FORMULATION AND EVALUATION OF GASTRORETENTIVE DRUG ...

“FORMULATION AND EVALUATION OF

GASTRORETENTIVE DRUG DELIVERY SYSTEM OF

METHYL DOPA”

By

PREETI KUDTARKAR

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

Mrs. AISHA KHANUM

&

Co-Guidance of

Mr. VINAY PANDIT

Department of Pharmaceutics,

Al-Ameen College of Pharmacy,

Hosur Road, Bangalore- 560027.

APRIL 2011

AL–AMEEN COLLEGE OF PHARMACY Hosur Road, Bangalore-560027

Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “FORMULATION AND

EVALUATION OF GASTRORETENTIVE DRUG DELIVERY SYSTEM OF

METHYL DOPA” is a bonafide and genuine research work carried out by me

under the guidance of Mrs. Aisha Khanum, Asst. Professor, Department of

Pharmaceutics, Al-Ameen College of Pharmacy, Bangalore.

Date:

Place:

Signature of the candidate

Preeti Kudtarkar

AL–AMEEN COLLEGE OF PHARMACY

Hosur Road, Bangalore-560027

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “FORMULATION AND


METHYL DOPA” is a bonafide research work done by Ms. Preeti Kudtarkar in

partial fulfillment of the requirement for the degree of Master of Pharmacy,

under my personal supervision and guidance.

Date:

Place:

Signature of the Guide

Mrs. Aisha Khanum,

Assistant Professor,

Dept. of Pharmaceutics,


Hosur Road. Bangalore 560 027


ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE

INSTITUTION



METHYL DOPA” is a bonafide research work done by Ms. Preeti Kudtarkar

under the guidance of Mrs. Aisha Khanum, Asst. Professor, Dept. of

Pharmaceutics, Al-Ameen College of Pharmacy, Bangalore.

Seal & Signature of the HOD:

Dr.V Kusum Devi

Date: Place:

Seal & Signature of the Principal:

Prof.B.G.Shivananda

Date: Place:

AL–AMEEN COLLEGE OF PHARMACY

Hosur Road, Bangalore-560027

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.

© Rajiv Gandhi University of Health Sciences, Karnataka.

Date:

Place:

Signature of the candidate

Preeti Kudtarkar


CERTIFICATE BY THE CO-GUIDE



METHYL DOPA” is a bonafide research work done by

Ms. Preeti Kudtarkar in partial fulfillment of the requirement for the degree of

Master of Pharmacy in Pharmaceutics, under my personal supervision and

guidance.

Date: Signature of the Co-Guide

Place: Bangalore Mr. Vinay Pandit

Lecturer,

Dept. of Pharmaceutics


Bangalore

ACKNOWLEDGEMENT

With the blessings of Almighty, encouragement of parents, continuous guidance and

support of my esteemed teachers and timely help of my friends, I take an opportunity

to thank them for making me to achieve the desired goal.

I take this opportunity to express my deep sincere gratitude, indebtedness and

heartfelt thanks to my esteemed research guide, Mrs. Aisha Khanum, Assistant

Professor, Department of Pharmaceutics, for her insightful thoughts, professional

expertise, kind support and co-operation in timely completion of the project. I am

thankful to her for being constant source of encouragement, kind nature, disciplined

technical advice and valuable suggestions.

I express my deep and heart-felt thanks to my esteemed research co-guide Mr. Vinay

Pandit, Lecturer, Department of pharmaceutics, for his concern, valuable support,

encouragement and sincere guidance throughout my research work.

I take an opportunity to thank Dr. Kusum Devi, HOD, Department of

pharmaceutics for her timely help and support throughout my research work.

I sincerely thank to Professor B.G. Shivananda, Principal of Al – Ameen College of

Pharmacy, for providing all the facilities and timely help during the course of my

research.

My earnest thanks to Dr. Sarasija Suresh and for helping me gain confidence and

overcome my disabilities. I would also thank Dr. Roopa S Pai, Dr Shoba Rani, Dr

Asha A.N and Mrs. Audity Ganguly for their support and care.

I am profoundly grateful and express my sincere thanks to Mr. Uday Bhosale, Mr.

