephritic syndrome, atherosclerosis, hypothyroidism etc.)

Primary hyperlipidemia: This was further classified by Frederickson based on

electrophoretic patterns of plasma lipoproteins:

Type-I: This is due to familial lipoprotein lipase deficiency

Type-IIa: This is caused by a defect in LDL receptors

Type-IIb: Both LDL and VLDL increase along with elevation in plasma

cholesterol and triglycerol. This is believed to be due to overproduction of apo B.

Type-III: This is characterized by the appearance of a broad β-band

corresponding to intermediate density lipoprotein (IDL) on electrophoresis.

Type-IV: This is due to overproduction of endogenous triacylglycerols with a

concomitant rise in VLDL. It is usually associated with obesity, alcoholism,

diabetes mellitus etc.

Type-V: Both chylomicrons and VLDL are elevated. This is mostly an acquired

condition, due to disorders such as obesity, diabetes and excessive alcohol

consumption etc.

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 4

Chapter-1 Introduction

Metabolic changes8,11

 Non-insulin diabetes mellitus: Abdominal fat, which exhibits accelerated

lipolytic, particularly in the visceral depot, can adversely affect insulin action and

the disposal of glucose through an increase in the release of free fatty

acids(FFAs). Increased FFA released from the visceral depot drains into the portal

circulation and adversely affects hepatic insulin sensitivity, leading to increased

hepatic glucose production. The increase in FFA circulation can then result in

ectopic accumulation of triglyceride in muscle and liver, thereby depressing

insulin action and increasing output of apo B- containing lipoproteins.

 Atherogenic dyslipidemia: Atherogenic dyslipidemia, a component of metabolic

syndrome is characterized by high levels of apolipoprotein B- containing

lipoproteins, including very-low-density lipoprotein remnants and small low-

density lipoprotein particles and reduced levels of high-density lipoprotein

cholesterol. Impaired regulation of adipokines, bioactive substances secreted from

adipose tissue are likely to produce systemic inflammation which can promote

atherogenesis.

 Coronary artery disease and stroke: As a result of atherosclerosis and

hypertension, there is increased risk of myocardial infarction and stroke in obese

individuals.

Management of obesity and hyperlipidemia 13,14,15,16

Regular exercise and a healthy diet are crucial when it comes to controlling weight.

The only method proven safe over the long term is to burn more calories than you

consume.

Diet: Dietary intake of polyunsaturated fatty acids (PUFA) reduces the plasma

cholesterol level. PUFA will help in transport of cholesterol and its excretion from

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 5

Chapter-1 Introduction

the body. Fibre present in vegetables decreases the cholesterol absorption from the

intestine. Diets rich in carbohydrates (particularly sucrose) should be avoided to

control hypercholesterolemia.

Exercise: To lose weight calories must be burned than intake. Walking a mile a

day for 30 days will help burn off 1 pound of fat as long as we don‟t eat more than

usual.

Medications: If lifestyle changes do not change cholesterol enough, doctor may

recommend medications. Some drugs are better at lowering LDL cholesterol,

some are good at lowering triglycerides, while other help raise HDL-C. For

treatment of Type-II, dietary modification is the initial approach but many people

require treatment with statins to reduce cardiovascular risk. If the triglyceride is

markedly raised, fibrates may be preferable due to their beneficial effects, other

agents commonly added to statins are ezetimibe, niacin and bile acid sequestrants.

Surgery: Weight loss surgery may be done to help lose weight if the person is

very obese and have not been able to lose weight with diet and exercise.

The two most common weight loss surgeries are:

 Laproscopic gastric banding- The surgeon places a band around the upper part

of stomach, creating a small pouch to hold food. The band helps you limit how

much food you can eat by making you feel full after eating small amounts.

 Gastric bypass surgery: Helps lose weight by changing how stomach and

small intestine handle the food you eat. After the surgery, person will not be

able to eat as much as before and body will not absorb all the calories and

other nutrients from the food.

 Liposuction can also be performed to remove excess fat.

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 6

Chapter-1 Introduction

Heart disease and stroke, the principle components of cardiovascular disease, are the

first and third leading causes of death in the U.S, accounting for more than 40% of all

deaths. The relationship between, elevated serum cholesterol and CVD was

recognized nearly a century ago by investigators. Since then multiple clinical and

epidemiological studies have further established this relationship beyond reasonable

doubt. The relationship between the cholesterol level and coronary heart disease

mortality has linear approximation with each 20mg/dl increase in total cholesterol

resulting in a 12% increase in CHD mortality. This led to the belief that decreasing

serum cholesterol level will decrease the CVD mortality. However, though treating

patients with hyperlipidemia with agents like bile acid sequesteants, nicotinic acid and

fibrates resulted in decreased in cholesterol level, no decrease in the rates of CHD

mortality or total mortality was seen. This could probably be related to the

identification of LDL-C as the main atherogenic component of serum cholesterol, or

the fact that these agents were not able to decrease the cholesterol level adequately

enough to decrease the CVD risk.7

The introduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

(statin) in the late 1980s was a major breakthrough in the treatment of hyperlipidemia

and CVD. Since then various multicentre clinical trials have shown a decrease in

total cholesterol and LDL-C levels with statins and a resulting reduction in the CVD

mortality.7

Statins are structurally similar to HMG-coenzyme-A, which is a precursor to

cholesterol and competitively inhibit the HMG-coA reductase that is the last step in

the synthesis of cholesterol. Subgroup analysis of large clinical trials indicate that

statin treated individuals have significantly less CVD than patients with comparable

serum cholesterol levels. This is probably due to their beneficial “pleiotropic” effects:

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 7

Chapter-1 Introduction

improving or restoring endothelial function, enhancing the stability of atherosclerotic

plaques and decreasing oxidative stress and vascular inflammation. Statins decreases

LDL-C level, lowers TGL levels, increases HDL-C and apolipoprotein A-I and

decreases oxidation of LDL-C.7

The present study is aimed to prepare the gastro-retentive floating tablet using

simvastatin which reduces the LDL-C concentration in the blood stream by inhibiting

the HMG-coA reductase. Simvastatin can reduce serum LDL-C by 41%, increases

serum HDL-C by 12%, reduce serum triglyceride by 18%.17

Gastroretentive drug delivery systems

Controlled release (CR) dosage forms have been extensively used to improve therapy

with several important drugs. However, the development processes are faced with

several physiological difficulties such as the inability to restrain and localize the

system within the desired region of the gastrointestinal tract and the highly variable

nature of the gastric emptying process. This variability may lead to unpredictable

bioavailability and time to achieve peak plasma level. On the other hand,

incorporation of the drug in a controlled release gastroretentive forms (CR-GRDF)

which can remain in the gastric region for several hours would significantly prolong

the gastric residence time of drugs and improve bioavailability, reduce drug waste,

and enhance the solubility of drugs that are less soluble in high pH environment.

Gastroretention would also facilitate local drug delivery to the stomach and proximal

small intestine. Thus, gastroretention could help to provide greater availability of new

products and consequently improved therapeutic activity and substantial benefits to

patients.2

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 8

Chapter-1 Introduction

Basic gastrointestinal tract physiology1,6,17

Stomach has mainly 4 main regions: The cardia, fundus, body and pylorus. The cardia

surrounds the superior opening of the stomach.

Pylorus has 2 main parts:- pyloric antrum which connects body of the stomach and the

pyloric canal leads to duodenum.

Body is the large central portion of the stomach which is inferior to the fundus.

Body acts as reservoir for undigested material, whereas the antrum is the main site for

mixing motions and acts as a pump for gastric emptying by propelling actions. Gastric

emptying occurs during fasting as well as fed states. The pattern of motility is

however distinct in the 2 states.

The fasted state is associated with some cyclic contractile events commonly known as

migrating myoelectric complex (MMC) which cycle both through stomach and

intestine every 2 to 3hours.

Apparently there are four consecutive phases of activity in the MMC.

Phase-I (basal phase): It is a quiescent period lasting from 30 to 60min with no

contractions.

Phase-II (preburst phase): It consists of intermittent contractions that gradually

increase in intensity as the phase progresses, and lasts about 20-40min. Gastric

discharge of fluid and very small particles begins later in this phase.

Phase-III (burst phase): This is a short period of intense distal and proximal gastric

contractions (4-5 contractions per minute) lasting about 10-20minutes. These

contractions also known as “house keeper waves” sweep gastric contents down the

small intestine.

Phase-IV: This is a short transitory period of about 0-5minutes, and the contractions

dissipate between the last part of phase-III and phase-I.

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Chapter-1 Introduction

The different phases originating in the foregut continue to the terminal ileum, another

begins in the stomach and duodenum. Liquid components easily pass through the

partially constricted sphincter. On the contrary, the large undigested materials are

retained by an “antral-seieving” process and are retropulsed into the body of stomach

and remain in the fed state. In the fed state, gastric contractions move the contents

towards the antrum and the pyloric sphincter.

After the ingestion of a mixed meal, the pattern of contractions changes from fasted to

that of fed state. This is also known as digestive motility pattern and comprises

continuous contractions as in the phase-II of fasted state. These contractions results in

reducing the size of food particles (to less than 1mm) which are propelled towards the

pylorus in a suspension form. During the fed, state onset of MMC is delayed resulting

in slow down of gastric emptying rate.

Approaches to prolong gastric residence time of drug delivery system2

The need for gastroretentive dosage forms (GRDFs) has led to extensive efforts in

both academia and industry towards the development of such drug delivery systems.

These efforts resulted in GRDFs that were designed in large part, based on the

following approaches.

1. Floating drug delivery systems

2. High density systems

3. Bioadhesion to stomach mucosa

4. Slowed motility of gastrointestinal tract by concomitant administration of drugs or

pharmaceutical excipients

5. Expansion by swelling or unfolding to a large size which limits emptying of

dosage form through the pyloric sphincter

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Chapter-1 Introduction

Floating drug delivery system

1. Single unit floating dosage form

3,9
a. Non-effervescent systems: The most commonly used excipients in non-

effervescent FDDS are gel forming or highly swellable cellulose type

hydrocolloids, polysaccharides and matrix forming polymers such as

polycarbonate, polyacrylate, polymethacrylate and polystyrene., which swells

in contact with gastric fluids after oral administration and maintains a relatve

integrity of shape, bulk density of less than unity. The air entrapped by the

swollen polymer confers buoyancy to these dosage forms.

i. Colloidal gel barrier system: 9This system incorporates a high level (20-

75%w/w) of one or more gel-forming, highly swellable, cellulose type

hydrocolloids(e.g. Hydroxy ethyl cellulose, hydroxy propyl cellulose,

hydroxy propyl methyl cellulose , sodium carboxymethyl cellulose)

polysaccharides and matrix forming polymers such as polycarbophil,

polyacrylates and polystyrene, incorporated either in tablets or in

capsules. On coming in contact with gastric fluid, the hydrocolloid in the

system hydrates and form colloidal gel barrier around its surface. This

gel- barrier control the rate of fluid penetration into the device and

consequent release of the drug. As the exterior surface of the dosage form

goes into the solution, the gel layer is maintained by the adjacent

hydrocolloid layer becoming hydrated. The air trapped in by the swollen

polymer maintains a density less than unity and confers buoyancy to these

dosage forms.

The HBS must comply with 3 major criteria:

1) It must have sufficient structure to form a cohesive gel barrier

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Chapter-1 Introduction

2) It must maintain an overall specific density lower than that of gastric

contents

3) It should dissolve slowly enough to serve as a reservoir for the

delivery system.

A bilayer tablet can also be prepared to contain one immediate-release

and sustained release layer. Immediate-release layer delivers the initial

dose, whereas SR layer absorbs gastric fluid and forms a colloidal gel

barrier on its surface. This results in a system with bulk density lesser

than that of the gastric fluid, and allows it to remain buoyant in stomach

for an extended period of time.

ii. Microporous compartment system:9 This technology is based on the

encapsulation of a drug reservoir inside a microporous compartment with

apertures along its top and bottom walls. The peripheral wall of the drug

reservoir compartment is completely sealed to prevent any direct contact

of gastric mucosal surface with the undissolved drug. In stomach, the

floatation chamber containing entrapped air causes the delivery system

to float over the apertures, dissolves the drug and carries the dissolved

drug for continuous transport across the intestine for absorption.

b. Effervescent systems:9 A drug delivery system can be made to float in the

stomach by incorporating a floating chamber, which may be filled with

vaccum, air or inert gas. The gas in the floating chamber can be introduced

either by the volatilization of an organic solvent or by the effervescent

reaction between organic acids and bicarbonate salts.

i. Volatile liquid containing systems:9 The GRT of a drug delivery

system can be sustained by incorporating an inflatable chamber which

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Chapter-1 Introduction

contains a liquid e.g. ether, cyclopentane that gasifies at body

temperature to cause the inflatation of the chamber in the stomach.

These devices are osmotically controlled floating systems containing

a hollow deformable unit that can convert from a collapsed to an

expanded position and returns to collapsed position after an extended

period. The deformable system consists of two chambers separated by

an impermeable, pressure-responsive, movable bladder. The first

chamber contains the volatile liquid. The device inflates and the drug

is continuously released from the reservoir into the gastric fluid. The

device may also consists of a bioerodible plug made up of PVA,

polyethylene etc. that gradually dissolves causing the inflatable

chamber to release gas and collapse after a predetermined time to

permit spontaneous ejection of the inflatable system from the stomach

4,9
ii. Gas- generating systems : These buoyant systems use matrices

prepared with swellable polymers like HPMC, polysaccharides like

chitosan, effervescent components like sodium bicarbonate, citric

acid, tartaric acid, Di-sodium glycine carbonate, citroglycine etc. The

optimal stoichiometric ratio of citric acid and sodium bicarbonate for

gas generation is reported to be 0.76:1. Effervescent reaction between

bicarbonate salts and citric acid/tartaric acid liberates CO2,which gets

entrapped in the gellified hydrocolloid layer of the system, thus

decreasing its specific gravity and making it to float over chyme.

These tablets may be either single layered wherein the carbondioxide

generating components are intimately mixed within the tablet matrix,

or they may be bilayered in which the gas generating components are

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Chapter-1 Introduction

compressed in hydrocolloid containing layer and the drug in other

layer formulated for a SR effect.

2. Multiple unit floating dosage form

a. Non-effervescent system

i. Alginate beads:9 Spherical beads of approximately 2.5mm in diameter

can be prepared by dropping a sodium alginate solution into aqueous

solution of calcium alginate. The beads are then separated, snap frozen

in liquid nitrogen and freeze-dried at -400C for 24 hours, leading to the

formation of a porous system, which can maintain a floating force for

12 hours

ii. Hollow microspheres:4 Hollow microspheres are considered as one of

the most promising buoyant systems as they possess the unique

advantages of multiple unit systems as well as better floating

properties, because of the central hollow space inside the microsphere.

The general techniques involved in their preparation include simple

solvent evaporation and solvent diffusion and evaporation. Polymers

such as polycarbonate, eudragit S and cellulose acetate are used in the

preparation of hollow microspheres and the drug release can be

modified by optimizing the amount of polymer-plasticizer ratio.

Hollow microspheres floated with drug in their outer polymer shelf can

also be prepared by a novel emulsion solvent-diffusion method. The

ethanol/dichloromethane solution of the drug and an enteric acrylic

polymer was poured into an agitated solution of poly vinyl alcohol that

was thermally controlled at 400C. The gas phase is generated in the

dispersed polymer droplet by the evaporation of dichloromethane

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Chapter-1 Introduction

formed an internal cavity in he microsphere of the polymer with drug.

The microballoon floated continuously over the surface of an acidic

dissolution media containing surfactant for more than 12 hours.

b. Gas-generating systems : 9Multi unit types of floating pills, which generate

CO2 have also been developed. The system consists of a SR pill as seed,

surrounded by double layers. The inner layer is an effervescent layer

containing sodium bicarbonate and tartaric acid. When the system is immersed

in buffer solution at 370C swollen pills, like balloons are formed having

density less than 1g/ml. This occurs due to CO2 neutralization of the inner

effervescent layer with the diffusion of water through the outer swellable

membrane layer. These kinds of systems float completely within 10min and

remain floating over extended periods of 5-6 hours.

c. Ion-exchange resin system:3 The system consisted of resin beads, which

were loaded with the bicarbonate and a negatively charged drug that was

bound to the resin. The resultant beads were then encapsulated in a

semipermeable membrane to overcome rapid loss of CO2. Upon arrival in the

acidic environment of stomach, an exchange of chloride and bicarbonate ions

took place. As a result of this reaction, carbondioxide was released and

trapped in the membrane, thereby carrying beads towards the top of gastric

contents and producing a floating layer of resin beads.

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Chapter-1 Introduction

Bio/Mucoadhesive systems2

Bioadhesive drug delivery systems (BDDS) are useful as a delivery device within the

lumen to enhance drug absorption in a site-specific manner. This approach involves

the use of bioadhesive polymers, which can adhere to the epithelial surface in the

stomach. Gastric mucoadhesion does not tend to be strong enough to impart the

dosage forms the ability to resist the strong propulsion forces of the stomach wall.

The continuous production of mucous that is lost through peristalitic contractions and

the dilution of the stomach contents also seem to limit the potential of mucoadhesion

as a gastroretentive force. Some of the most promising excipients that have been used

commonly in these systems include polycarbophil, carbopol, lectins, chitosan and

gliadin etc. The adhesion of the polymers with the mucous membrane may be

mediated by hydration, bonding or receptor mediated.