Shantkumar, Mr. Nagaraju and Miss. Nidhi for their concern and sincere guidance

throughout my research work.

I am thankful to Mrs. Sabiha Banu who made all the required chemicals available

in time for my project work. And I also thank the non teaching staff Padma,

Siddharaju, Manjula, Shekhar, Salim, library staff and office staff for extending

timely help in carrying out my work.

Special thanks to Atoz Pharmaceuticals Pvt. Ltd and Hardik Shah (Umedica

Laboratories Pvt. Ltd) for providing me the pure drug and to Diya Labs, Mumbai,

for helping me to do analysis for my formulation.

A lovely thanks to my friends, Chaitanya, Nagendra, Raghu, Chandu, Teju, Rishab,

Yasmeen and Priya. I thank my seniors Hardik, Sandeep, Riyaz, Gurinder, Rajani

and Mojdeh and juniors Payaam, Shreyas, Soumya, Mohiuddin, Sapan, Azmi and

Prasad who have bestowed on me love and affection when I needed them the most.

A special thanks to my roommates Ramya, Priyanka, Payal, Samar, Nishat, hostel

and MMCP friends for their constant love and support.

I express my heartfelt thanks to my sister Pooja and husband Vishal who stood

beneath to hold me each time I fell and imbibe in me the energy and confidence to fly

better again and again.

I proudly thank from the bottom of my heart to my parents, Mrs. Saroja Kudtarkar

and Mr. Manohar Kudtarkar for their love, concern, constant encouragement and

untiring support and trust, who built in the sense of optimism in me to fly and chase

my dreams.

Thanks Ma for being the pillar of support, you always have been a great inspiration.

Thanks for encouraging, guiding and supporting me in all my endeavours.

Thanks to all my teachers, friends, relatives and acquaintances who don’t find a

mention here, but to whom I remain indebted.

Thank You to the Almighty, for giving me the finest opportunity to express my

gratitude to all those people who have helped me and guided me throughout my life.

I bow my head in complete submission before Him for the blessings showered on me.

April 2011 Preeti Kudtarkar

List of abbreviations

Al-Ameen College Of Pharmacy, Bangalore.

LIST OF ABBREVIATIONS

Abs Absorbance

ACE Angiotensin Converting Enzyme

AUC Area Under Curve

AVG Average

BP British Pharmacopoeia

CMC Carboxy Methyl Cellulose

CPR Cumulative Percentage Release

CR Controlled Release

°C Degree Centigrade

Cm Centimeter

Conc. Concentration

DSC Differential Scanning Colorimetery

EC Ethyl Cellulose

F Floating Force

FDDS Floating Drug Delivery System

FTIR Fourier Transform Infrared

GI Gastro Intestinal

GIT Gastrointestinal Tract

gm Gram

GRDDS Gastro Retentive Drug Delivery System

GRDF Gastroretentive Dosage Forms

GRT Gastric Residence Time

HBS Hydrodynamically Balanced System

HCl Hydrochloric acid

HPMC Hydroxy Propyl Methyl Cellulose

hrs Hours

ICH International Conference of Harmonization

IP Indian Pharmacopoeia

Abstract


ABSTRACT

Methyldopa has been the most widely used drug for the treatment of gestational

hypertension. The present investigation concerns the development and evaluation of

floating tablets of methyldopa which, after oral administration, are designed to

prolong the gastric residence time, increase drug bioavailability and sustain the drug

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

(K4M/K15M) ratio (polymer blend) and sodium bi carbonate on floating lag time and

drug release at 12 hrs. The tablets were prepared by direct compression method and

further evaluated for pre compression parameters, physical characteristics, in-vitro

release, buoyancy, lag-time and swelling index. Formulations were evaluated for in-

vitro buoyancy and drug release study using United States Pharmacopeia (USP) 24

basket-type dissolution apparatus using pH 1.2 as a dissolution medium. Multiple

regression analysis was performed for factorial design batches to evaluate the

response. All formulations had floating lag times below 3 minutes and constantly

floated on dissolution medium for 24 hrs. The optimized formulations were subjected

to various kinetic release investigations and it was found that the mechanism of drug

release was predominantly diffusion in combination with polymeric relaxation. The

best formulation (F3) remained buoyant and showed a sustained drug release (98%)

for 24 hrs. F3 showed no significant change in physical appearance, drug content or

floating lag time after storage at 45 °C/75% RH for three months.