Swelling systems1

Swelling systems are also referred to as plug type systems. The presence of polymers

in the systems promotes their swelling to a size that prevents their passage through

pyloric sphincter resulting in prolonged GRT. However, a balance between the rate

and extent of swelling and the rate of erosion of the polymer is crucial to achieve

optimum benefits and to avoid unwanted side effects.

High density system10

This approach involves formulation of dosage forms with the density that must exceed

density of normal stomach content (1.004g/cm3). These formulations are prepared by

coating drug on a heavy core or mixed with heavy inert materials such as iron powder,

zinc oxide, titanium dioxide or barium sulphate. These resultant pellets can be coated

with diffusion controlled membrane. These systems with a density of about 3g/cm3

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 Chapter-1 Introduction

are retained in the rugae of the stomach and are capable of withstanding its peristalitic

movements. 2.6-2.8g/cm3 acts as a threshold density after which such systems can be

retained in the lower part of the stomach.

Expansive gastroretentive dosage form10

This is a class of gastroretentive systems capable of expanding in stomach. The

expanded structure is trapped in stomach for prolonged period leading to sustained

drug release and subsequent controlled absorption in stomach and intestine. These

systems are administered perorally in the form of capsule bearing the dosage form in

folded and compact configuration. When exposed to gastric environment capsule shell

breaks and the dosage form attains its expanded structure, which is retained in stomach

for longer time. The serous drawback of this system is clogging of pylorus end of

stomach.

Raft forming systems3,4

Raft forming systems have received much attention for the delivery of antacids and

drug delivery for gastrointestinal infections and other disorders. The mechanism

involved in the raft formation includes the formation of a viscous cohesive gel in

contact with gastric fluids, wherein each portion of the liquid swells forming a

continuous layer called a raft. This raft floats on gastric fluids because of the low bulk

density created by the formation of CO2. Usually, the system contains a gel forming

agents and alkaline bicarbonates or carbonates responsible for the formation of CO2 to

make the system less dense and able to float on the gastric fluids. This floating rafts

impedes the reflux of acids and food by acting as a physical barrier. The raft has a pH

value higher than that of the stomach contents so that in the event of gastric reflux, the

wall of the esophagus is not subjected to irritation by HCl.

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Chapter-1 Introduction

Suitable drug candidates for gastroretention.2

In general, appropriate candidates for CR-GRDF are molecules that have poor colonic

absorption but are characterized by better absorption properties at the upper parts of

the GIT:

Narrow absorption window in GI tract, e.g. Riboflavin and levodopa

Primarily absorbed from stomach and upper part of GI tract e.g. calcium

supplements, chlorodiazepoxide and cinnarazine.

Drugs that act locally in the stomach e.g. antacids and misoprostol

Drugs that degrade in the colon e.g. ranitidine HCl and metronidazole

Drugs that disturb normal colonic bacteria, e.g. amoxicillin trihydrate

Factors affecting floating drug delivery system1, 2, 4

1. Density of dosage form: Dosage forms having a density lower than that of gastric

fluid experience floating behavior and hence gastric retention. Density <1.0g/cm3

is required to exhibit floating property.

2. Size of dosage form: The size of the dosage form is another factor that influences

gastric retention .The mean gastric residence times of non-floating dosage forms

are highly variable and greatly dependent on their size, which may be small,

medium and large units. In fed conditions, the smaller units get emptied from the

stomach during the digestive phase and the larger units during the house keeping

waves. In most cases, the larger the size of the dosage form the greater will be the

gastric retention time because the larger size would not allow the dosage form to

quickly pass through the pyloric sphincter into the intestine. Dosage form units

with a diameter more than 7.5mm are reported to increase GRT compared with

those with diameter of 9.9mm.

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Chapter-1 Introduction

3. Food intake and nature of food: Food intake, the nature of the food, caloric

content and frequency of feeding have a profound effect on the gastric retention of

dosage forms. The presence or absence of food in the stomach influences the GRT

of the dosage forms. Usually, the presence of food increases the GRT of the

dosage form and increases drug absorption by allowing it to stay at the absorption

site for a longer time. Usually fats tend to form an oily layer on the other gastric

contents. As such, fatty substances are emptied later than other. Also, increased

acidity and osmolality slow down gastric emptying.

4. Stress: stress appears to cause an increase in gastric emptying rate, while

depression slows it down.

5. Sex: women and elderly have a slower gastric emptying rate than men and young

people respectively.

6. Posture: In a comparative study in humans by Gansbeke et al; the floating and

non floating systems behaved differently. In the upright position, the floating

systems floated to the top of the gastric contents and remained for a longer time,

showing prolonged GRT. But the non floating units settled to the lower part of the

stomach and underwent faster emptying as a result of peristalitic contractions and

the floating units remained away from the pylorus. However, in supine position,

the floating units are emptied faster than non floating units of similar size. A study

by Mojaverian et al showed that effect of posture on GRT found no significant

difference in mean GRT for individuals in upright, ambulatory and supine state.

7. Shape: Tetrahedron and ring-shaped devices with a flexural modulus of 48 and

22.5 kilo pounds per square inch (KSI) are reported to exhibit a better GRT and

90%-100% retention at 24hour compared with other shapes.

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Chapter-1 Introduction

8. Concomitant drug administration: Anticholinergics like atropine and

propantheline, opiates like codeine and prokinetic agents like metoclopramide and

cisapride affect the FDDS.

9. Biological factors: Diabetes and crohn‟s disease also affect the FDDS.

Advantages of gastro retentive drug delivery system2,5

1. Enhanced bioavailability: The bioavailability of riboflavin CR-GRDF is

significantly enhanced in comparison to the administration of non-GRDF CR

polymeric formulation.

2. Enhanced first-pass biotransformation: In a similar fashion to the increased

efficacy of active transporters exhibiting capacity limited activity, the pre-

systemic metabolism of the tested compound may be considerably increased when

the drug is presented to the metabolic enymes (Cytochrome P450, in particular

CYP3A4) in a sustained manner, rather than by a bolus input.

3. Sustained drug delivery/ reduced frequency of dosing: For drug with relatively

short biological half-life, sustained and slow input from CR-GRDF may result in a

flip-flop pharmacokinetics and enable reduced dosing frequency. This feature is

associated with improved patient compliance and thereby improves therapy.

4. Targeted therapy for local ailments in the upper GIT: The prolonged and

sustained administration of the drug from GRDF to the stomach may be

advantageous for local therapy in the stomach and small intestine as in the case of

case of H.pylori induced peptic ulcer.

5. Reduced fluctuations of drug concentration: Continuous input of the drug

following CR-GRDF administration produces blood drug concentrations within a

narrow range compared to the immediate release dosage forms. Thus, fluctuations

in drug effects are minimized and concentration dependent adverse effects that are

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Chapter-1 Introduction

associated with peak concentrations can be prevented. This feature is of special

importance for drugs with a narrow therapeutic index.

6. Extended time over critical (effective) concentration: The sustained mode of

administration enables extension of the time over a critical concentration and thus

enhances the pharmacological effects and improves the clinical outcomes.

7. Site specific drug delivery: A floating dosage form is a feasible approach for

drugs which have limited absorption sites in upper small intestine

8. Minimized adverse activity at the colon: Retention of the drug in the GRDF at

the stomach minimizes the amount of drug that reaches the colon. Thus,

undesirable activities of drug in the colon may be prevented as in the case of β-

lactam antibiotics.

9. Administration of a prolonged release floating dosage form tablets or capsules

will result in dissolution of the drug in gastric fluid. After emptying of the

stomach contents, the dissolved drug available is for absorption in the small

intestine. It is therefore expected that a drug will be fully absorbed from the

floating dosage form if it remains in solution form even at alkaline pH of the

intestine.

10. When there is vigorous intestinal movement and a short transit time as might

occur in certain type of diarrhea, poor absorption is expected under such

circumstances and it may be advantageous to keep the drug in floating condition

in stomach to get a relatively better response.

11. Many drugs categorized as once-a-day delivery have been demonstrated to have

suboptimal absorption due to dependence on the transit time of the dosage form

making traditional extended release development challenging. Therefore, a system

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Chapter-1 Introduction

designed for longer gastric retention will extend the time within which drug

absorption can occur in small intestine.

Limitations of Floating drug delivery system9,10

1. They require a sufficiently high level of fluids in the stomach, for enabling the

system to float and to work efficiently. This limitation can be overwhelmed by

coating the dosage form with bioadhesive polymer or alternatively by prescribing

the dosage form to be take up with a glass full of water (200-250ml).

2. FDDS are not suitable candidates for drugs with stability or solubility problem in

stomach.

3. Some drugs like nifedipine, which is well absorbed along the entire GI tract and

undergoes extensive first pass metabolism may not be suitable for FDDS as the

slow gastric emptying limits the systemic bioavailability.

4. Drugs with irritant effect on gastric mucosa also limit the applicability of FDDS.

5. In case of bioadhesive systems, which form electrostatic and hydrogen bonds with

the mucus, the acidic environment and the thick mucus prevent the bond

formation at the mucus polymer interface. High turnover rate of the mucus may

further aggravate the problem

6. For swellable systems, the maintenance of their size larger than the aperture of

resting pylorus for required period of time is the major limiting factor.

7. Above all, any dosage form designed to stay in stomach during the fasting state

should be capable of resisting the house keeper waves of phase-III contractions of

MMC.

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Chapter-1 Introduction

Applications of floating drug delivery systems5,6

1. Sustained drug delivery: HBS systems can remain in the stomach for long

periods and hence can release the drug over a prolonged period of time. The

problem of short gastric residence time encountered with an oral CR formulation

hence can be overcome with these systems. These systems have a bulk density of

less than1 ass a result of which they can float on the gastric contents. These

systems are relatively large in size and passing from the pyloric opening is

prohibited.

Recently sustained release floating capsules of nicardipine hydrochloride were

developed and were evaluated in vivo. The formulation compared with

commercially available MICARD capsules using rabbits. Plasma concentration

time curves showed a longer duration for administration (16hours) in the sustained

release floating capsules as compared with conventional MICARD capsules

(8hours).

2. Site-specific drug delivery: These systems are particularly advantageous for

drugs that are specifically absorbed from stomach or the proximal part of the

small intestine e.g. riboflavin and furosemide.

A bilayer-floating capsule was developed for local delivery of misoprostol, which

is a synthetic analog of prostaglandin E1 used as a protectant of gastric ulcers

caused by administration of NSAIDs. By targeting slow delivery of misoprostol to

the stomach, desired therapeutic levels could be achieved and drug waste could be

reduced.

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Chapter-1 Introduction

3. Absorption enhancement: Drugs that have poor bioavailability because of site-

specific absorption from the upper part of the gastrointestinal tract are potential

candidates to be formulated as floating drug delivery systems, thereby maximizing

their absorption.

A significant increase in the bioavailability of floating dosage forms (42.9%)

could be achieved as compared with commercially available LASIX tablets

(33.4%) and enteric coated LASIX-long product (29.5%).

4. Medopar HBS – containing L-dopa and benserazide-here drug was released and

absorbed over a period of 6-8 hour and maintain substantial plasma concentration

in parkinson‟s patients

5. Cytotech- containing misoprostol, a synthetic prostaglandin-E1 analog, for

prevention of gastric ulcers caused by NSAIDs.

As it provides high concentration of drug within gastric mucosa, it is used to

eradicate pylori.

6. 5-Flurouracil has been successfully evaluated in patients with stomach neoplasm.

7. Developing HBS dosage form for Tacrine provides a better delivery system and

reduces its GI side effects in Alzheimer‟s patients.

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Chapter-1 Introduction

Table no-2: Commonly used drugs in formulation of gastroretentive dosage

forms2

SL.NO Dosage form Drug

1 Floating microspheres Aspirin, griseofulvin, p-nitroaniline,

ibuprofen, terfinadine and Tranilast

2 Floating granules Diclofenac sodium, indomethacin and

prednisolone

3 Films Cinnarazine

4 Floating capsules Chlordiazepoxide hydrogen chloride,

diazepam, furosemide, misoprostol, L-

dopa, benserazide, Ursodeoxycholic acid

and pepstatin

5 Floating tablets and pills Acetaminophen, acetylsalicylic acid,

ampicillin, amoxicillin trihydrate,

atenolol, diltiazem, fluorouracil,

isosorbide mononitrate, p-aminobenzoic

acid, theophylline and verapamil

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Chapter-1 Introduction

Table no-3: Marketed products of FDDS3

Sl.No. Brand Drug (dose) Company Remarks

name

1 Madopar Levodopa (100mg), Roche products Floating, CR

Benserazide (25mg) capsule

2 Valrelease Diazepam (15mg) Hoffmann- Floating capsule

LaRoche

3 Liquid Al-hydroxide Glaxo Smith Effervescent

Gaviscon (95mg), Mg Kline, India floating liquid

carbonate (385mg) alginate

preparation

4 Topalkan Al-Mg antacid Pierre Fabre Floating liquid

Drug alginate

5 Amalgate Al-Mg antacid Floating liquid

FloatCoat form

6 Conviron Ferrous sulphate Ranbaxy, India Colloidal gel

forming FFDS

7 Cifran OD Ciprofloxacin(1g) Ranbaxy, India Gas-generating

floating form

8 Cytotec Misoprostal Pharmaacia Bilayer floating

(100mcg/200mcg) capsule

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Chapter-2 Objective

2. OBJECTIVE

The purpose of this research is to prepare gastroretentive effervescent floating tablet

consisting of polymers (1) HPMC K4M, HPMC K15M, HPMC K100M (2)

Simvastatin (drug), a Dyslipidemic drug, by direct compression method and to

evaluate their gastro-retentive and controlled-release properties. The effect of various

formulations and process variables on the in- vitro floating behavior, and in- vitro

drug release was studied.

Hence, the objectives of the present work include:

1. Drug-polymer interaction studies

2. Preparation of Simvastatin floating tablets using different viscosity grades of

HPMC by direct compression technique.

3. Physical parameters like hardness, friability, weight variation, drug content

estimation.

4. Evaluation of drug loaded floating tablet for pre and post compression parameters.

5. To develop suitable formulae and procedure for the manufacture of simvastatin

floating tablets in a relatively economical way.

6. In vitro evaluations of floating tablets for the release characteristics. To evaluate

drug release profile with respect to mathematic modeling.

7. To develop an optimized formulation.

8. Stability studies of the promising formulations

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Chapter-2 Objective

Plane of work:

Literature survey

Selection of drug and polymer

Preformulation studies.

DSC and isothermal stress testing to rule out any incompatibility of drug with

excipients. .

Evaluation of matrix tablets.

 Thickness

 Hardness

 Weight variation

 Assay

 Swelling index and erosion index

 Floating lag time

 In-vitro drug release study

Stability studies.

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Chapter-3 Review of Literature

3. Review of Literature

 Shishu, et al; developed floating drug delivery system for 5-Fluoro uracil for

chemotherapy of gastrointestinal cancer which after oral administration, are

designed to prolong the gastric residence time, increasing drug bioavailability and

target the stomach cancer. A floating drug delivery system was developed using

gas forming agents like sodium bicarbonate, citric acid and hydrocolloids, like

hydroxypropyl methylcellulose and carbopol 934P. The prepared tablets were

evaluated in terms of their physical characteristics, in vitro release, buoyancy lag

time and swelling index. The formulations were optimized for type of filler, like

lactose, microcrystalline cellulose and dicalcium phosphate as well; different

viscosity grades of HPMC and concentrations. The results of the in vitro release

studies showed that the optimized formulation could sustain drug release for 24h

and remain buoyant for 16h. From various kinetic release investigations it was

found that the mechanism of drug release was predominantly diffusion with a

minor contribution from polymer relaxation. The anti-tumour activity of 5-FU was

studied in albino female mice (Balb/c strain) using benzo(a)pyrene to induce

stomach tumours. It was found that the tumour incidence was reduced by 75%

using FDDS of 5-FU whereas only a 25% reduction was observed using the

conventional tablet form of 5-FU.27

 Patel V.F et al; developed intragastric drug-delivery system for Cefuroxime

axetil. A 32 full factorial design was employed to evaluate contribution of

hydroxypropyl methylcellulose(HPMC) K4M/ HPMC K100 LV ratio and sodium

lauryl sulfate on drug release from HPMC matrices. Tablets were prepared using

direct compression technique. Formulations were evaluated for in vitro buoyancy

and drug release study using USP 24 paddle type dissolution apparatus using 0.1N

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Chapter-3 Review of Literature

HCl as a dissolution media. All formulations had floating lag times below 2min

and constantly floating for 8h. It was found that polymer blend and SLS

significantly affect the time required for 50% of drug release, percentage drug

release at 12hours, release rate constant, and diffusion exponent (p<0.05). Also

linear relationships were obtained between the amount of HPMC K100 LV and

diffusion exponent as well as release rate constant. Kinetic treatment to

dissolution profiles revealed drug release ranges from anomalous transport to case

I transport, which was mainly dependent on both the independent variables.33

 Tadros M.I, et al; developed controlled-release effervescent matrix tablets of

ciprofloxacin hydrochloride with swelling, floating and adhesive properties.

Ciprofloxacin hydrochloride has a short elimination half-life, a narrow absorption

window and is mainly absorbed in proximal areas of GIT. Ten tablet formulations

were designed using hydroxypropyl methylcellulose(HPMC K15M) and/ or

sodium alginate as release retardant polymer(S) and sodium bicarbonate or

calcium carbonate as a gas former. Swelling ability, floating behaviour, adhesion

period and drug release studies were conducted in 0.1N HCl (pH1.2) at 37+/-

0.50C. Drug release profiles of all formulae followed non-Fickian diffusion.34

 Robles V.L et al; developed sustained release floating matrix tablets of captopril.

In this work, the in vitro sustained release of captopril from Metolose SH 4000

SR/ sodium bicarbonate floating tablets has been studied, varying the proportions

of Metolose and bicarbonate. This was studied at two different compaction

pressures. Other studied variables include the kinetics of the hydration volume,

the matrices floating time and the matrix density. The results show that matrices

compacted at 55MPa float in the dissolution medium for more than 8h while those

compacted at 165MPa float only when sodium bicarbonate is included in the

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formulation. The matrix density is lower when compacted at 55MPa. The drug

release constant (k) decreases and the exponent indicative of the release

mechanism (n) increases with increasing polymer contents. The drug released

with the time is lesser when sodium bicarbonate is included in the formulation.

Carbondioxide bubbles obstruct the diffusion path and decrease the matrix

coherence. The effect of compaction pressure to reduce the drug release rate has to

be made clear in further studies and concluded that floatability of metolose

matrices depends on the porosity obtained after compaction at a given pressure;

matrices with insufficient porosity can be made float by increasing their porosity

with carbondioxide bubbles obtained from the reaction of sodium bicarbonate

with the acidic dissolution media. An increasing proportion of the swelling

polymer in the matrix increases the maximal hydration volume as well as the time

necessary to attain it. Matrices containing sodium bicarbonate show greater

hydration volumes because of matrix expansion produced by the evolution of

carbondioxide bubbles. This matrix expansion is associated to less consistent or

more vulnerable to erosion matrices. The matrix density was found to decrease by

reducing the compaction pressure and by addition of sodium bicarbonates.35

 Strubing S et al; developed and characterized poly(vinyl acetate) based floating

matrix tablets containing propronolol HCl. The tablets were prepared by using

direct compression method. Kollidon SR was able to delay propronolol HCl

release efficiently. Drug release kinetics was evaluated using the Korsmeyer-

peppas model and found to be governed by Fickian diffusion. Tablet floating

started immediately and continued for 24h. Floating strength was related to

kolliodon SR level with improved floating characteristics of the tablets were

analyzed by applying the equation according to Therien-Aubin et al. The influence

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of the polymer content on swelling characteristics was found to be only

marginal.36

 Streubel A et al; developed floating matrix tablets based on low density foam

powder. The aim of this was to develop and physicochemically characterize single

unit, floating controlled drug delivery systems consisting of (i) polypropylene

foam powder (ii) matrix-forming polymers (iii) drug (iv) filler(optional). The

highly porous foam powder provided low density and thus, excellent in vitro

floating behaviour of the tablets. All foam powder containing tablets remained

floating for atleast 8h in 0.1N HCl at 370C. Different types of matrix-forming

polymers like: hydroxypropyl methylcellulose, polyacrylates, sodium alginate,

corn starch, carrageenan, guar gum and gum arabic were studied. The tablets

eroded upon contact with the release medium and the relative importance of drug

diffusion, polymer swelling and tablet erosion for the resulting release patterns

varied significantly with the type of matrix former. The release rate could

effectively be modified by varying the “matrix-forming polymer/foam powder”

ratio, the initial drug loading, the tablet geometry, the type of matrix-forming

polymers, the use of polymer blends and the addition of water-soluble or water-

insoluble fillers (such as lactose or microcrystalline cellulose)24.

 Dave B.S et al; developed gastroretentive drug delivery system of ranitidine

hydrochloride. Guar gum, xanthan gum and hydroxypropyl methylcellulose were

evaluated for gel-forming properties. Sodium bicarbonate was incorporated as a

gas-generating agent. The effects of citric acid and stearic acid on drug release

profile and floating properties were investigated. The addition of stearic acid

reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial

design was applied to systemically optimize the drug release profile. The results

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of the full factorial design indicated that a low amount of citric acid anhydrous

and a high amount of stearic acid favours sustained release of ranitidine

hydrochloride from a gastroretentive formulation and concluded that addition of

gel –forming polymer HPMC K4M and gas-generating agent sodium bicarbonate

was essential to achieve in vitro buoyancy. Addition of citric acid, to achieve

buoyancy under the elevated pH of stomach, caused an enhancement in drug

release that was retarded by incorporation of stearic acid in the formulation. The

32 full factorial design revealed that the amount of citric and stearic acid had a

significant effect on t50, t80 and f2. Thus by selecting a suitable composition of

release rate enhancer (citric acid) and release rate retardant (stearic acid), the

desired dissolution profile can be achieved.25

 Gambhire M.N et al; formulated oral floating matrix tablet of Diltiazem

hydrochloride (DTZ). Floating matrix tablets of DTZ were developed to prolong

gastric residence time and increase its bioavailability. The tablets were prepared

by direct compression technique, using polymers such as hydroxypropyl

methylcellulose (HPMC, Methocel K100M CR), compritol 888ATO, alone or in

combination and other standard excipients. Effect of Sodium bicarbonate and

succinic acid on drug release profile and property were investigated. A 32factorial

design was applied to systematically optimize the drug release profile. The results

of factorial design indicated that a high level of both Methocel K100M CR and

compritol888ATO favours the preparation of floating controlled release of DTZ

tablets. All the formulations followed Korsmeyer and peppas model while tablet

hardness had little or no effect on the release kinetics and was found to be a

determining factor with regard to the buoyancy of the tablets.28

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 Kulkarni A et al; designed bilayer regioselective floating tablets of atenolol and

lovastatin to give immediate release of lovastatin and sustained release of atenolol.

Bilayer floating tablets comprised two layers, i.e immediate release and controlled

release layers. The immediate release layer comprised sodium starch glycollate as

a super disintegrant and the sustained release layer comprised HPMC K100M and

xanthan gum as the release retarding polymers. Sodium bicarbonate was used as a

gas-generating agent. DCP and Lactose (tablettose 80) were used as diluents.

Direct compression method was used for formulation of the bilayer tablets. The

optimized formulation was found to be buoyant for 8h in stomach. More than 90%

of lovastatin was released within 30min. HPMC K100M and xanthan gum

sustained the release of atenolol from the controlled release layer for 12h. The

release of atenolol was found to follow a mixed pattern of Korsmeyer-peppas,

Hixson-crowell and zero order release models.37

 Arunkumar N et al; developed a floating drug delivery system for the model

drug Atorvastatin Calcium. Four formulations containing varying proportions of

polymers like HPMC K4M and ethyl cellulose and fixed amount of gas generating

agent such as sodium bicarbonate and hydrophobic meltable material like bees

wax were prepared. The tablets were prepared by melt granulation technique and

the prepared tablets remained buoyant for more than 8hours in the release media.

The proportions of the polymers showed significant difference in the release of the

drug. All the formulations exhibited diffusion drug release and were found to be

stable.38

 Patel D.M et al; developed floating tablets of carbamazepine using melt

granulation technique. Bees wax was used as a hydrophobic meltable material.

Hydroxypropyl methylcellulose, sodium bicarbonate and ethyl cellulose were

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used as matrix forming agent, gas-generating agent and floating enhancer

respectively. A simplex lattice design was applied to investigate the combined

effect of 3 formulation variables i.e. amount of hydroxypropyl methylcellulose

(x1), ethyl cellulose (x2) and sodium bicarbonate (x3). Results of multiple

regression analysis indicated that, low level of x1, x2 and high level of x3 should

be used to manufacture the tablet formulation with desired in vitro floating time

and dissolution.29

 Pare A et al; developed Amlodipine besylate effervescent floating tablets using

different grades of polymers and effervescent agents such as sodium bicarbonate

and citric acid by direct compression method. Optimized formulation showed

maximum floating time of 24h and gave slow and maximum drug release of

Amlodipine besylate spread over 24h and whereas Amlodipine besylate release

from marketed tablet was rapid and maximum within 12hours.39

 Manavalan R et al; prepared floating tablets containing theophylline as a model

drug. Tablets are prepared by direct compression method. Formulations were

optimized for type of filler and different concentration of polyethylene oxide.

Sodium bicarbonate was used as gas-generating agent. A 32 randomized factorial

design was employed in formulating gastric floating drug delivery system with

content of PEO (x1) and ratio of starch 1500 to lactose as filler (x2) were selected

as independent variables. Study revealed that type of filler has significant effect

on the release of drug and floating property from different concentration of PEO.

Lactose gave higher drug release with mechanism towards zero order compared to

starch 1500 which gave slow release with release mechanism towards diffusion

based. Drug release kinetics showed that drug release occurred in the direction of

anamolous transport and diffusion mechanism with erosion. Hardness of tablet

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had major influence on floating lag time which might be due to decreased

porosity.31

 Hu L et al; develop the dextromethorphan hydrobromide sustained-release

(DMB-SR) tablets using floating technique to prolong the gastric residence time

and compared their pharmacokinetic behavior with conventional sustained release

tablets. DMB-SR floating tablets were prepared by wet granulation method

employing HPMC as hydrophilic gel material, sodium bicarbonate as gas-

generating agent and hexadecanol as floating assistant agent. The optimized

tablets were prepared with HPMC K4M 25mg, sodium bicarbonate 20mg and

hexadecanol 18mg. The prepared tablets could float within 3min and maintain for

more than 24h. Drug release at 12h was more than 85%.40

 Sorkar M.S et al; designed a sustained release system for ketoprofen to increase

its residence time in the stomach without contact with the mucosa was achieved

through the preparation of floating microparticles by the emulsion-solvent

diffusion technique. Four different ratios of Eudragit S100 (ES) with Eudragit RL

(ERL) were used to form the floating microparticles. The drug retained in the

floating microparticles decreased with increase in ERL content. All floating

micropartilce formulations showed good flow properties and packability.

Scanning electron microscopy and particle size analysis revealed differences

between the formulations as to their appearance and size distribution. X-ray and

DSC examination showed the amorphous nature of the drug. Release rates were

generally low in 0.1N HCl especially in the prescence of high content of ES while

in phosphate buffer pH6.8 high amounts of ES tends to give a higher release rate.

Floating ability in 0.1N HCl containing 0.02% Tween20 and simulated gastric

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fluid without pepsin was also tested. The formulation containing ES:ERL 1:1

exhibited high percentage of floating particles in all examined media.32

 Tanwar Y.S et al; prepared a gastroretentive drugs delivery system of famotidine.

Floating tablets were prepared by wet granulation method employing two different

grades of methocel K100 and Methocel K15M by effervescent technique. These

grades of methocel were evaluated for their gel forming properties. Sodium

bicarbonate was incorporated as a gas-generating agent. The effect of citric acid

on drug release profile and floating properties was investigated. The prepared

tablets exhibited satisfactory physico-chemical characteristics. All the prepared

batches showed good in vitro buoyancy. The tablet swelled radially and axially

during in vitro buoyancy studies. It was observed that the tablet remained buoyant

for 6-10 hours. Decrease in the citric acid level increased the floating lag time but

tablets floated for longer duration. A combination of sodium bicarbonate (130mg)

and citric acid (10mg) was found to achieve optimum in vitro buoyancy. The

tablets with methocel K100 were found to float for longer duration as compared

with formulations containing methocel K15M. The drug release from the tablets

was sufficiently sustained and non-Fickian transport of the drug from tablets was

confirmed.41

 Havaldar V.D et al; prepared floating matrix tablets of atenolol and studied the

influence of different polymers on its release rates. Nine formulations of atenolol

containing varying concentrations of polymers were designed by optimization.

The floating matrix tablets of atenolol were prepared by direct compression

method. The floating lag time of all the formulations was within the prescribed

limit (10min): All the formulations showed good matrix integrity and retarded the

release of drug for 8h. A significant difference in drug release at 0.5, one, four and

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eight hours were observed. Diffusion exponent (n) value was found in the range of

0.52-0.99 indicating diffusion as a release mechanism. The swelling study of all

the formulations showed that formulations containing xanthan gum has higher

swelling indices than HPMC K100M and HPMC K4M. It can be concluded that

formulations with higher swelling indices retarded the release of drugs more than

those with lower swelling indices.42

 Srinath M.S et al; developed an optimized bilayer gastric floating drug delivery

system containing metoprolol tartrate as a model drug by wet granulation

technique. Drug-loading granules (as an immediate dose) were prepared by

mixing metoprolol tartrate(MT), starch, PVP and di-calcium phosphate using

water as a wetting agent. Floating granules containing MT (as a sustained dose)

were prepared by mixing the drug with the excipients (HPMC, SCMC). Exactly

0.3g of floating granule and 0.1g of drug-loading granules were weighed and

compressed into bilayer tablets by single punch tablet compression machine. A

23factorial design was employed in formulating the GFDDS with total polymer

content-to-drug ratio (x1), polymer-to-polymer ratio (x2) and different viscosity

grades of HPMC (x3) as independent variables. The results indicated that x1 and x2

significantly affected the floating time and release properties, but the effect of

different viscosity grades of HPMC (K4M and K10M) was non significant.

Fickian release transport was confirmed as the release mechanism from the

optimized formulation.26

 Heeba G.H et al; investigated the possible mechanisms underlying the

gastroprotective effect of simvastatin against indomethcin-induced gastric ulcer in

rats. Rats were randomly assigned to vehicle-, simvastatin-, simvastatin+L-

arginine- and simvastatin+N(G)-nitro-L-arginine methylester(L-NAME)- preated

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groups for two weeks. Pyloric ligation was performed for the collection of gastric

juice and gastric ulceration was induced by a single intraperitoneal injection of

indomethacin (30mg/Kg). Gastric juice parameters (total acid output, pepsin

activity and mucin concentration) were determined. The stomach tissues used for

determination of gastric mucosal lipid peroxides, superoxide dismutase, catalase,

total nitrites and prostaglandin E2 levels. Pretreatment with simvastatin (10mg/kg,

orally for 2 weeks) caused significant reduction in gastric mucosal lesions and

lipid peroxides associated with a significant increase in gastric juice mucin

concentration. Simvastatin significantly increased the gastric mucosal total nitrite

and prostaglandin E2 levels. Additionally, simvastatin significantly attenuated the

elevations in gastric mucosal superoxide dismutase observed with indomethacin.

The gastroprotective effect afforded by simvastatin was significantly augmented

by co-administration with L-arginine (a nitric oxide precursor) and inhibited by

co-administration with L-NAME (a nitric oxide synthase inhibitor). Results

confirm a gastroprotective effect for simvastatin and indicate that the anti-ulcer

effect of simvastatin is mediated by scavenging free radicles, increasing nitric

oxide and prostaglandin E2 levels, and increasing gastric juice mucin production.

It was conclude that simvastatin represents a more suitable antihyperlipidemic

therapy for patients who are at risk of gastric ulcers that were induced by the use

of nonsteroidal anti-inflammatory drugs.30

 Valenzuela C et al; developed a liquid chromatography stability-indicating

method and applied to study the hydrolytic behaviour of simvastatin in different

pH values and temperatures. The selected chromatographic conditions were a C18

coloumn; acetonitrile-28mM phosphate buffer solution, pH 4 (65+35) as the

mobile phase and flow rate 1ml/min. The degradation of simvastatin fitted to

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pseudo-first order kinetics. The degradation was pH dependent, being much

higher at alkaline pH than at acid pH.43

 Boppanna R et al; prepared carboxy methylcellulose based hydrogel microbeads

loaded with simvastatin using ionotropic gelation method. The beads were

characterized by differential scanning calorimetric (DSC) analysis and scanning

electron microscopy (SEM). DSC confirmed the amorphous dispersion of the drug

in the hydrogel matrix. The effect of crosslinking agent and polymer concentration

on drug release was studied. Increase in concentration of crosslinking agent and

polymers decreased the release rate of simvastatin. Drug release followed

anomalous/ non-Fickian transport mechanism.44

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DRUG PROFILE45,46,47,49,50,51

Name of the drug: SIMVASTATIN

Chemical name: 2,2-Dimethylbutyric acid,8-ester with (4R,6R)-6-2-

[(1S,2S,6R,8S,8αR) -1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-

naphthyl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one.

CAS registry number: [79902-63-9]

Structural formula:

Empirical formula and molecular weight: C25H38O5 418.57

Description: Simvastatin is a white to off-white, non-hygroscopic, crystalline

powder.

Functional category: Antihyperlipidemic

Melting point: 1350C-1380C

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Solubility: practically insoluble in water and freely soluble in ethanol, acetonitrile,

chloroform, methanol, ethanol, DMSO

Storage: Preserve in well-closed containers. Store between 150C and 300C, or under

refrigeration

Purity: 99.5% pure as per certificate of analysis provided by Biocon India.

Clinical Pharmacology: On the basis of clinical trial evidence, the most commonly

prescribed lipid-modifying therapies are the hydroxymethylglutaryl-coenzyme A

(HMG-CoA) reductase inhibitors, more commonly known as statins. Simvastatin

belong to the category of statin which inhibits the enzyme HMG-CoA reductase.