Key words: Methyldopa, Floating drug delivery system, Hydrocolloids, Gastric

residence time, Buoyancy

Table of contents

Al-Ameen college of pharmacy, Bangalore.

TABLE OF CONTENTS

1 Introduction 1-23

2 Objectives 24-26

3 Review of Literature 27-47

4 Methodology 48-66

5 Results 67-98

6 Discussion 99-106

7 Conclusion 107

8 Summary 108-109

9 Bibliography 110-115

List of abbreviations


IV Intravenous

K Dissolution Rate Constant

mg Milligram

mins Minutes

ml Milliliter

MC Methyl Cellulose

MMC Migrating Myoelectric Cycle

µg Microgram

No. Number

nm Nanometer

PO Per Oral

R2 Regression Coefficient / Correlation Coefficient

RH Relative Humidity

RT Room Temperature

rpm Rotations Per Minute

Sl Serial

SCMC Sodium Carboxy Methyl Cellulose

SD Standard Deviation

USP United States Pharmacopoeia

UV Ultraviolet

λmax Absorption maxima

List of Tables


LIST OF TABLES

Sl.No Tables Page No

1 Gastric emptying time 8

2 Viscosity grades of HPMC 33

3 Uses of Sodium bicarbonate 34

4 Uses of talc 36

5 Materials and sources 48

6 Instruments Used 49

7 Optimization of ratio of polymers 53

8 Optimized formulations prepared by 32 full factorial design 54

9 Factorial Design Batches of Methyldopa. 54

10 Coded Values and Actual Values for the Independent

Variables. 55

11 Formula for coating solution 56

12 Consolidation Index 58

13 Angle of Repose 59

14 Weight Variations 60

15 Standard graph of Methyldopa by UV-Visible

spectrophotometry 68

16 Selection of hydrocolloids 69

17 Evaluation of prepared batches of trial formulations 70

18 Evaluation of flow properties of tablet blend 71

19 Post compressional evaluation parameters 72

20 Swelling index of optimized formulations (F1 to F9) 73

21 Dissolution Profile for F1 76





List of Tables






30 Release kinetics of floating tablets of Methyldopa 87

31

Comparison of Dissolution efficiency, % Drug release,

Mean Dissolution time and T 50% and T90% drug release

of the optimised formulations.

88

32 Result of erosion study of the formulation F3 89

33 Dissolution for the Marketed formulation 90

34 Evaluation parameters for the check points C1and C2 92

35 Stability data for the final formulation F3 97

List of Figures


LIST OF FIGURES

Sl.No Tables Page No

1 Mechanism of floating system 12

2 Schematic representation of IR studies 50

3 Schematic diagram of DSC 65

4 IR spectra of pure drug 67

5 IR spectra of physical mixture 67

6 Standard graph of Methyldopa UV Spectrophotometry 69

7 Comparison graph for Swelling Index of F1 to F3 74



10 Comparison Graph for dissolution profile of F1 to F3 85



13 Graph for erosion study of the formulation F3 89

14 Comparison Graph for dissolution profile of marketed

formulation and F3 91

15 Response surface plot showing effect of factorial

variables on floating lag time. 91

16 Response surface plot showing effect of factorial

variables on drug release at 12 hrs. 92

17 FTIR for pure drug 93

18 FTIR for physical mixture 93

19 FTIR for final formulation 94

20 DSC graph for the pure drug 94

21 DSC for physical mixture 95

22 DSC for the final formulation F3 95

23 In-Vitro Buoyancy studies of the Best formulation F3 98

Chapter 1 Introduction

Al-Ameen college of pharmacy, Bangalore. Page 1

1. INTRODUCTION

1.1. Hypertension1 is a chronic medical condition in which the blood pressure is

elevated. Hypertension can be classified as either essential (primary) or secondary.

Essential or primary hypertension means that no medical cause can be found to

explain the raised blood pressure. About 90-95% of hypertension is essential

hypertension. Secondary hypertension indicates that the high blood pressure is a result

of another condition, such as kidney disease or tumours (adrenal adenoma or

pheochromocytoma).