HMG-CoA reductase catalyses the conversion of HMG-CoA to mevalonate, the rate

limiting step in de novo cholesterol synthesis. Competitive inhibition of this enzyme

by Simvastatin decreases hepatocyte cholesterol synthesis. The associated reduction

in intracellular cholesterol concentration induces LDL-receptor expression on the

hepatocyte cell surface. Which results in increased extraction of LDL-C from the

blood and decreased circulating LDL-C concentration. Simvastatin also have

beneficial effects on other lipid parameters including increase in high-density

lipoprotein cholesterol (HDL-C) concentration and decreases in triglyceride

concentration. Secondary mechanism by which simvastatin may reduce levels of

atherogenic lipoproteins include inhibition of hepatic synthesis of apolipoprotein

B100 and a rduction in the synthesis and secreation of triglyceride-rich lipoproteins.

In addition, simvastatin may excert beneficial cardiovascular effects independent of

their lipid-modifying properties. These pleiotropic properties may be explained by

inhibition of synthesis of nonsteroidal isoprenoid compounds, which are also

produced from mevalonic acid and include improvement of endothelial cell function,

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modification of inflammatory responses and reduction of smooth muscle cell

proliferation and cholesterol accumulation.

Pharmacokinetic properties of Simvastatin

Bioavailability: 5%

Effect of food on absorption- No effect

Protein binding- 95-98%

Elimination half-life: 2h

Renal excreation-13%

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CYP450 and isoenzyme metabolism – CYP3A4

Active metabolite- Simvastatin β-hydroxy Acid

Excreation: Following oral administration in man, 13% of the dose was

excreated in urine and 60% in feces

Absorption: 60-85%

Metabolite: β-hydroxy acid of simvastatin and its 6I-hydroxy,6I-hydroxy

methyl and 6I-exomethylene derivatives.

Efficacy:

Serum LDL-C reduction (%)b-41%

Serum HDL-C increase (%)b- 12%

Serum triglyceride reduction (%)b- 18%

(b)- represents that this effect was elicited in patient with hypercholesterolemia by a

daily dose of 40mg.

Side effects: Abdominal pain, diarrhea, indigestion, and a general feeling of

weakness. Rare side effect include joint pain, memory loss, and muscle cramp.

Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis and myosistis have been

reported in patients receiving the drug chronically.

Interactions: Grapefruit juice inhibit intestinal CYP3A4 enzyme. This in turn slows

metabolization of simvastatin and resulting in higher plasma levels of drug. Due to

risk of toxicity patients taking simvastatin should avoid intake of grapefruit and

grapefruit containing products.

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Also, a 2010 FDA, review of simvastatin drug-drug interactions stated that patient

should not take a simvastatin with itraconazole, ketoconazole, erythromycin,

clarithromycin, HIV protease inhibitors.

Excipient profile23

Hypromellose

1. Nonproprietary names:
BP: Hypromellose

JP: Hypromellose

PhEur: Hypromellose

USP: Hypromellose

2. Synonyms: Hydroxypropyl methyl cellulose; Methocel

Metolose, Hypermellosum, methyl hydroxypropylcellulose

3. Chemical name and CAS Registry Number:

Cellulose hydroxyl propyl methyl ether (9004-65-3)

4. Structural Formula:

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5. Molecular weight: approx- 10000-150000

6. Functional category: coating agent, controlled-release agent, dissolution

enhancer Bioadhasive material, modified release agent, viscosity-increasing agent.

7. Description: Hypromellose is an odorless and tasteless, white or creamy white

fibrous or granular powder.

8. Typical properties

Acidity/alkalinity: pH=5.0-8.0 for a 2%w/w aqueous solution

Density (bulk): 0.341g/cm3

Density (tapped):0.557g/cm3

Density (true): 1.326g/cm3

Melting point: Brown at 190-2000C; chars at 225-2300C;

Glass transition temperature is 170-1800C

9. Moisture content: Hypromellose absorbs moisture from the atmosphere; the

amount of water absorbed depends upon the initial moisture content and the

temperature and relative humidity of the surroundings.

10. Solubility: Soluble in cold water forming a viscous colloidal solution; practically

insoluble in hot water, chloroform, ethanol(95%) and ether but soluble in mixtures

of ethanol and dichloromethane, mixtures of methanol and dichloromethane and

mixtures of water and alcohol.

11. Specific gravity: 1.26

12. Viscosity (dynamic): Aqueous solutions are commonly prepared, although

hypromellose may also be dissolved in aqueous alcohols such as ethanol and

propan-2-ol provided the alcohol content is less than 50%w/w. Dichloromethane

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and ethanol mixtures may also be used to prepare viscous hypromellose solutions.

Solutions prepared using organic solvents tend to be more viscous; increasing

concentration also produces more viscous solutions. To prepare an aqueous

solution, it is recommended that hypromellose is dispersed and thoroughly

hydrated in about 20-30% of the required amount of water. The water should be

vigorously stirred and heated to 80-900C, and then the hypromellose should be

added. The heat source can be removed once the hypromellose has been

thoroughly dispersed into the hot water, sufficient cold water should then be

added to produce the required volume while continuing to stir.

13. Applications in pharmaceutical formulation or technology

Hypromellose is widely used in oral, ophthalmic, nasal and topical pharmaceutical

formulations.

In oral products, hypromellose is primarily used as a tablet binder, in film coating

and as a matrix for use in extended release tablet formulations. Concentrations

between 2% and 5%w/w may be used as a binder in either wet- or dry-granulation

processes. High –viscosity grades may be used to retard the release of drugs from

a matrix at levels of 10-80%w/w in tablets and capsules. Depending upon the

viscosity grade, concentrations of 2-20%w/w are used for film-forming solutions

to film-coat tablets. Lower viscosity grades are used in aqueous film-coating

solutions, while higher-viscosity grades are used with organic solvents. Examples

of film-coating materials that are commercially available include Anycoat C,

Spectracel, Pharmacoat and the Methocel E premium LV series.

Hypromellose is also used as suspending and thicknening agent in topical

formulations and liquid oral dosage forms.

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14. Incompatibilities: Hypromellose is incompatible with some oxidizing agents.

Since it is nonionic, hypromellose will not complex with metallic salts or ionic

organics to form insoluble precipitates.

15. Storage: Hypromellose powder should be stored in a well-closed container, in a

cool, dry place.

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Citric acid anhydrous

1. Nonproprietary names: USP: Anhydrous citric acid

2. Synonyms: Acidum citricum anhydricum; citric acid,

2-hydroxypropane 1,23-tricarboxylic acid

3. Chemical name and CAS Registry Number:

2-Hydroxy-1, 2, 3-propanetricarboylic acid (77-92-9)

4. Structural Formula:

5. Empirical formula and Molecular weight: C6H8O7 and 192.13

6. Functional category: Acidifying agent,antioxidant, buffering agent,chelating

agent, flavor enhancer, preservative.

7. Description: Odorless or almost odorless, colorless crystals or a white crystalline

powder.

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8. Typical properties

Acidity/alkalinity: pH=2.2 (1%w/v aqueous solution)

Density: 1.665g/cm3

Melting point: 1530C

9. Hygroscopicity: At relative humidities between about 25-50% anhydrous citric

acid absorbs insignificant amounts of water at 250C. However, at relative

humidities between 50% and 75% it absorbs significant amounts with the

monohydrate being formed at relative humidities approaching 75%.

10. Solubility: Soluble 1 in 1 part of ethanol (95%) and 1 in 1 of water; sparingly

soluble in ether.

11. Applications in pharmaceutical formulation or technology

Citric acid (as either the monohydrate or anhydrous material) is widely used in

pharmaceutical formulations and food products, primarily to adjust pH of

solutions. Citric acid anhydrous is widely used in the preparation of effervescent

tablets. In food products, citric acid is used as flavor enhancer for its tart, acidic

taste..

12. Incompatibilities: Citric acid is incompatible with potassium tartrate, alkali and

alkaline earth carbonates and bicarbonates, acetates and sulfides. Incompatibilities

also include oxidizing agents, bases, reducing agents and nitrates. On storage

sucrose may crystallize from syrups in the presence of citric acid.

13. Storage: The bulk monohydrate or anhydrous material should be stored in airtight

containers in a cool, dry place.

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SODIUM BICARBONATE

1. Nonproprietary names:

BP: Sodium Bicarbonate

JP: Sodium Bicarbonate

PhEur: Sodium hydrogen Carbonate

USP: Sodium Bicarbonate

2. Synonyms: Baking soda, monosodium carbonate, Effer-Soda

3. Chemical name and CAS Registry Number:

Carbonic acid monosodium salt (144-55-8)

4. Structural Formula: NaHCO3.

5. Empirical formula and Molecular weight: NaHCO3 and 84.01

6. Functional category: Alkalizing agent, therapeutic agent

7. Description: Sodium bicarbonate occurs as an odorless, white, crystalline powder

with a saline, slightly alkaline taste

8. Typical properties

Acidity/alkalinity: pH=8.3 for a freshly prepared 0.1M aqueous solution at 250C

Density (bulk): 0.869g/cm3

Density (tapped):1.369g/cm3

Density (true): 2.173g/cm3

Melting point: 2700C (with decomposition)

9. Moisture content: Below 80% relative humidity, the moisture content is less than

1%w/w. Above 85% relative humidity, sodium bicarbonate rapidly absorbs

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excessive amounts of water and may start to decompose with loss of

carbondioxide.

10. Solubility:

Solvent Solubility at 200C unless otherwise stated

ethanol Practically insoluble

ether Practically insoluble

water 1 in 11

1 in 4 at 1000C

1 in 10 at 250C

1 in 12 at 180C

11. Applications in pharmaceutical formulation or technology

Sodium bicarbonate is generally used in pharmaceutical formulations as a source

of carbondioxide in effervescent tablets and granules. It is also widely used to

produce or maintain an alkaline pH in a preparation.

In effervescent tablets and granules, sodium bicarbonate is usually formulated

with citric and/ or tartaric acid; combinations of citric and tartaric acid are often

preferred in formulations as citric acid alone produces a sticky mixture that is

difficult to granulate, while if tartaric acid is used alone, granules lose firmness,

when the tablets or granules come into contact with water, a chemical reaction

occurs, carbondioxide is evolved and the product disintegrates.

Tablets may also be prepared with sodium bicarbonate alone since the acid of

gastric fluid is sufficient to cause effervescence and disintegration. Sodium

bicarbonate is also used in tablet formulations to buffer the drug molecules that

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Chapter-3 Review of Literature

are weak acids, thereby increasing the rate of tablet dissolution and reducing

gastric irritation.

In some parenteral formulations e.g. Niacin, sodium bicarbonate is used to

produce a sodium salt of the active ingredient that has enhanced solubility.

Recently, sodium bicarbonate has been used as a gas forming agent in alginate raft

systems and in floating, controlled-release oral dosage forms for a range of drugs.

Therapeutically, sodium bicarbonate has been used as an antacid and as a source

of bicarbonate anion in treatment of metabolic acidosis. Sodium bicarbonate may

also used as a component of oral rehydration salts and as a source of bicarbonate

in dialysis fluids.

12. Incompatibilities: Sodium bicarbonate reacts with acids, acidic salts, and many

alkaloidal salts with the evolution of carbondioxide. Sodium bicarbonate can also

intensify the darkening of salicylates. In solution, sodium bicarbonate has been

reported to be incompatible with many drug substances such as ciprofloxacin,

amidarone, nicardipine and levofloxacin

13. Storage: Store in well-closed container in a cool, dry place.

14. Use:

Use Concentration(%)

Buffer in tablets 10-40

Effervescent tablets 25-50

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Chapter-3 Review of Literature

LACTOSE ANHYDROUS

1. Nonproprietary names:

BP: Anhydrous Lactose

JP: Anhydrous Lactose

PhEur: Lactose, anhydrous

USP: Anhydrous Lactose

2. Synonyms: Anhydrous 60M, Anhydrous direct tableting, Lactopress anhydrous

3. Chemical name and CAS Registry Number:

O-β-D- Galactopyranosyl-(1→4)-β-D-glucopyranose (63-42-3)

4. Structural Formula:

5. Empirical formula and Molecular weight: C12H22O11 342.30

6. Functional category: Directly compressible tablet excipient; dry powder inhaler

carrier, Tablet and capsule diluents and capsule filler.

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Chapter-3 Review of Literature

7. Description: Anhydrous lactose occurs as a white to off-white crystalline

particles or powder. Anhydrous lactose typically contain 70-80% anhydrous β-

lactose and 20-30% anhydrous α-lactose.

8. Typical properties

Density (bulk): 0.71g/cm3for SuperTab 21AN; 0.66g/cm3 for Super-Tab 22AN

Density (tapped): 0.88g/cm3 for Supertab 21AN; 0.78 for Super-tab 22AN

Density (true): 1.589g/cm3 for anhydrous β-lactose

Melting point: 2230C for anhydrous α-lactose

9. Solubility: Soluble in water, sparingly soluble in ethanol (95%) and ether.

10. Applications in pharmaceutical formulation or technology

Anhydrous lactose is widely used in direct compression tableting applications and

as a tablet and capsule filler and binder. Anhydrous lactose can be used with

moisture sensitive drugs due to its low moisture content.

11. Incompatibilities: Lactose anhydrous is incompatible with strong oxidizers.

Lactose anhydrous is a reducing sugar with the potential to interact with primary

and secondary amines when stored under conditions of high humidity for

extended periods

12. Storage: Lactose anhydrous should be stored in a well-closed container, in a cool,

dry place.

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Calcium phosphate, Dibasic Anhydrous

1. Nonproprietary names:

BP: Anhydrous Calcium Hydrogen Phosphate

JP: Anhydrous Dibasic Calcium Phosphate

PhEur: Calcium Hydrogen Phosphate, Anhydrous

USP: Anhydrous Dibasic Calcium Phosphate

2. Synonyms: Calcium orthophosphate, Calcium monohydrogen Phosphate,

dicalcium orthophosphate.

3. Chemical name and CAS Registry Number:

Dibasic Calcium Phosphate (7757-93-9).

4. Structural Formula: CaHPO4.

5. Empirical formula and Molecular weight: CaHPO4 & 136.06

6. Functional category: Tablet and capsule diluent.

7. Description: Anhydrous dibasic calcium phosphate is a white, odorless, tasteless

powder or crystalline solid.

8. Typical properties

Acidity/alkalinity: pH=7.3 (20% slurry)

pH=5.1 (20% slurry of A-TAB)

pH= 6.1-7.2 (5% slurry of Fujicalin)

Density : 2.89g/cm3

Density (tapped):0.82g/cm3 for A-TAB; 0.46g/cm3 for Fujicalin

Density (bulk): 0.78g/cm3 for A-TAB; 0.45g/cm3 for Fujicalin

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Melting point: Does not melt; decomposes at approx 4250C to form calcium

pyrophosphate

9. Solubility: Practically insoluble in ether, ethanol and water; soluble in dilute acids

10. Applications in pharmaceutical formulation or technology

Anhydrous dibasic calcium phosphate is used both as an excipient and as a source

of calcium in nutritional suppliments. It is used particularly in the nutrition/ health

food sectors. It is also used in pharmaceutical products because of its compaction

properties, and the good flow properties of the Coarse-grade material.

Two particle-size grades of anhydrous dibasic calcium phosphate are used in the

pharmaceutical industry. Milled material is typically used in wet-granulated or

roller-compaction formulations. The “unmilled” or coarse-grade material is

typically used in direct compression formulations. Anhydrous dibasic calcium

phosphate is nonhygroscopic and stable at room temperatures. It does not hydrate

to form the dihydrate. Anhydrous dibasic calciumphosphate is used in tooth paste

and dentifrice formulations for its abrasive properties. Anhydrous dibasic calcium

phosphate is abrasive and a lubricant is required for tableting, for example 1%w/w

magnesium stearate or 1%w/w sodium stearyl fumerate.

11. Incompatibilities: Dibasic calcium phosphate should not be used to formulate

tetracycline antibiotics. The surface of milled anhydrous dibasic calcium

phosphate is alkaline and consequently it should not be used with drugs that are

sensitive to alkaline pH. The unmilled form has an acidic surface environment.

12. Storage: The bulk material should be stored in a well-closed container in a dry

place.

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Magnesium stearate
1. Nonproprietary names:

BP: Magnesium stearate

JP: Magnesium stearate

PhEur: Magnesium stearate

USP: Magnesium stearate

2. Synonyms: Dibasic magnesium stearate; magnesium distearate

3. Chemical name and CAS Registry Number:

Octadecanoic acid magnesium salt (557-04-0)

4. Structural Formula: [CH3(CH2)16COO]4Mg

5. Empirical formula and Molecular weight: C36H70MgO4 591.24

6. Functional category: Tablet and capsule lubricant.

7. Description: Magnesium stearate is a very fine, light white, precipitated or

milled, impalpable powder of low bulk density, having a faint odor of stearic acid

and characteristic taste. The powder is greasy to the touch and readily adheres to

the skin.