It is estimated that nearly one billion people are affected by hypertension worldwide,

and this figure is predicted to increase to 1.5 billion by 2025. Over 90-95% of adult

hypertension is of the essential hypertension type. It is estimated that 43 million

people in the United States have hypertension or are taking antihypertensive

medication, which is almost 24% of the adult population. For the secondary

hypertension its known that primary aldosteronism is the most frequent endocrine

form of secondary hypertension. The incidence of exercise hypertension is reported

to range from 1 to 10% of the total population.

1.1.1. Hypertension during Pregnancy:

Hypertensive disorders are the most common medical complications of pregnancy and

are important cause of maternal and perinatal morbidity and mortality. Hypertension

is present in 6 to 8% of young women of childbearing age, but the prevalence

increases with advancing age and in women with diabetes mellitus, primary renal

http://en.wikipedia.org/wiki/Chronic

http://en.wikipedia.org/wiki/Disease

http://en.wikipedia.org/wiki/Blood_pressure

http://en.wikipedia.org/wiki/Secondary_hypertension

http://en.wikipedia.org/wiki/Kidney_disease

http://en.wikipedia.org/wiki/Tumours

http://en.wikipedia.org/wiki/Adrenal_adenoma

http://en.wikipedia.org/wiki/Pheochromocytoma

http://en.wikipedia.org/wiki/Essential_hypertension

http://en.wikipedia.org/wiki/United_States

http://en.wikipedia.org/wiki/Primary_aldosteronism

http://en.wikipedia.org/wiki/Endocrine

http://en.wikipedia.org/wiki/Incidence

http://en.wikipedia.org/wiki/Exercise_hypertension



disease or collagen vascular diseases reaching up to 20% in such populations.

Hypertensive disorder may complicate in about 3-10% of all pregnancies with

variable incidence among different hospitals and countries.

1.1.2. Classification of Hypertension:

1. Chronic hypertension

2. Pregnancy induced hypertension

a. Pre-eclampsia

b. Eclampsia

c. Pre-eclampsia superimposed on chronic hypertension

d. Gestational hypertension

Chronic hypertension: Hypertension detected prior to conception or diagnosed

before the 20th week of gestation. Hypertension diagnosed for the first time during

pregnancy which does not resolve post-partum is also defined as chronic

hypertension.

Pre-eclampsia: Blood pressure of ≥ 140/90 mm Hg after 20 week of gestation, if

prior blood pressure is unknown and accompanied by proteinuria is considered

sufficient for the diagnosis of pre-eclampsia. The diagnosis of pre-eeclampsia in

absence of proteinuria is highly suggestive when hypertension is accompanied by

headache, blurring of vision, abdominal pain or certain laboratory abnormalities

particularly low platelet count and elevated liver enzyme either alone or in

combination.



Eclampsia: Occurrence of seizure in women with pre-eclampsia that cannot be

attributed to other causes.

Superimposed Pre-eclampsia

1. In women with hypertension and no proteinuria in early pregnancy (<20 week‟s

gestation)

2. In women with hypertension and proteinuria before 20 weeks gestation, any one of

the following will suggest superimposed pre-eclampsia

a. Sudden increase in proteinuria

b. Sudden increase in blood pressure, where hypertension was previously well

controlled.

c. Thrombocytopenia (<10000/mm3)

Gestational hypertension: Hypertension detected for the first time after mid-

pregnancy but unaccompanied by proteinuria. Blood pressure returns to normal by 6

week postpartum or elevated blood pressure persist to be become chronic

hypertension.

1.2. Anti-hypertensive agents2: The anti-hypertensives are a class of drugs that are

used to treat hypertension (high blood pressure). Evidence suggests that reduction of

the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic

heart disease by 21%, and reduce the likelihood of dementia, heart failure, and

mortality from cardiovascular disease. There are many classes of anti-hypertensives,

which lower blood pressure by different means; among the most important and most

http://en.wikipedia.org/wiki/Medication

http://en.wikipedia.org/wiki/Hypertension

http://en.wikipedia.org/wiki/Blood_pressure

http://en.wikipedia.org/wiki/Ischaemic_heart_disease

http://en.wikipedia.org/wiki/Ischaemic_heart_disease

http://en.wikipedia.org/wiki/Dementia

http://en.wikipedia.org/wiki/Heart_failure

http://en.wikipedia.org/wiki/Death

http://en.wikipedia.org/wiki/Cardiovascular_disease



widely used are the thiazide diuretics, the ACE inhibitors, the calcium channel

blockers, the beta blockers, central sympatholytics and angiotensin II receptor

antagonists.

Many different types of drugs are used, alone or in combination with other drugs, to

treat high blood pressure.

The major categories are: ·

Angiotensin-converting Enzyme Inhibitors: ACE inhibitors work by

preventing a chemical in the blood, angiotensin I, from being converted into a

substance that increases salt and water retention in the body. These drugs also

make blood vessels relax, which further reduces blood pressure. ·

Angiotensin II Receptor Antagonists: These drugs act at a later step in the

same process that ACE inhibitors affect. Like ACE inhibitors, they lower

blood pressure by relaxing blood vessels. ·

Beta blockers: Beta blockers affect the body's response to certain nerve

impulses. This, in turn, decreases the force and rate of the heart's contractions,

which lowers blood pressure. ·

Blood Vessel Dilators (Vasodilators): These drugs lower blood pressure by

relaxing muscles in the blood vessel walls. ·

Calcium Channel Blockers: Drugs in this group slow the movement of

calcium into the cells of blood vessels. This relaxes the blood vessels and

lowers blood pressure. ·

Diuretics: These drugs control blood pressure by eliminating excess salt and

water from the body. ·

http://en.wikipedia.org/wiki/Thiazide

http://en.wikipedia.org/wiki/Diuretic

http://en.wikipedia.org/wiki/ACE_inhibitor

http://en.wikipedia.org/wiki/Calcium_channel_blocker



http://en.wikipedia.org/wiki/Beta_blocker

http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist





Nerve Blockers: These drugs control nerve impulses along certain nerve

pathways. This allows blood vessels to relax and lowers blood pressure.

1.3. Gastro Retentive Drug Delivery System:

Oral drug delivery system is the most popular delivery system due to its ease of

administration. In the past, oral route has been explored for the systemic delivery of

drugs through different types of dosage forms. However the drug or the active moiety

must be absorbed well throughout the Gastrointestinal Tract (GIT) in order to produce

an optimized therapeutic effect. Absorption may be hindered, if there is a narrow

absorption window for drug absorption in the GIT or if the drug is unstable in the GI

fluids. Thus the real challenge is to develop an oral controlled release dosage form not

only to prolong the delivery but also to prolong the retention of the dosage form in the

stomach or small intestine until the entire drug is released.

1.3.1. Gastric emptying:

Gastric emptying of dosage forms is an extremely variable process and ability to

prolong and control emptying time is a valuable asset for dosage forms, which reside

in the stomach for a longer period of time than conventional dosage forms. Several

difficulties are faced in designing controlled release systems for better absorption and

enhanced bioavailability. One of such difficulties is the inability to confine the dosage

form in the desired area of the gastrointestinal tract. Drug absorption from the

gastrointestinal tract is a complex procedure and is subject to many variables. It is

widely acknowledged that the extent of gastrointestinal tract drug absorption is related



to contact time with the small intestinal mucosa.3 Thus small intestinal transit time is

an important parameter for drugs that are incompletely absorbed.

Gastro retentive systems can remain in the gastric region for several hours and hence

significantly prolong the gastric residence time of drugs. Prolonged gastric retention

improves bioavailability, reduces drug waste and improves solubility for drugs that

are less soluble in a high pH environment. It has applications also for local drug

delivery to the stomach and proximal small intestines. Gastro retention helps to

provide better availability of new products with new therapeutic possibilities and

substantial benefits for patients. The controlled gastric retention of solid dosage forms

may be achieved by the mechanisms of mucoadhesion, floatation, sedimentation,

expansion modified shape systems or by the simultaneous administration of

pharmacological agent that delay gastric emptying. Several recent examples have

been reported showing the efficiency of such systems for drugs with bioavailability

problems.