8. Typical properties

Acidity/alkalinity: pH=5.0-8.0 for a 2%w/w aqueous solution

Density (bulk): 0.15g/cm3

Density (tapped): 0.286g/cm3

Density (true): 1.092g/cm3

Melting point: 117-1500C (commercial samples)

126-1300C (high purity magnesium stearate)

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9. Moisture content: hypromellose absorbs moisture from the atmosphere; the

amount of water absorbed depends upon the initial moisture content and the

temperature and relative humidity of the surrounding.

10. Solubility: practically insoluble in ethanol, ethanol(95%), ether and water;

slightly soluble in warm benzene and warm ethanol(95%)

11. Applications in pharmaceutical formulation or technology

Magnesium stearate is widely used in cosmetics, foods and pharmaceutical

formulations. It is primarily used as lubricant in capsule and tablet manufacturing

at concentrations between 0.25% and 5%. It is also used in barrier creams.

12. Incompatibilities: Incompatible with strong acids, alkalies and iron salts. Avoid

mixing with strong oxidizing materials, magnesium stearate cannot be used in

products containing aspirin, some vitamins, and most alkaloidal salts.

13. Storage: Magesium stearate is stable and should be stored in a well-closed

container in a cool, dry place.

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Chapter-4 Methodology

4. METHODOLOGY

Table no-4. List of Excipients

Name of the

Sl.no excipients Company

1 Simvastatin (drug) Biocon India, Bangalore

2 Methocel K4M Colorcon Asia Pvt.Ltd, Goa

3 Methocel K15M Colorcon Asia Pvt. Ltd, Goa

4 Methocel K100M Colorcon Asia Pvt. Ltd, Goa

5 Citric acid anhydrous Thermo Fischer Scientific India Pvt. Ltd, Mumbai

6 Sodium bicarbonate Thermo Fischer Scientific India Pvt. Ltd, Mumbai

7 Dicalcium Phosphate Nice chemicals Pvt. Ltd, cochin

8 Lactose S. D. Fine Chem. Ltd., Mumbai

9 Magnesium stearate S.D.Fine Chem.Ltd., Mumbai

Sodium Lauryl
10 S.D.Fine Chem.Ltd., Mumbai
Sulphate

Hydrochloric acid
11 Ranbaxy Fine Chemicals Ltd., New Delhi.
(LR)

12 Acetonitrile (AR) Merck India Ltd. Mumbai

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Table no-5: List of Equipments/Apparatus

Sl.
Name of equipments Company
No

Electronic Weighing Balance

1 Sartorius cp225d
(0.0001mg to 200 gm)

UV-Vis Spectrophotometer (UV-

2 Shimadzu, Japan.
1800)

3 FTIR 1700S Spectrophotometer Shimadzu, Japan

Dissolution test apparatus TDT-

4 08T Electrolab, Mumbai

Dissolution Tester (USP)

5 Digital Vernier Caliper Mitutoyo, China

6 Digital pH meter 7007 Dgisun Electronics Hyderabad

7 Test Sieve (No.24, 40) Scientific Engineering Corp. Delhi.

Servewell Instrument PVT LTD,

8 Hot Air Oven
Bangalore

9 Stability Chamber Lab Control Equipment Co. Mumbai.

10 Friabilator USP EF-2 Electrolab, Mumbai

Tablet punching machine (Rimek

Karnavati Engineering Ltd, Mehsana,
11 mini press-1) ( 10 stations 8 mm
Gujarat.
concave punches)

12 Monsanto Hardness Tester Ketan engineering Ltd, Mumbai

13 Bulk density apparatus USP tap density tester, Electrolab

14 HPLC Shimadzu UV. Detector 1100 series

15 Thermonik melting point apparatus Campbell electronics, Mumbai

16 Differential scanning calorimetry Perkin Elmer Diamond DSC

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METHOD

STANDARDIZATION OF DRUG:

Identification of pure drug: Identification of Simvastatin was carried out by Infra

Red Absorption Spectrophotometry.

Determination of Melting Point:

Melting point of Simvastatin was determined by capillary method. Fine powder of

Simvastatin was filled in glass capillary tube (previously sealed on one end). The

capillary tube is inserted into the melting point apparatus and observed the

temperature at which drug started to melt by using the thermometer which was

already immersed into the liquid paraffin in the apparatus.

U.V-Visible Spectrophotometry

Analytical method development

Preparation of Buffers and Reagents

Hydrochloric acid solution, 0.1 N (pH 1.2): Concentrated hydrochloric (8.5 ml) acid

was diluted with distilled water and volume was made up to 1000 ml with distilled

water. pH (1.2) was adjusted with dilute hydrochloride.

Preparation of 0.5% SLS solution in 0.1N HCl (pH 1.2): Dissolve 5g of Sodium

lauryl Sulphate in 1000ml 0.1N HCl (pH 1.2) and adjust the pH with 0.1N HCl or

dilute sodium hydroxide

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Determination of absorption maxima in 0.1N HCl with 0.5%SLS

Procedure:

Preparation of primary stock solution

100mg of Simvastatin was accurately weighed and transferred into 100ml volumetric

flask and dissolved in sufficient quantity of Acetonitrile . The volume was made up

with Acetonitrile (1mg/ml solution).

Preparation of secondary stock solution

1ml was pippetted out from primary stock solution into 100ml volumetric flask and

made up the volume with 0.5% SLS solution in pH1.2 simulated gastric acid media

(0.1N HCl) (10µg/ml solution)

Determination of analytical wavelength: The 10µg/ml solution of Simvastatin was

scanned between the range 200nm-400nm in UV-Visible spectrophotometry and the

λmax of Simvastatin was found to be 239nm.

Determination of absorption maxima in Acetonitrile

Procedure:

Preparation of primary stock solution

100mg of Simvastatin was accurately weighed and transferred into 100ml volumetric

flask and dissolved in sufficient quantity of Acetonitrile. The volume was made up

with Acetonitrile (1mg/ml solution).

Preparation of secondary stock solution

1ml was pippetted out from primary stock solution into 100ml volumetric flask and

the volume was made up with Acetonitrile(10µg/ml solution)

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Determination of analytical wavelength: The 10µg/ml solution of Simvastatin was

scanned between the range 200nm-400nm in UV-Visible spectorphotometry and the

λmax of Simvastatin was found to be 239nm.

Standard curve of simvastatin with 0.5% SLS solution in pH1.2 simulated

gastric acid media (0.1N HCl)

Procedure:

Preparation of primary stock solution

100mg of simvastatin was accurately weighed and transferred into 100ml volumetric

flask and dissolved in sufficient quantity of Acetonitrile. The volume was made up

with Acetonitrile(1mg/ml solution).

Preparation of secondary stock solution

1ml was pippetted out from primary stock solution into 100ml volumetric flask and

the volume was made up with 0.5% SLS solution in pH1.2 simulated gastric acid

media (0.1N HCl) (10µg/ml solution)

Preparation of different dilutions from secondary stock solution

2ml, 4ml, 6ml and 8ml was pippeted out from secondary stock solution and

transferred into 10ml volumetric. The volume was made up with 0.5%SLS solution in

pH1.2 simulated gastric acid media (0.1N HCl) to get 2µg/ml, 4µg/ml, 6µg/ml,

8µg/ml solution respectively.

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Chapter-4 Methodology

Table no-6: Standard calibration curve of Simvastatin in 0.1N HCl containing

0.5%SLS (pH1.2) at λmax239nm

Absorbance in pH1.2 (0.1N HCl with 0.5%

SL.NO. Concentration
(mcg/ml) SLS

1 0 0.0000

2 2 0.125±0.0007

3 4 0.2453±0.00458

4 6 0.3763±0.006293

5 8 0.5026±0.00205

6 10 0.6038±0.001473

Average of 3 determinations

Fig-1: Standard curve of Simvastatin in pH 1.2 (0.1N HCl with 0.5%SLS)

pH1.2 ( 0.5%SLS in 0.1N HCl)

0.7 y = 0.0616x
R² = 0.9987
0.6

0.5
Absorbance

0.4

0.3 avg

0.2 Linear (avg)

0.1

0
0 2 4 6 8 10 12
Concentration mcg/mL

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Chapter-4 Methodology

Table no-7: Optical characteristics and precision of the proposed method at pH

1.2

Optical Characteristics pH1.2 (0.1N HCl with 0.5% SLS)

λmax (nm) 239nm

Beers‟s law limit (mcg/ml) 2-10

Correlation co-efficient 0.9987

Slope(m) 0.0616

Regression equation 0.0616x

Standard curve of simvastatin with Acetonitrile

Procedure:

Preparation of primary stock solution

100mg of simvastatin was accurately weighed into 100ml volumetric flask and

dissolved in sufficient quantity of acetonitrile. The volume was made up with

acetonitrile(1mg/ml solution).

Preparation of secondary stock solution

1ml was pippetted out from primary stock solution into 100ml volumetric flask and

the volume was made up with acetonitrile

Preparation of different dilutions from secondary stock solution

2ml, 4ml, 6ml and 8ml was pippetted out from secondary stock solution and

transferred into 10ml volumetric flask. The volume was made up with acetonitrile to

get 2µg/ml, 4µg/ml, 6µg/ml, 8µg/ml solution respectively.

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Table no-8: Standard calibration curve of Simvastatin in Acetonitrile at λmax

239nm

Concentration
SL.NO. Absorbance in Acetonitrile
(mcg/ml)
1 0 0.0000
2 2 0.1186±0.000115
3 4 0.2380±0.001311
4 6 0.3601±0.007146
5 8 0.4752±0.001823
6 10 0.5946±0.000651
Average of 3 determinations

Fig-2: Standard curve of Simvastatin in Acetonitrile

Standard curve of simvastatin in

acetonitrile y = 0.0595x + 0.0003
1 R² = 1.0000
absorbance

0.5
0 avg

0 5 10 15 Linear (avg)

concentration (mcg/ml)

Table no-9: Optical characteristics and precision of the proposed method in acetonitrile

Optical Characteristics Acetonitrile

λmax (nm) 239nm

Beers‟s law limit (mcg/ml) 2-10

Correlation co-efficient 1.0000

Slope(m) 0.0595

Intercept (A) 0.0003

Regression equation 0.0595x+0.0003

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Chapter-4 Methodology

 Compatibility study:

The objective of drug/excipient compatibility considerations and practical studies is to

delineate, as quickly as possible, real and possible interactions between potential

formulation excipients and the API. This is an important risk reduction exercise early

in formulation development. The drug-excipient incompatibility can alter the stability

and/or the bioavailability of drugs, thereby, affecting its safety and/or efficacy.

Differential Scanning Calorimetry: DSC can be used to investigate and predict any

physiochemical interactions between components in a formulation and, therefore, can

be applied to the selection of suitable chemically compatible excipients. Differential

scanning calorimeter has been proposed as a rapid method for evaluating the drug-

excipient interaction. Though it has certain advantages, such as requirement of small

sample size and fast results, there are certain limitations also. This is because of

exposure of drug –excipient mixture to high temperatures(up to 3000C or more),

which in real situations, is not experienced by the dosage form. Therefore, the DSC

results should be interpreted carefully, as the conclusions based on the DSC results

alone can be often misleading and inconclusive.

Procedure: DSC of Simvastatin(drug) alone and binary mixture of drug and

excipients(HPMC K4M, HPMC K15M, HPMC K100M, Sodium bicarbonate, citric

acid anhydrous, Lactose, magnesium stearate) was performed by increasing the

temperature from 400C to 2000C at 50C/min

Isothermal stress testing: Isothermal stress testing involves storage of drug-excipient

blends with or without moisture at high temperature for a specific period of time to

accelerate drug ageing and interaction with excipients and then analyzing using

suitable method like HPLC.

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Chapter-4 Methodology

Procedure:

Table no-10: Binary mixture composition

SL.NO Binary mixtures Ratio

1 Simvastatin

2 Simvastatin and HPMC K4M 1:1

3 Simvastatin and HPMC K15M 1:1

4 Simvastatin and HPMC K100M LV 1:1

5 Simvastatin and Dicalcium phosphate 1:1

6 Simvastatin and Sodium bicarbonate 1:1

7 Simvastatin and Citric acid anhydrous 1:1

8 Simvastatin and Magnesium stearate 1:1

9 Simvastatin and Lactose 1:1

Table no-11: Compatibility study testing plan

Condition Storage time (in days)

Control 14

400C/75% RH 14

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Chapter-4 Methodology

1. Assay by HPLC

Chromatographic conditions:

Column : Supelcosil C18 33mmX4.6mm, 3µm or equivalent

Detection : UV-VIS

Wavelength : 238nm

Flow rate: 3.0mL/min

Injection volume: 5µL

Run time: 15.0 minutes

Mobile phase: Variable mixtures of solution-A and solution-B were used.

Solution-A: Filtered and degassed mixture of acetonitrile and dilute phosphoric acid

(50:50) was prepared.

Solution-B: 1mL of phosphoric acid was diluted in 1000mL of Acetonitrile and

Sonicated to degas

Preparation of dilute phosphoric acid: 1mL of phosphoric acid (85%w/w) was

dissolved in 1000mL of water. The solution was filtered through 0.45µm membrane

and degassed before using.

Diluent: 1.4g of monobasic potassium phosphate was dissolved in 1000mL of water

and the pH was adjusted to 4.00 with Phosphoric acid. 400mL of this solution was

mixed with 600mL of Acetonitrile and filtered.

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Chapter-4 Methodology

Table no-12: HPLC Gradient program:

Time (min) Solution-A(%) Solution-B (%) Comment

0-4.5 100 0 Isocratic

4.5-4.6 100-95 0-5 Linear gradient

4.6-8.0 95-25 5-75 Linear gradient

8.0-11.5 25 75 Isocratic

11.5-11.6 25-100 75-0 Linear gradient

11.6-15.0 100 0 Re-equilibration

Note: Solutions was stable upto 3 days when stored at 40C. Without refrigeration the

solutions should be used immediately after preparation.

Standard preparation: Simvastatin working standard was accurately weighed

between 0.0675g and 0.0825g into 50mL volumetric flask and dissolved with the

diluent. The volume was made up with the diluent.

Procedure: 5µL of standard preparation was injected in replicate (6 injections) and

the chromatograms were recorded. The RSD of six replicate injections of standard

should be NMT 1.0%. 5µL of the test preparation was injected in duplicate and the

chromatograms were recorded. The sensitivity of the system was adjusted so that the

height of the principle peak in chromatogram obtained is at least 20% of the full scale

of the recorder.

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Chapter-4 Methodology

Formulation development

Method: Direct Compression

Direct compression was followed to manufacture the gas generating floating tablets of

simvastatin. All the polymers selected, drug and excipients were passed through sieve

no. 40 before using into formulation.

Polymers selected for tablets are

1. HPMC K4M

2. HPMC K15M

3. HPMC K100M,

Excipients like Dicalcium phosphate, Lactose, Sodium bicarbonate, citric acid

anhydrous, Magnesium Stearate were selected for the study. Sodium bicarbonate and

citric acid were used as gas generating agent. Citric acid was also used as an

antioxidant.

Steps involved in the manufacture of tablets

First the drug, polymer and other excipients selected were passed through 40-

mesh sieve. Required quantity of drug, polymer and excipients were weighed

properly and transferred into polyethylene bag and the blend was mixed for at

least 15 min.

The blend obtained was then lubricated by adding 1% magnesium stearate and

again mixed for another 5min.

The tablets were compressed using 8mm diameter punches in “Remik mini press-

1” tablet punching machine.

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Chapter-4 Methodology

Table no-13: Preliminary trial formulae:

Ingredients P1 P2 P3 P4 P5 P6 P7 P8

Simvastatin(drug) 20 20 20 20 20 20 20 20

HPMC K4M 40 40 40 40 40 40 80 -

HPMC K15M - - - - - - - 80

HPMC K100M - - - - - - - -

Sodium
20 20 20 20 15 20 20 20
bicarbonate

Citric acid 15.2 10 10 5 5 5 5 5

Dicalcium
- - 110 57.5 15 15 15 15
phosphate

Lactose 104.8 110 - 57.5 105 100 60 60

All the ingredients are added in „mg‟ as per the above formula and the total weight

of the tablet of all the batches was kept at 200mg. All the batches contain 1% Mg.

stearate.

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Chapter-4 Methodology

Table no-14: Floating tablets of simvastatin with various formulae:

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Simvastatin(drug) 20 20 20 20 20 20 20 20 20

HPMC K4M 40 60 80 - - - - -

HPMC K15M - - - 40 50 60 80 - -

HPMC K100M - - - - - - - 40 60

Sodium
20 20 20 20 20 20 20 20 20
bicarbonate

Citric acid 5 5 5 5 5 5 5 5 5

Dicalcium
15 15 15 15 15 15 15 15 15
phosphate

Lactose 100 80 60 100 90 80 60 100 80

Preformulation studies

Preformulation testing is the first step in the rationale development of dosage forms of

a drug substance. It can be defined as an investigation of physical and chemical

properties of a drug substance alone and when combined with excipients. The overall

objective of Preformulation testing is to generate information useful to the formulator

in developing stable and bioavailable dosage forms, which can be mass-produced.

Evaluation of Powder Blend and Melt Granules:

Angle of repose: The angle of repose of powder blend was determined by the funnel

method. The accurately weighed powder blend was taken in the funnel. The height of

the funnel was adjusted in such a way that the tip of the funnel just touched the apex

of the powder blend. The powder blend was allowed to flow through the funnel freely

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Chapter-4 Methodology

on to the surface. The diameter of the powder cone was measured and angle of repose

was calculated using the following equation.