1.3.2. Physiology of Gastrointestinal Tract4: Anatomically the stomach is divided

into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus

and body acts as a reservoir for undigested material, whereas the antrum is the main

site for mixing motions and act 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. During the fasting state an interdigestive series of

electrical events take place, which cycle both through stomach and intestine every 2 to

3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric



cycle (MMC), which is further divided into following 4 phases as described by

Wilson and Washington.5

1. Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.

2. Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action

potential and contractions. As the phase progresses the intensity and frequency also

increases gradually.

3. Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular

contractions for short period. It is due to this wave that all the undigested material is

swept out of the stomach down to the small intestine. It is also known as the

housekeeper wave.

4. Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2

consecutive cycles.

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 phase II of fasted state. These contractions result in

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

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

in slowdown of gastric emptying rate.

Scintigraphic studies determining gastric emptying rates revealed that orally

administered controlled release dosage forms are subjected to basically 2

complications, that of short gastric residence time and unpredictable gastric emptying

rate.



Table 1: Gastric emptying time

50% of stomach contents emptied 2.5 to 3 hrs

Total emptying of the stomach 4 to 5 hrs

50% emptying of the small intestine 2.5 to 3 hrs

Transit through the colon 30 to 40 hrs

1.3.3. Factors Affecting Gastric Retention 3

There are several factors that can affect gastric emptying (and hence GRT) of an oral

dosage form. These factors include:

Density of the dosage form: A dosage form having a density of less than that

of the gastric fluids floats.

Size of the dosage form: Small-sized tablets leave the stomach during the

digestive phase while the large-sized tablets are emptied during the

housekeeping waves. Dosage forms having a diameter of more than 7.5 mm

show a better gastric residence time compared with one having 9.9 mm.

Shape of the dosage form: It is reported that tetrahedron and ring-shaped

devices have a better gastric residence time as compared with other shapes.

Gender: Generally females have slower gastric emptying rates than males.

Posture: When subjects were kept in the supine position it was observed that

the floating forms could only prolong their stay because of their size;

otherwise the buoyancy remained no longer an advantage for gastric retention.



Temperature of meal: Cold meal increases and hot meal decreases the

emptying of gastric contents.

Composition and Viscosity of meal: Fats, particularly fatty acids inhibit

gastric secretion and have a pronounced reductive effect on the rate of

emptying. Proteins and starch are shown to have inhibitory effect on gastric

emptying, though to a less extent. As the viscosity of the gastric fluids is

increased, there is a corresponding decrease in the rate of emptying.

Volume: As the volume of liquid present in the gastric pouch increases, the

rate of gastric emptying decreases.

Increase in acidity of the duodenal contents slow down gastric emptying time.

Diseased states: Gastric emptying is affected in diseased conditions like

diabetes, Crohn‟s disease, etc.

1.3.4. Approaches to Design Gastro Retentive Dosage Forms 6

Over the years, various approaches have been pursued to increase the retention of an

oral dosage form in the stomach. Gastro retentive systems remain in the gastric region

for several hours and hence significantly prolong the gastric residence time of drugs.

These may be:

Floating Dug Delivery Systems (FDDS) or Hydrodynamically Balanced

Systems (HBS): These are systems which have a bulk density lower than

gastric fluids and thus remain buoyant in the stomach without affecting the

gastric emptying rate for a prolonged period of time. While the system is

floating on the gastric contents, the drug is released slowly at a desired rate

from the system.



Swelling and Expanding Drug Delivery Systems: These type of dosage forms

are such that after swallowing, these products swell to an extent that prevents

their exit from the stomach through the pylorus. As a result, the dosage form is

retained in the stomach for a long period of time. These systems may be

referred to as „plug type systems‟ since they exhibit a tendency to remain

lodged at the pyloric sphincter.

Bioadhesive Systems: These systems are used to localize a delivery device

within the lumen and cavity of the body to enhance the drug absorption

process in a site-specific manner. The approach involves the use of

bioadhesive polymers that can adhere to the epithelial surface of the GI tract.

The proposed mechanism of bioadhesion is the formation of hydrogen and

electrostatic bonding at the mucus-polymer boundary. Rapid hydration in

contact with the muco-epithelial surface appears to favor adhesion,

particularly if water can be excluded at the reactive surfaces.

Modified Shape Systems: These systems are non disintegrating geometric

shapes moulded from silastic elastomer or extruded from polyethylene blends,

which extend the GRT depending on size, shape and flexural modulus of the

drug delivery device.

High Density Systems: These formulations include coated pellets, which have

a density greater than that of the stomach contents (approx. 1.004 g/ cm3 ).

This is accomplished by coating the drug with a heavy inert material such as

barium sulfate, zinc oxide, titanium dioxide, iron powder, etc.



Delayed gastric emptying systems: These approaches of interest include

feeding of indigestible polymers or fatty acid salts that change the motility

pattern of the stomach to a fed state, thereby decreasing the gastric emptying

rate and permitting considerable prolongation of drug release.

1.4. FLOATING DRUG DELIVERY SYSTEM:

Floating systems or hydrodynamically controlled systems are low-density systems

that have sufficient buoyancy to float over the gastric contents and remain buoyant in

the stomach without affecting the gastric emptying rate for a prolonged period of

time. While the system is floating on the gastric contents, the drug is released slowly

at the desired rate from the system. After release of drug, the residual system is

emptied from the stomach. This results in an increased GRT and a better control of

the fluctuations in plasma drug concentration. However, besides a minimal gastric

content needed to allow the proper achievement of the buoyancy retention principle, a

minimal level of floating force (F) is also required to keep the dosage form reliably

buoyant on the surface of the meal. Many buoyant systems have been developed

based on granules, powders, capsules, tablets, laminated films and hollow

microspheres.



Figure 1: Mechanism of floating system.

1.4.1. SUITABLE DRUG CANDIDATES FOR GASTRORETENTION7:

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, chlordiazepoxide 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

1.4.2. APPROACHES TO DESIGN FLOATING DOSAGE FORMS6:

The following approaches have been used for the design of floating dosage

forms of single and multiple unit systems.



Single-Unit Dosage Forms: In low density approaches, the globular shells

apparently having lower density than that of gastric fluid can be used as a

carrier for drug for its controlled release. A buoyant dosage form can also be

obtained by using a fluid-filled system that floats in the stomach. In coated

shells popcorn, poprice, and polystyrol have been exploited as drug carriers.

Sugar polymeric materials such as methacrylic polymer and cellulose acetate

phthalate have been used to undercoat these shells. These are further coated

with a drug polymer mixture. The polymer of choice can be either ethyl

cellulose or hydroxypropyl cellulose depending on the type of released

desired. Finally the product floats on the gastric fluid while releasing the drug

gradually over a prolonged duration. Fluid-filled floating chamber type of

dosage forms includes incorporation of a gas-filled floatation chamber into a

microporous component that houses a drug reservoir. Aperture or opening are

present along the top and bottom walls through which the gastrointestinal fluid

enters to dissolve the drug. The other two walls in contact with the fluid are

sealed so that the undissolved drug remains therein. The fluid present could be

air, under partial vacuum or any other suitable gas, liquid, or solid having an

appropriate specific gravity and an inert behaviour. The device is of

swallowable size, remains afloat within the stomach for a prolong time and

after the complete release, the shell disintegrates, passes off to the intestine

and is eliminated.

Hydrodynamically balanced systems (HBS) are designed to prolong the stay

of the dosage form in the gastro intestinal tract and aid in enhancing the



absorption. Such systems are best suited for drugs having a better solubility in

acidic environment and also for the drugs having specific site of absorption in

the upper part of the small intestine. To remain in the stomach for a prolong

period of time the dosage form must have a bulk density of less than 1. It

should stay in the stomach, maintain its structural integrity and release drug

constantly from the dosage form. Single unit formulations are associated with

problems such as sticking together or being obstructed in the gastrointestinal

tract, which may have a potential danger of producing irritation.

Multiple-Unit Dosage Forms: The purpose of designing multiple-unit dosage

form is to develop a reliable formulation that has all the advantages of a

single-unit form and also is devoid of any of the above mentioned

disadvantages of single-unit formulations. In pursuit of this endeavour many

multiple unit floatable dosage forms have been designed. Microspheres have

high loading capacity and many polymers have been used such as albumin,

gelatin, starch, polymethacrylate, polyacrylamine, and polyalkyl

cyanoacrylate. Spherical polymeric microsponges also referred to as

“microballoons” have been prepared. Microspheres have a characteristic

internal hollow structure and show an excellent in-vitro floatability.22

In

Carbon di oxide generating multiple-unit oral formulations several devices

with features that extend, unfold or are inflated by carbon dioxide generated in

the devices after administration have been described. These dosage forms are

excluded from the passage of the pyloric sphincter if a diameter of ~12 to18

mm in their expanded state is exceeded.