Where, h and r are the height and radius of the powder cone.

Table no-15: Comparision between angle of repose and flow property

Comparison between Angle of Repose and Flow Property

Angle of Repose ( θ ) Flow

< 25 Excellent

25 – 30 Good

30 – 40 Moderate (addition of 0.2% glidant required)

> 40 Poor

Bulk density:

Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A

quantity of 2 gm of powder blend from each formula, previously shaken to break any

agglomerates formed, was introduced in to 10 ml measuring cylinder. After that the

initial volume was noted and the cylinder was allowed to fall under its own weight on

to a hard surface from the height of 2.5 cm at second intervals. Tapping was

continued until no further change in volume was noted. LBD and TDB were

calculated using the following equations.

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Chapter-4 Methodology

Total Porosity:

Total porosity was determined by measuring the volume occupied by a selected

weight of a powder (V bulk) and the true volume of the powder blend (The space

occupied by the powder exclusive of spaces greater than the intermolecular spaces,

V).

Hausner’s Ratio:

It indicates the flow properties of the granules and is measured by the ratio of tapped

density to the bulk density.

Table no-16: Limits in Hausner’s ratio

limits in Hausner’s Ratio

SL.No. Hausner’s Property

Ratio
1. 0-1.2 Free flowing

2. 1.2-1.6 Cohesive powder

Compressibility index (Carr’s Index): CI

Compressibility index is an important measure that can be obtained from the bulk and

tapped densities. In theory, the less compressible a material is the more flowable it is.

A material having values of less than 20% has good flow property

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Chapter-4 Methodology

Table no-17: Compressibility index:

Sr. No % Comp. Index Properties

1 5-12 Free flowing

2 12-16 Good

3 18-21 Fair

4 23-35 Poor

5 33-38 Very poor

6 >40 Extremely poor

Post formulation evaluation

The tablets were evaluated for in process and finished product quality control tests i.e.

appearance, dimensions (diameter and thickness), weight variation, hardness,

friability, assay, and drug content.

Appearance: The tablet should be free from cracks, depressions, pinholes etc. The

color and the polish of the tablet should be uniform on whole surface. The surface of

the tablets should be smooth.

Tablets were subjected to evaluation of properties including drug content uniformity,

weight variation, tablet hardness, friability, and thickness, and in-vitro drug release

with different media.

Weight variation

The weight of the tablet being made was routinely determined to ensure that a tablet

contains the proper amount of drug. The USP weight variation test is done by weighing

20 tablets individually, calculating the average weight and comparing the individual

weights to the average. The tablets met the USP specification that not more than 2

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Chapter-4 Methodology

tablets are outside the percentage limits and no tablet differs by more than 2 times the

percentage limit. USP official limits of percentage deviation of tablet are presented in

the table.

Table no-18: Tablet weight variation

Average weight of Maximum %

Sr. No.
tablet (mg) difference allowed

1 130 or less 10

2 130-324 7.5

3 324< 5

Tablet hardness

The resistance of tablets to shipping or breakage under conditions of storage,

transportation and handling before usage depends on its hardness. The hardness of

each batch of tablet was checked by using Monsanto hardness tester. The hardness

was measured in terms of kg/cm2. six tablets were chosen randomly and tested for

hardness. The average hardness of six determinations was recorded.

Friability

Friability determines the resistance of tablets to shipping or breakage under conditions

of storage, transportation and handling before usage. Friability generally refers to loss

in weight of tablets in the containers due to removal of fines from the tablet surface.

Friability generally reflects poor cohesion of tablet ingredients. If there is any

chipping, capping, cracking or breaking of tablet; then the batch should be rejected.

Method

20 tablets were weighed and the initial weight of these tablets was recorded and

placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions.

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Chapter-4 Methodology

Then tablets were removed from the friabilator, dusted off the fines and again

weighed and the weight was recorded.

Where: w1= weight of the tablet before test.

. w2 = weight of the tablet after test

Dimensions: The dimensions of the tablets are thickness and diameter. The tablets

should have uniform thickness and diameter. The manufacturer normally states these.

Thickness and diameter of a tablet were measured using vernier calipers. These values

were checked and used to adjust the initial stages of compression.

Content Uniformity: The tablets were tested for their drug content uniformity. 20

tablets were weighed randomly and powdered. The powder equivalent to 100 mg of

Simvastatin was weighed accurately and dissolved in 100ml of Acetonitrile and 1mL

was pippetted out from the solution into another 100mL volumetric flask and diluted

to 100mL with Acetonitrile . The solution was shaken thoroughly. The undissolved

matter was removed by filtration through Whatman No.1 filter paper. Then the serial

dilutions were carried out. The absorbance of the diluted solutions was measured at

239 nm with acetonitrile as blank. The concentration of the drug was computed from

the standard curve of the Simvastatin in Acetonitrile.

In-vitro Dissolution studies

In-vitro dissolution study of Simvastatin was carried using Electrolab TDT-08L USP

dissolution test apparatus. The details are given as below.

Electrolab TDT-08L USP dissolution test apparatus

Medium : pH 1.2 buffer solution (0.1N HCl with 0.5%SLS)

RPM : 50
Time : 12hrs

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Chapter-4 Methodology

Temp : 370C ± 50C

Volume :900mL
Procedure

Tablet was introduced into dissolution test apparatus and the apparatus was set at

50rpm. 5 ml of sample was withdrawn at every 1hr interval and replaced by the

respective buffer solutions. Samples withdrawn were analyzed by UV

spectrophotometer at 239nm in 1.2pH for estimation of amount of drug released using

buffer solution as blank.

Release kinetics:20,22

Data obtained from in-vitro release studied was evaluated to check the goodness of fit

to various kinetics equations for quantifying the phenomena controlling the release

from microspheres. The kinetic models used were zero order, first order, and Higuchi

and Korsmeyer-peppas model. The goodness of fit was evaluated using the correlation

coefficient values (R2).

Zero Order Kinetics: It describes the system in which the drug release rate is

independent of its concentration.

Qt = Qo + Ko t (1)

Where

Qt= Amount of drug dissolved in time t

Qo = Initial amount of drug in the solution, which is often zero and

Ko = zero order release constant.

If the zero order drug release kinetic is obeyed, then a plot of Qt versus t will give a

straight line with a slope of K0 and an intercept at zero.

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Chapter-4 Methodology

First Order Kinetics:

It describes the drug release from the systems in which the release rate is

concentration

Dependent.

log Qt = log Qo + kt/ 2.303 (2)

Where

Qt = amount of drug released in time t.

Qo = initial amount of drug in the solution

k = first order release constant

If the first order drug release kinetic is obeyed, then a plot of log (Qo - Qt) versus t

will be straight line.

With a slope of kt/ 2.303 and an intercept at t=0 of log Qo

Higuchi Model:

It describes the fraction of drug release from a matrix is proportional to square root of

time.

Mt / M∞= kt 1/2 (3)

Where Mt and M∞ are cumulative amounts of drug release at time t and infinite

time, and k = Higuchi dissolution constant reflection formulation characteristics.

If the Higuchi model of drug release (i.e. Fickian diffusion) is obeyed, then a plot of

Mt / M∞ versus t1/2 will be straight line with slope of k.

Korsmeyer-Peppas model (Power Law):

The power law describes the drug release from the polymeric system in which release

deviates from Fickian diffusion, as expressed in following equation.

Mt / M∞= ktn (4)

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Chapter-4 Methodology

log [Mt / M∞] = log k + n log t (5)

Where Mt and M∞ are cumulative amounts of drug release at time t and infinite time

(i.e. fraction of drug release at time t),

k = constant incorporating structural and geometrical characteristics of CR device,

n = diffusion release exponent indicative of the mechanism of drug release for drug

dissolution.

To characterize the release mechanism,

The dissolution data {Mt / M∞ <0.6} are evaluated.

A plot of log {Mt / M∞} versus log t will be linear with slope of n and intercept

gives the value of log k. Antilog of log k gives the value of k.

Table no-19: Interpretation of diffusion release mechanisms from polymeric

films

‘n’ Mechanism

0.5 Fickian diffusion

0.5<n<1 Non- fickian diffusion

1 Class II transport

> 1.0 Super case-II transport

In vitro buoyancy studies:

In vitro buoyancy was determined by floating lag time as per the method described by

Rosa et al. The tablets were placed in a 100ml glass glass beaker containing simulated

gastric fluid (SGF), pH 1.2 as per USP. The time required for the tablet to raise to the

surface and float was determined as floating lag time.

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Chapter-4 Methodology

Determination of swelling and erosion index:19

Floating matrix tablet was introduced into basket type dissolution apparatus

containing 900mL of 0.1N HCl (pH 1.2 at 370C) at 100rpm. The tablets were

removed at definite time intervals and swollen weight of each tablet was determined

.To determine matrix erosion, swollen tablets were placed in a vaccum oven at 400C

and after 48 hours, tablets were removed and weighed. Swelling (%) and erosion (%)

was calculated according to the following formula, where S is the weight of the

floating matrix tablets after swelling; R is the weight of the eroded matrix tablet and T

is the initial weight of the matrix tablets.

Swelling index= (S-T)/T*100

% Erosion = (T-R)/T*100

STABILITY STUDIES:

Stability testing has become an integral part of formulation development. Stability of

a pharmaceutical preparation can be defined as “the capability of a particular

formulation (dosage form or drug product) in a specific container/closure system to

remain within its physical, chemical, microbiological, therapeutic and toxicological

specifications throughout its shelf life”.

In an attempt to reduce the time required to obtain information on instabilities, various

tests like stability testing studies were under taken. The stability testing of

pharmaceutical products is based on the principle of chemical kinetics.

Factors affecting stability

Factors affecting stability are as follows:-

1) Storage time

As the storage time of the formulation increases, the degradation of medicament in the

formulation increases and the physical stability of the formulation decreases.

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Chapter-4 Methodology

2) Storage condition

Storage conditions such as temperature and percentage relative humidity directly

affect the stability of the formulation. An increase in the temperature and relative

humidity results in the decrease in the stability of the formulation.

Purpose of Stability Testing

1. To ensure the efficacy, safety and quality of active ingredient(s) and formulation.

2. To establish shelf life or expiry date and to support label claim.

3. It provides for a rapid means of quality control.

4. The promising formulations were tested for a period of 30 days at different

temperature of 400C and 75% RH, for their drug content. At regular intervals, the

tablets were taken in 100 ml of acetonitrile and were shaken for 1 hr. The resultant

solutions were filtered, properly diluted and estimated spectrophotometrically by

keeping acetonitrile as blank. % drug remained undecomposed was checked for

directly compressed tablets.

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Chapter-5 Results

5. Results

Pre formulation parameters

1. Melting point: The melting point of simvastatin was found to be 1350C

to1380C

2. Identification of simvastatin using FTIR

Fig-3: FTIR spectra of Simvastatin

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Chapter-5 Results

Table no-20: FTIR Peaks of Simvastatin

Standard
Peak observed in
SL.NO Functional group wave number
simvastatin API (cm-1)
-1
(cm )

1 Free O-H stretch 3546 3551.75

Methyl C-H symmetric stretch;

2 Methylene C-H assymmetric 2924 2929.77

stretch

3 Ester C=O stretch, associated 1697 1698.05

Methylene C-H symmetric

4 bend; Methyl C-H assymmetric 1461 1459.29

bend

5 Lactone –C-O-C bend 1268 1268.10

6 Ester –C-O-C- bend 1164 1165.82

7 Secondary alcohol C-O stretch 1072 1073.38

8 Trisubstitute olefinic C-H wag 869 869.81

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Chapter-5 Results

3. Compatibility study of drug with different excipients using DSC

Fig-4: DSC thermogram of pure drug

Fig-5: DSC thermogram of mixture of drug and HPMC K4M

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Chapter-5 Results

Fig-6: DSC thermogram of mixture of drug and HPMC K15M

Fig-7: DSC thermogram of mixture of drug and HPMC K100M

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Chapter-5 Results

Fig-8: DSC thermogram of mixture of drug and citric acid anhydrous

Fig-9: DSC thermogram of mixture of drug and sodium bicarbonate

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Chapter-5 Results

Fig-10: DSC thermogram of mixture of drug and Lactose

Fig-11: DSC thermogram of mixture of drug and Dicalcium phosphate

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Chapter-5 Results

Fig-12: DSC thermogram of mixture of drug and magnesium stearate

Table no-21: Peak temperature and enthalpy values of simvastatin in various drug-excipient mixtures
Tonset
SL.NO Sample 0 Tpeak (0C) ΔH J/g
Ratio ( C)
1 Simvastatin drug 142.19 143.74 81.2754
Simvastatin+HPMCK
2 141.26 143.02 47.6417
4M 1:1
Simvastatin+HPMC
3 139.53 141.15 52.1922
K15M 1:1
Simvastatin+HPMC
4 141.05 143.15 63.5450
k100M 1:1

5 Simvastatin+citric acid 126.19 130.74 81.8536

1:1
Simvastatin+Sodium
6 141.18 143.27 171.9135
bicarbonate 1:1

7 Simvastatin+Lactose 141.31 142.85 63.4461

1:1

8 Simvastatin+DCP 141.48 143.01 88.6051

1:1
Simvastatin+Magnesium
9 140.40 142.23 56.3951
stearate 1:1

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Chapter-5 Results

Isothermal stress testing using HPLC

Fig-13: Standard run of simvastatin

Fig-14: Simvastatin API (250C)

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Chapter-5 Results

Fig-15: Simvastatin and HPMC K4M mixture (250C)

Fig-16: Simvastatin and HPMC K15M mixture (250C)

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Chapter-5 Results

Fig-17: Simvastatin and HPMC K100M mixture (250C)

Fig-18: Simvastatin and citric acid mixture (250C)

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Chapter-5 Results

Fig-19: Simvastatin and sodium bicarbonate mixture (250C)

Fig-20: Simvastatin and lactose mixture (250C)

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Chapter-5 Results

Fig-21: Simvastatin and Dicalcium phosphate mixture (250C)

Fig-22: Simvastatin and Magnesium stearate mixture (250)

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Chapter-5 Results

With conditions (400C/75%RH)

Fig-23: Simvastatin API (400C/75%RH)

Fig-24: Simvastatin and HPMC K4M mixture (400C/75%RH)

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Chapter-5 Results

Fig-25: Simvastatin and HPMC K15M mixture (400C/75%RH)

Fig-26: Simvastatin and HPMC K100M mixture (400C/75%RH)

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Chapter-5 Results

Fig-27: Simvastatin and citric acid mixture (400C/75%RH)

Fig-28: Simvastatin and sodium bicarbonate (400C/75%RH)

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Chapter-5 Results

Fig-29: Simvastatin and Lactose mixtures (400C/75%RH)

Fig-30: Simvastatin and Dicalcium phosphate mixture (400C/75%RH)

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Chapter-5 Results

Fig-31: Simvastatin and magnesium stearate mixture (400C/75%RH)

Table no-22: Isothermal stress testing studies

Rt
(min) Rt (min) at
SL.NO Sample Ratio Area Area
at 400C/75%RH
250C

1 Simvastatin standard
2.286 12605.091

2 Simvastatin API 2.281 12672.291

2.281 12711.957
Simvastatin+HPMC
3 1:1 2.282 12664.769
K4M 2.278 12617.909
Simvastatin+HPMC
4 1:1 2.279 12653.150
K15M 2.283 12639.785
Simvastatin+HPMC
5 1:1 2.281 12737.619
k100M 2.281 12619.100

6 Simvastatin+citric acid 1:1 2.279 12547.321

2.283 12641.771
Simvastatin+Sodium 1:1
7 2.283 12425.507
bicarbonate 2.282 12451.199

8 Simvastatin+Lactose 1:1 2.276 12898.278

2.282 12706.190

9 Simvastatin+DCP 1:1 2.280 12649.943

2.280 12685.689
Simvastatin+
1:1
10 Magnesium 2.278 12675.289
2.282 12641.637
stearate

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Chapter-5 Results

4. Table no-23: Pre- compression parameters of direct compressed floating

tablet
Bulk Tap Angle of
Carr’s Hausner’s Porosity
Batch density density repose*
3 3
index ratio (%)
(g/cm ) (g/cm )

F1 0.634 0.740 14.28 1.16 14.28 25.19±0.594

F2 0.597 0.727 17.91 1.218 17.91 23.89±1.607

F3 0.625 0.727 14.06 1.163 14.06 26.68±0.586

F4 0.689 0.869 20.68 1.260 20.68 26.53±0.781

F5 0.701 0.851 17.54 1.212 17.54 21.28±1.160

F6 0.677 0.851 20.33 1.255 20.33 23.77±1.178

F7 0.714 0.833 14.28 1.166 14.28 25.62±0.475

F8 0.714 0.888 19.64 1.244 19.64 24.943±0.788

F9 0.689 0.869 20.68 1.260 20.68 27.61±0.459

*Angle of repose, n=3

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Chapter-5 Results

5. Table no-24: Post-compression parameters of directly compressed floating

tablet of Simvastatin
Content
Weight Hardness Thickness Diameter Friability
Batch uniformity
2
variation (g) Kg/cm (mm) (mm) (%)
(%)

F1 0.205±0.008 6.22±0.133 3.05±0.064 8.00±0.017 0.23 94.32

F2 0.201±0.005 6.03±0.186 3.22±0.085 7.99±0.006 0.42 97.42

103.10
F3 0.200±0.006 6.15±0.187 3.17±0.110 7.96±0.04 0.36

98.20
F4 0.200±0.006 6.15±0.237 2.95±0.056 7.99±0.019 0.32

96.75
F5 0.199±0.005 6.14±0.135 3.13±0.067 7.99±0.016 0.18

99.38
F6 0.200±0.006 6.01±0.172 3.02±0.124 7.98±0.039 0.45

97.04
F7 0.200±0.005 6.11±0.116 3.02±0.03 7.97±0.017 0.62

F8 0.201±0.005 5.91±0.231 2.99±0.085 7.96±0.049 0.51 101.16

F9 0.199±0.007 6.03±0.186 3.00±0.061 7.99±0.021 0.38 98.30

Weight variation, n=20; Thickness, n=6

Hardness, n=6; Diameter, n=6

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Chapter-5 Results

6. Table no-25: Floating lag time

Batch Floating lag time (sec)

F1 9.45±0.13

F2 29.42±0.433

F3 98.74±0.948

F4 11.87±0.835

F5 12.56±0.680

F6 18.80±0.614

F7 54.07±1.597

F8 11.32±0.310

F9 89.87±1.020

Floating lag time, n=3

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Chapter-5 Results

Table no-26: In-vitro drug release studies of floating tablet of simvastatin

containing HPMC K4M
% cumulative drug release
Time (hrs)
F1 F2 F3

0 0 0 0

1 75.0487±1.9943 26.469±1.666 7.012±1.1959

2 83.476±1.250 31.315±0.8488 9.900±1.3709

3 86.568±0.4907 34.338±0.7904 12.756±1.6396

4 90.161±0.5507 38.691±0.6842 16.722±1.9265

5 92.310±0.6316 42.677±0.6534 20.321±2.6955

6 47.999±2.6139 24.377±3.6714

7 52.693±0.9873 30.720±3.008

8 56.704±0.6896 36.632±1.4432

9 63.926±0.4042 41.509±0.6174

10 71.358±1.0930 47.263±0.5771

11 79.486±0.6531 52.414±1.1282

12 85.830±0.6384 57.835±2.0477

Fig-32: Dissolution profile of Simvastatin with HPMC K4M.

100
90
80
70
60
cpr-2
CPR

50
cpr-3
40
30 crp-4
20
10
0
0 2 4 6Time(Hr)8 10 12 14

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Chapter-5 Results

Table no-27: In-vitro drug release studies of floating tablet of simvastatin

containing HPMC K15M
Time % cumulative drug release
(hrs) F4 F5 F6 F7
0 0 0 0 0

1 80.308±1.0493 71.420±1.6027 18.920±2.0178 5.917±0.8424

2 82.337±0.3920 76.029±0.8539 23.676±1.3092 6.997±0.9673

3 86.6154±0.4473 81.685±0.5363 28.896±1.2964 8.058±0.8132

4 88.576±0.2868 85.251±1.5485 33.341±1.4357 10.562±0.5894

5 90.230±0.2163 90.198±0.3640 38.540±0.7112 12.958±0.9678

6 91.816±0.4808 93.441±1.0616 44.328±0.5615 15.756±1.2187

7 95.969±0.4259 50.243±0.8609 18.496±1.0432

8 96.755±1.0751 54.437±0.4118 22.761±1.7646

9 96.252±1.0903 59.578±0.7386 29.484±0.6745

10 95.4511±1.717 62.822±0.6816 32.835±1.1085

11 94.107±1.8657 66.789±0.6801 40.562±2.3432

12 92.874±1.1163 73.185±1.0892 45.653±1.0812

Fig-33: Dissolution profile of simvastatin with HPMC K15M

120

100

80
cpr-2
CPR

60
cpr-2.5

40 cpr-3
cpr-4
20

0
0 2 4 6 8 10 12 14
Time (Hr)

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Chapter-5 Results

Table no-28: In-vitro drug release studies of floating tablet of simvastatin

containing HPMC K100M

% cumulative drug release

Time (hrs)
F8 F9
0 0 0

1 77.313±0.9810 8.1818±1.2461

2 82.661±0.4357 10.978±1.1810

3 85.358±0.4144 14.643±0.5217

4 86.826±0.2926 17.719±1.8154

5 88.884±0.3316 22.808±1.8621

6 90.658±0.4457 27.877±1.8649

7 92.926±0.6014 32.485±1.6224

8 39.335±0.6440

9 43.250±1.2744

10 46.943±1.9978

11 55.915±0.5864

12 62.597±0.5301

Fig-34: Dissolution profile of Simvastatin with K100M.

100
90
80
70
60
CPR

50 cpr-2
40 cpr-3
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time( Hr)

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Chapter-5 Results

Release Kinetics
Table no-29: Kinetic modeling of simvastatin formulation F2:
Time (H) CPR Log CPR Log t SQRT t % Drug retained Log % drug retained

1 26.46916 1.42274 0 1 73.53084 1.86647

2 31.31588 1.495765 0.30103 1.414214 68.68412 1.836856

3 34.33807 1.535776 0.477121 1.732051 65.66193 1.817314

4 38.69102 1.58761 0.60206 2 61.30898 1.787524

5 42.67749 1.630199 0.69897 2.236068 57.32251 1.758325

6 47.99986 1.68124 0.778151 2.44949 52.00014 1.716004

7 52.69332 1.721756 0.845098 2.645751 47.30668 1.674923

8 56.70468 1.753619 0.90309 2.828427 43.29532 1.636441

9 63.92695 1.805684 0.954243 3 36.07305 1.557183

10 71.35809 1.853443 1 3.162278 28.64191 1.457002

11 79.48606 1.900291 1.041393 3.316625 20.51394 1.312049

12 85.83076 1.933643 1.079181 3.464102 14.16924 1.151346

Fig-35: Zero order plot of formulation F2

Zero order plot y = 5.3098x + 18.1105

R² = 0.9818
100
90
80
70
60
cpr

50
40 avg cpr
30
Linear (avg cpr)
20
10
0
0 5 10 15
time h

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Chapter-5 Results

Fig-36: First order plot of formulation F2

First order plot y = -0.0583x + 2.0098

R² = 0.8834
log % drug retained 2.5
2
1.5
1
log r av cpr
0.5
Linear (log r av cpr)
0
0 5 10 15
time h

Fig-37: Higuchi plot of formulation F2

Higuchi plot y = 23.7920x - 5.3668

100 R² = 0.9246

80
60
cpr

40 avg cpr
20 Linear (avg cpr)
0
0 1 2 3 4
sqrt t

Fig-38: Korsmeyer-Peppas plot of formulation F2

korsmeyer-Peppas plot y = 0.4788x + 1.3471

R² = 0.9191
2.5
2
log cpr

1.5
1 log av cpr
0.5 Linear (log av cpr)
0
0 0.2 0.4 0.6 0.8 1 1.2
log t

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Chapter-5 Results

Table no-30: Kinetic modeling of simvastatin formulation F3:

Log % drug

Time (h) CPR Log CPR Log t SQRT t % Drug retained retained

1 7.012987 0.845903 0 1 92.98701 1.968422

2 9.900973 0.995678 0.30103 1.414214 90.09903 1.95472

3 12.75609 1.105718 0.477121 1.732051 87.24391 1.940735

4 16.72254 1.223302 0.60206 2 83.27746 1.920527

5 20.32102 1.307946 0.69897 2.236068 79.67898 1.901344

6 24.3773 1.386986 0.778151 2.44949 75.6227 1.878652

7 30.7201 1.487423 0.845098 2.645751 69.2799 1.840607

8 36.63271 1.563869 0.90309 2.828427 63.36729 1.801865

9 41.50988 1.618151 0.954243 3 58.49012 1.767083

10 47.26326 1.674524 1 3.162278 52.73674 1.722113

11 52.41423 1.719449 1.041393 3.316625 47.58577 1.677477

12 57.8359 1.762198 1.079181 3.464102 42.1641 1.624943

Fig-39: Zero order plot of formulation F3

Zero order plot y = 4.7638x - 1.1755

R² = 0.9885
80
60
cpr

40
20 avg cpr

0 Linear (avg cpr)

0 2 4 6 8 10 12 14

time h

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Chapter-5 Results

Fig-40: First order plot of formulation F3

First order plot y = -0.0311x + 2.0357

R² = 0.9611
2.5
log % drug retained

2
1.5
1 log avg rcpr
0.5
Linear (log avg rcpr)
0
0 5 10 15
time h

Fig-41: Higuchi plot of formulation F3

Higuchi Plot y = 21.3890x - 22.3450

80 R² = 0.9348

60
cpr

40
avg cpr
20
Linear (avg cpr)
0
0 1 2 3 4
-20
sqrt t

Fig-42: Korsmeyer-Peppas plot of formulation F3

korsmeyer-Peppas plot
2 y = 0.8976x + 0.7417
R² = 0.9678
1.5
log cpr

1
log avg cpr
0.5
Linear (log avg cpr)
0
0 0.2 0.4 0.6 0.8 1 1.2
log t

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Chapter-5 Results

Table no-31: Kinetic modeling of simvastatin formulation F6:

Log %Drug Log %
Time (h) CPR CPR Log t SQRT t retained drug retained

1 18.92046 1.2769 0 1 81.07954 1.908911

2 23.67654 1.3743 0.30103 1.414214 76.32346 1.882658

3 28.89678 1.4608 0.477121 1.732051 71.10322 1.851889

4 33.34172 1.5229 0.60206 2 66.65828 1.823854

5 38.54099 1.5859 0.69897 2.236068 61.45901 1.788586

6 44.32819 1.6466 0.778151 2.44949 55.67181 1.745635

7 50.24378 1.7010 0.845098 2.645751 49.75622 1.696847

8 54.43763 1.7358 0.90309 2.828427 45.56237 1.658606

9 59.5786 1.7750 0.954243 3 40.4214 1.606611

10 62.82278 1.7981 1 3.162278 37.17722 1.570277

11 66.78936 1.8247 1.041393 3.316625 33.21064 1.521277

12 73.18515 1.8644 1.079181 3.464102 26.81485 1.428375

Fig-43: Zero order plot of formulation F6

Zero order plot y = 4.9203x + 14.2484

R² = 0.9977
80
70
60
50
cpr

40
30 cpr
20 Linear (cpr)
10
0
0 2 4 6 8 10 12 14
time h

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Chapter-5 Results

Fig-44: First order plot of formulation F6

First order plot y = -0.0421x + 1.9805

R² = 0.9823
2.5
log %drug retained
2
1.5
1 log rcpr
0.5 Linear (log rcpr)
0
0 5 10 15
time h

Fig-45: Higuchi Plot of formulation F6

Higuchi plot
y = 22.5186x - 8.6570
80 R² = 0.9803
60
cpr

40
20 cpr
0 Linear (cpr)
0 1 2 3 4
sqrt t

Fig-46: Korsmeyer-Peppas plot of formulation F6

korsmeyer- Peppas plot y = 0.5678x + 1.2198

R² = 0.9780
2

1.5
log cpr

1
log cpr
0.5
Linear (log cpr)
0
0 0.2 0.4 0.6 0.8 1 1.2
log t

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Chapter-5 Results

Table no-32: Kinetic modeling of simvastatin formulation: F7

Log %Drug

Time (h) CPR CPR Log t SQRT t retained Log % drug Retained

1 5.917208 0.7721 0 1 94.08279 1.97351

2 6.997159 0.8449 0.30103 1.414214 93.00284 1.968496

3 8.058577 0.9062 0.477121 1.732051 91.94142 1.963511

4 10.56236 1.0237 0.60206 2 89.43764 1.95152

5 12.95806 1.1125 0.69897 2.236068 87.04194 1.939729

6 15.75636 1.1974 0.778151 2.44949 84.24364 1.925537

7 18.49675 1.2670 0.845098 2.645751 81.50325 1.911175

8 22.76163 1.3572 0.90309 2.828427 77.23837 1.887833

9 29.48471 1.4695 0.954243 3 70.51529 1.848283

10 32.83536 1.5163 1 3.162278 67.16464 1.827141

11 40.5625 1.6081 1.041393 3.316625 59.4375 1.774061

12 45.653 1.6594 1.079181 3.464102 54.347 1.735176

Fig-47: Zero order plot of formulation F7

Zero order plot y = 3.6342x - 2.7853

R² = 0.9426
50
40
30
cpr

20
cpr
10
0 Linear (cpr)

0 2 4 6 8 10 12 14
time h

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Chapter-5 Results

Fig-48: First order plot of formulation F7

y = -0.0210x + 2.0288
First order plot R² = 0.9085
2.05
log %drug retained

2
1.95
1.9
1.85
logrcpr
1.8
1.75 Linear (logrcpr)
1.7
0 2 4 6 8 10 12 14
time h

Fig-49: Higuchi plot of formulation F7

Higuchi plot y = 15.9941x - 18.1473

50 R² = 0.8564

40
30
cpr

20 cpr
10 Linear (cpr)
0
-10 0 1 2 3 4
sqrt t

Fig-50: Kormeyer-Peppas plot of formulation F7

korsmeyer-Peppas plot
y = 0.8729x + 0.5965
2 R² = 0.8991
1.5
log cpr

1
log cpr
0.5
Linear (log cpr)
0
0 0.2 0.4 0.6 0.8 1 1.2

log t

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Chapter-5 Results

Table no-33: Kinetic modeling of simvastatin formulation F9:

Log

Time (h) CPR CPR Log t SQRT % Drug retained Log % drug retained

1 8.181818 0.9128 0 1 91.81818 1.962929

2 10.97889 1.0405 0.30103 1.414214 89.02111 1.949493

3 14.64353 1.1656 0.477121 1.732051 85.35647 1.931236

4 17.71943 1.2484 0.60206 2 82.28057 1.915297

5 22.80871 1.3581 0.69897 2.236068 77.19129 1.887568

6 27.87703 1.4452 0.778151 2.44949 72.12297 1.858074

7 32.4858 1.5116 0.845098 2.645751 67.5142 1.829395

8 39.33523 1.5947 0.90309 2.828427 60.66477 1.782937

9 43.25095 1.6359 0.954243 3 56.74905 1.753959

10 46.94372 1.6715 1 3.162278 53.05628 1.724737

11 55.91545 1.7475 1.041393 3.316625 44.08455 1.644286

12 62.59794 1.7965 1.079181 3.464102 37.40206 1.572895

Fig-51: Zero order plot of formulation F9

Zero order plot y = 4.9334x - 0.1723

70 R² = 0.9866
60
50
40
cpr

30
cpr
20
10 Linear (cpr)
0
0 2 4 6 8 10 12 14
time h

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Chapter-5 Results

Fig-52: First order plot of formulation F9

y = -0.0337x + 2.0366
First order plot R² = 0.9461
2.5
log %drug retained

2
1.5
1 log rpr
0.5
Linear (log rpr)
0
0 2 4 6 8 10 12 14
time h

Fig-53: Higuchi plot of formulation F9

Higuchi plot y = 22.1539x - 22.1034

80 R² = 0.9332

60
cpr

40
cpr
20
Linear (cpr)
0
0 1 2 3 4
sqrt t

Fig-54: Korsmeyer-peppas plot of formulaton F9

korsmeyer-Peppas plot y = 0.8552x + 0.8088

R² = 0.9663
2

1.5
logcpr

1
log cpr
0.5
Linear (log cpr)
0
0 0.2 0.4 0.6 0.8 1 1.2
log t

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Chapter-5 Results

Table no-34: Correlation co-efficients of different mathematical models for

formulations
Korsmeyer-
Zero order Higuchi model First order
Batch Peppas

R2 K0 R2 intercept R2 n R2 K1

F2 0.9818 18.1105 0.9246 -5.3668 0.9191 0.4788 0.8834 2.009

F3 0.9885 -1.1755 0.9348 -22.3450 0.9678 0.8976 0.9611 2.0357

F6 0.9977 14.2484 0.9803 -8.6570 0.9780 0.5678 0.9823 1.9805

F7 0.9426 -2.7853 0.8564 -18.1473 0.8991 0.8729 0.9085 2.0288

F9 0.9866 -0.1723 0.9332 -22.1034 0.9663 0.8552 0.9461 2.0366

Swelling index and erosion index

Table no-35: Swelling and erosion index of formulation F2

Time Initial weight Final weight swelling Weight after Erosion

(h) (g) (g) (%) drying (g) (%)

0 0 0 0 0 0

2 0.2 0.44 120 0.04 20

4 0.2 0.48 140 0.06 30

6 0.2 0.5 150 0.1 50

8 0.2 0.51 155 0.11 55

10 0.2 0.49 145 0.12 60

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Chapter-5 Results

Fig-55: Swelling index of formulation F2

Swelling (%)
200

150
Swelling (%)

100

50 swel (%)

0
0 2 4 6 8 10 12
time h

Fig-56: Erosion index of formulation F2

Erosion (%)
80

60
Erosion (%)

40

20 erosion (%)
0
0 2 4 6 8 10 12
Time h

Table no-36: Swelling and erosion index of formulation F3

Time Initial Final weight Swelling Weight after Erosion
(h) weight (g) (g) (%) drying (g) (%)

0 0 0 0 0 0

2 0.2 0.5 150 0.17 15

4 0.2 0.56 180 0.14 30

6 0.2 0.59 195 0.12 40

8 0.2 0.58 190 0.11 45

10 0.2 0.56 180 0.1 50

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Chapter-5 Results

Fig: 57: Swelling index of formulation F3

swelling (%)
250
200
Swelling (%)

150
100
swel (%)
50
0
0 2 4 6 8 10 12
time h

Fig-58: Erosion index of formulation F3

Erosion (%)
60
50
Erosion (%)

40
30
20
ersion
10
0
0 2 4 6 8 10 12
Time h

Table no-37: Swelling and erosion index of formulation F6

Time Initial weight Final weight Swelling Weight after Erosion

(h) (g) (g) (%) drying (g) (%)

0 0 0 0 0 0

2 0.2 0.39 95 0.18 10

4 0.2 0.49 145 0.15 25

6 0.2 0.55 175 0.13 35

8 0.2 0.51 155 0.12 40

10 0.2 0.47 135 0.11 45

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Chapter-5 Results

Fig-59: Swelling index of formulation F6

swelling (%)
200

150
Swelling (%)

100

swel (%)
50

0
0 2 4 6 8 10 12
time h

Fig-60: Erosion index of formulation F6

Erosion (%)
50
40
Erosion (%)

30
20
ersion
10
0
0 2 4 6 8 10 12
Time h

Table no-38: Swelling and erosion index of formulation F7

Weight
Time Initial weight Final weight Swelling after Erosion
(h) (g) (g) (%) drying (g) (%)

0 0 0 0 0 0

2 0.2 0.5 150 0.18 10

4 0.2 0.61 205 0.17 15

6 0.2 0.69 245 0.16 20

8 0.2 0.64 220 0.14 30

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Chapter-5 Results

Fig-61: Swelling index of formulation F7

Swelling (%)
300
250
Swelling (%)

200
150
100 swell (%)
50
0
0 2 4 6 8 10
time h

Fig-62: Erosion index of formulation F7

Erosion (%)
35
30
25
Erosion (%)

20
15
10 erosion
5
0
0 2 4 6 8 10
time h

Table no-39: Swelling and erosion index of formulation F9

Time Initial weight Final weight swelling Weight after Erosion(
(h) (g) (g) (%) drying (%) %)
0 0 0 0 0 0
2 0.2 0.54 170 0.19 5
4 0.2 0.61 205 0.19 5
6 0.2 0.67 235 0.18 10
8 0.2 0.71 255 0.17 15
10 0.2 0.6 200 0.15 25
12 0.2 0.56 180 0.14 30

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Chapter-5 Results

Fig-63: Swelling index of formulation F9

swelling (%)
300

250
Swelling (%)

200

150

100 swell (%)

50

0
0 2 4 6 8 10 12 14
time h

Fig-64: Erosion index of formulation F9

Erosion (%)
35
30
25
Erosion (%)

20
15
10 erosion

5
0
0 2 4 6 8 10 12 14
time h

Stability Studies:

Stability Studies were carried out at 40oC temp and 75% RH for 30 days. The tablets

of optimized formulation (F2) were packed in amber-colored bottles tightly plugged

with cotton and capped and %drug remained undecomposed was checked at regular

time intervals.

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Chapter-5 Results

Table no-40: Stability studies:

F2-Drug content

Time in days % undecomposed

10 97.21%

20 97.18%

30 97.03%

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Chapter-6 Discussion

6. DISCUSSION

In the present study, gastro retentive effervescent floating tablets of Simvastatin 20mg

were prepared using different viscosity grades of hydroxypropyl methylcellulose

(HPMC K4M, HPMC K15M, HPMC K100M), gas generating agents like sodium

bicarbonate and citric acid anhydrous (citric acid also plays an antioxidant role),

combination of lactose anhydrous and dicalcium phosphate as fillers and magnesium

stearate as lubricant.

The pre and post compression parameters for all the formulations were evaluated. The

preformulation parameters evaluated for the formulation ingredients are as follows.

1. Melting point: This was done by capillary method, the melting point of

simvastatin was found to be 1350C to 1380C.

2. FTIR study: FTIR peaks observed in the Simvastatin sample were

3551.75cm-1, 2929.77 cm-1, 1698.05 cm-1, 1459.29 cm-1, 1268.10 cm-1, 1165.82 cm-1,

1073.38 cm-1, 869.81 cm-1. Which co-relates with the peaks of standard simvastatin

sample as mentioned in table no.20

3. Compatibility studies: Compatibility studies of Simvastatin with various

excipients were carried out by Differential Scanning Calorimetry and also by

isothermal stress testing, where 1:1binary mixture of Simvastatin with various

excipients were stored at 400C/75%RH for 14 days and control samples of similar

binary mixtures at 250C and analysed by HPLC. The tonset, tpeak obtained from DSC

were reported in the table no.21. The DSC of mixture of Simvastatin and citric acid,

Simvastatin and sodium bicarbonate showed that there might be some kind of

interaction, but we can’t conclude that there is interaction by solely depending on

DSC because in DSC, the drug and excipients were exposed to very high temperature

which is abnormal compared to the normal storage conditions. At extreme

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Chapter-6 Discussion

temperatures there might be some kind of interaction which may lead to

misinterpretation of results. So to rule out this doubt, isothermal stress testing was

conducted and analysed by HPLC. The retention time of Simvastatin and peak areas

were tabulated in table no.22. The retention time and peak areas of Simvastatin

obtained by HPLC shows that there is no potential of interaction between the drug and

excipients because there is no significant difference between the retention time and

peak areas of standard Simvastatin, Simvastatin present in control samples and the

binary mixtures stored at 400C/75%RH. Compatibility study is a very important step

before formulation. It rules out any possible interaction between drug and excipients

which may affect the efficacy, safety and drug release pattern of drug and also helps

in proper selection of excipients.

Standard drug curve:

Different concentrations of Simvastatin ranging from 2-10µg/ml was prepared using

pH 1.2 (0.1N HCl with 0.5%SLS). The primary stock solution was prepared using

acetonitrile. Secondary stock and further dilutions were prepared using pH 1.2 (0.1N

HCl with 0.5%SLS). The λmax was found to be 239nm. The plot of absorbance Vs

drug concentration was linear, with R2=0.9987 and slope=0.0616.

Standard drug curve of Simvastatin ranging from 2-10µg/ml was also prepared using

only acetonitrile. The λmax was found to be 239nm. The plot of absorbance Vs drug

concentration was linear with R2=1 and slope=0.0595.

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Chapter-6 Discussion

Pre-compression parameters evaluation for powder flow:

1. Angle of repose: The angle of repose for the formulation blends was carried out

after lubrication and results were reported in the table no.23, which ranges

between21.280 to 27.610. The optimized batch F2 showed angle of repose 21.390.

It concludes that for all the formulation blends, angle of repose was below 300,

which shows all the formulation blends have good flow property.

2. Compressibility index: It was calculated for all the formulation blends after

lubrication. It ranged from 14.06 to 20.68 for all the blends. The optimized batch

showed compressibility index of 17.91. It indicates that flow property was good

for all the.

3. Hausner’s ratio: It was calculated for all the formulation blends and was found to

be between1.16 to 1.260. The optimized formula F2 batch showed Hausner’s ratio

of 1.218. This shows that all blends were having good flow property.

Post formulation evaluation:

1. Shape of tablets: Tablets of all formulations were found to be circular with no

cracks and are white in colour.

2. Diameter and thickness: The diameter of all formulations ranged between 7.96

to 8.00mm and thickness was in the range of 2.95 to 3.22mm. The tablets of

optimized F2 formula had diameter of 7.99±0.006mm and thickness

3.22±0.085mm

3. Hardness test: All the batches showed hardness in the range 5.91 to 6.22Kg/cm2.

The optimized formula F2 showed hardness of 6.03±0.186Kg/cm2.

4. Friability test: The friability was found to be below 1% ensuring that all the

formulations were mechanically stable. The optimized formula F2 showed

friability of 0.42%.

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Chapter-6 Discussion

5. Uniformity of dosage units: Dosage uniformity was evaluated usually by weight

variation and content uniformity test.

Weight variation test: All the batches showed weight variation ranging from

0.199g to 0.205g. The optimized batch F2 showed weight variation of

0.201±0.005g. This ensures that it was within the limit of I.P specifications of

7.5%.

Content uniformity: USP specifies that Simvastatin tablets contain not less than

90.0 percent and not more than 110.0 percent of labeled amount of Simvastatin.

F2 batch showed 97.42%. All the formulations complied with the USP

specification. The results were shown in table no.24.

6. Floating lag time: All formulations showed floating lag time between 9.45 to

98.74 sec. Formulation F2 showed floating lag time of 29.42sec. Formulations F1-

F3 were prepared using different drug to polymer ratios (drug : HPMC K4M:, 1:2,

1:3, 1:4). Formulations F4-F7 were prepared using different drug to polymer ratio

(drug : HPMC K15M: 1:2, 1:2.5, 1:3, 1:4). Formulations F8-F9 were prepared with

drug to polymer ratios (drug : HPMC K100M: 1:2, 1:3). Floating lag time

increased as the polymer concentration increased. This showed that as the drug to

polymer ratio increases floating lag time increases. Tablets of P5 formula

(preliminary trial formulation with 1:2 drug to polymer (HPMC K4M) ratio and

7.5% sodium bicarbonate) did not float. This shows that minimum 10% sodium

bicarbonate is required for floating of tablets.

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Chapter-6 Discussion

7. In vitro drug release studies of floating tablets of Simvastatin:

The floating tablets of Simvastatin were prepared with different viscosity grades

of HPMC (HPMC K4M, HPMC K15M, HPMC K100M) and with different drug

to polymer ratios. Formulations from F1 to F3 were prepared using HPMC K4M

with different drug to polymer ratios (1:2, 1:3, 1:4). Formulations from F4 to F7

were prepared using HPMC K15M with different drug to polymer ratios (1:2,

1:2.5, 1:3, 1:4). Formulations from F8 to F9 were prepared by using HPMC

K100M with different drug to polymer ratios (1:2, 1:3). All the batches contained

20mg of sodium bicarbonate, 5mg citric acid anhydrous, 15mg dicalcium

phosphate and lactose as fillers.

Formulation F1 (drug: HPMC K4M: 1:2), F4 (drug :HPMC K15M; 1:2), F5 (drug :

HPMC K15M: 1:2.5), F8 (drug : HPMC K100M: 1:2) showed first hour release of

75.0478%, 80.308%, 71.420%, 77.313% respectively. These formulations failed

to maintain integrity. As soon as the tablet gets disintegrated, it forms a layer of

polymer on the surface. So, this might be the reason for the high drug release in

the first hour.

At the end of 5th hour, F1 formulation showed 92.31% release, F4 formulation

showed 91.816% release at the end of 6th hour, F5 formulation showed release of

96.969% at the end of 8th hour and F8 shows 92.926% at the end of 7th hour. This

sustained release of drug from these formulations after a high drug release in the

first hour might be due to the slow release of drug from the polymer matrix which

was floating as a layer.

The reason for disintegration of tablet might be due to low amount of polymer and

high amount of water soluble diluent lactose. Hence the tablet was not able to

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Chapter-6 Discussion

withstand the pressure generated by the release of CO2 from the effervescent

mixture. So, the formulations F1, F4, F5, and F8 failed as gastro-retentive dosage

forms.

Formulations F2 (drug: HPMC K4M; 1:3), F3 (drug : HPMC K4M; 1:4), F6 (drug :

HPMC K15M; 1:3), F7 (drug : HPMC K15M; 1:4), F9 (drug : HPMC K100M;

1:3) showed first hour release of 26.469%, 7.012%, 18.920%, 5.917%, 8.1818%

respectively and maintained the integrity. The F2 formulation showed 26.469%

release in first hour. This might be due to the pores formed due to release of

carbondioxide, and also due to erosion. The release may also be due to the drug

which was stuck to the surface of the tablet. This can be justified by swelling

index and erosion index. The erosion index of F2 formulation at 2hr is 20%.

From 2nd hr to 12th hour, the release is sustained. This can be justified by swelling

index which reaches maximum of 156% at 8th hr.

At the end of 12 hours, F2 formulation showed 85.83% drug release, F3

formulation showed 57.835% release, F6 formulation showed 73.185% release, F7

formulation showed 45.653% release and F9 formulation showed 62.577%release.

Though the F2 formulation showed 26.469% release in the 1st hour, it is an

advantage. Since the mechanism of absorption of Simvastatin is by passive

diffusion, concentration gradient is very important. The drug release of 26.469%

will provide the concentration gradient and it is maintained by the sustained

release of drug. Since the formulation F2 showed the best release of 85.83% at the

end of 12 hrs, it was selected as the optimized formulation. Formulation F2

follows zero order kinetics and anomalous non-fickian diffusion.

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Chapter-6 Discussion

8. Stability study: The stability testing of the selected formulation F2 was carried

out as per the ICH guidelines. The optimized formulation was subjected to

stability studies at 400C/75%RH for a period of one month. The physical stability

was assessed by the appearance and there was no change in colour or shape of the

tablet and the chemical stability by change in the drug content as mentioned in the

table no. 40, which concludes that there was no change in the physical and

chemical properties of formulation. So the F2 formulation was stable at the end of

one month.

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Chapter-7 Conclusion

7. CONCLUSION

From the present study, the following conclusions can be drawn.

Gastro retentive effervescent floating tablets of Simvastatin using different

viscosity grades of HPMC (HPMC K4M, HPMC K15M, HPMC K100M)

prepared by direct compression method were found to be good without chipping,

capping and sticking.

The drug content was uniform in all the formulations of the tablets prepared. The

low values of standard deviation indicate uniform distribution of drug within the

matrices.

DSC and isothermal stress testing indicates that the drug is compatible with the

excipients.

The drug-polymer ratio was found to influence the release of drug from the

formulation. As the polymer level was increased, the drug release rates were

found to be decreased.

The drug release was also influenced by the viscosity grades of the polymer

(HPMC). As the viscosity of polymer increased, the release of drug decreased.

Amount of sodium bicarbonate and citric acid has influence on floating lag time.

It was found that minimum 10% sodium bicarbonate is required to attain

buoyancy. All the formulations (F1 to F9) floated for more than 12 hours.

The mechanism of the drug release for the optimized formulation F2 was found to

be anamolous non-Fickian diffusion with Zero order release.

Formulations F1, F4, F5, F8 fail to maintain the integrity and hence failed. Among

formulations F2, F3, F6, F7, F9 only F2 batch (drug: HPMC K4M; 1:3) showed 85%

release at the end of 12th hour which indicates that F2 is the optimized formulation.

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Chapter-7 Conclusion

Short term stability studies indicated no appreciable changes in the drug content

and in vitro drug release rates of optimized formulation.

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Chapter-8 Summary

8. SUMMARY

Simvastatin is an anti-hyperlipidemic agent used to lower the plasma LDL-C,

triglyceride level and hence also used in the treatment of atherosclerosis. It also

increases HDL-C. It has short biological half life of 2 hrs. Its dose is 10 to 80mg per

day. Simvastatin will get metabolized by intestinal CYP3A4 enzyme to its active form

Simvastatin-β-hydroxy acid. This active form is also a substrate for CYP3A4 enzyme

and gets converted to its inactive form. Once the Simvastatin-β-hydroxy acid gets

absorbed from intestine into the systemic circulation and into the liver which is the

site of action, some of it gets converted into its inactive form by CYP3A4 enzyme

present in liver and hence decreased efficacy. Since the Simvastatin is stable in the

acidic pH compared to that of the alkaline pH in intestine, Simvastatin as a molecule

gets absorbed and enters the liver. In liver, the Simvastatin gets converted to its active

form, Simvastatin-β-hydroxy acid and hence efficacy increases. The other important

thing of Simvastatin is its ability to heal peptic ulcers by increasing the prostaglandin

E2, gastric mucin secretion and release of nitric oxide and hence considered as an

ideal drug for designing an gastro retentive floating tablets.

In the present study, an attempt was made to prepare effervescent floating tablet of

simvastatin by direct compression method. Simvastatin is prone for oxidation. Since

direct compression reduces the exposure to moisture, reduced time, it is best method

for the preparation of simvastatin floating tablet. Simvastatin is poorly soluble in

water; by using the effervescent mixture of sodium bicarbonate and citric acid,

hydrophilic polymers and water soluble fillers like lactose we can improve the

solubility of drug.

Prepared floating tablets of Simvastatin were evaluated for hardness, friability, weight

variation, content uniformity, drug-polymer compatibility, in vitro release and short

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 134

Chapter-8 Summary

term stability studies. The drug release from the F2 formulation (1:3 - drug: HPMC

K4M) was governed by anamolous non-Ficikian diffusion and zero order release.

Among various formulations prepared with different viscosity grades of HPMC and

different drug-polymer ratios, the F2 formulation which was prepared using HPMC

K4M (1:3) shows 85% drug release at the end of 12 hours and also maintained the

integrity of tablet. Hence, HPMC K4M with drug to polymer ratio 1:3 can be used as

an optimized formula for designing the floating tablet of Simvastatin.

Nargund college of pharmacy, Dept. of Pharmaceutics Bangalore-85 Page 135

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