1.4.3. CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEMS

(FDDS)6: Floating drug delivery systems are classified depending on the use of 2

formulation variables: Effervescent and Non-effervescent systems.

Effervescent Floating Dosage Forms: These are matrix types of systems prepared

with the help of swellable polymers such as methylcellulose and chitosan and various

effervescent compounds, eg, sodium bicarbonate, tartaric acid, and citric acid. They

are formulated in such a way that when in contact with the acidic gastric contents,

CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides

buoyancy to the dosage forms.

Non-effervescent Floating Dosage Forms: Non-effervescent floating dosage forms

use a gel forming or swellable cellulose type hydrocolloids, polysaccharides, and

matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and

polystyrene. The formulation method includes a simple approach of thoroughly

mixing the drug and the gel-forming hydrocolloid. After oral administration, this

dosage form swells on contact with gastric fluids and attains a bulk density of < 1.

The air entrapped within the swollen matrix imparts buoyancy to the dosage form.

The so formed swollen gel-like structure acts as a reservoir and allows sustained

release of drug through the gelatinous mass.

1.4.4. ADVANTAGES OF FLOATING DRUG DELIVERY SYSTEMS8:

1. Improvement of bioavailability: Furosemide has poor bioavailability because its

absorption is restricted to upper GIT. This was improved by formulating its floating

dosage form. The floating system containing furosemide exhibit 42.9% bioavailability



as compared to 33.4% shown by commercial tablet and 27.5% shown by enteric

coated tablet.

2. Reduction in plasma level fluctuations: The reduced plasma level fluctuations

results from delayed gastric emptying. For example bioavailability of standard

Madopar was found to be 60-70% and the difference in the bioavailability of standard

and HBS formulations was due to the incomplete absorption.

3. Reduction in the variability in transit performance: Floating dosage forms with

sustained release characteristics are useful in reducing the variability in transit

performance. For example formulating Tacrine as HBS dosage form reduces its

gastrointestinal side effects in Alzeihmer‟s patients.

4. Dosage reductions: The recommended adult oral dosage of Ranitidine is 150 mg

twice daily or 300 mg once daily. A conventional dose of 150 mg can inhibit gastric

acid secretion upto 5 hrs only and if 300 mg is administered it leads to plasma

fluctuations. On formulating ranitidine as floating system, the dosage has been

reduced and sustained action was observed.

5. Enhancement of therapeutic efficacy: Floating systems are particularly useful for

acid soluble drugs that are poorly soluble or unstable in intestinal fluids. For example

Bromocriptine used in the treatment of Parkinson‟s disease have low absorption

potential that can be improved by HBS dosage form and thus its therapeutic efficacy

could be enhanced.

6. Eradication of Helicobacter pylori: H.pylori is responsible for chronic gastritis and

peptic ulcers. This bacterium is highly sensitive to most antibiotics, and its eradication



from patients requires high concentrations of drug to be maintained within gastric

mucosa which could be achieved by floating system.

1.4.5. DISADVANTAGES OF FLOATING DRUG DELIVERY SYSTEM8:

1. Floating system is not feasible for those drugs that have solubility or stability

problem in G.I. tract.

2. These systems require a high level of fluid in the stomach for drug delivery to float

and work efficiently.

3. The drugs that are significantly absorbed through out gastrointestinal tract, which

undergo significant first pass metabolism, are only desirable candidate.

4. Some drugs present in the floating system causes irritation to gastric mucosa.

1.4.6. APPLICATION OF FLOATING DRUG DELIVERY SYSTEMS6:

Floating drug delivery offers several applications for drugs having poor

bioavailability because of the narrow absorption window in the upper part of the

gastrointestinal tract. It retains the dosage form at the site of absorption and thus

enhances the bioavailability. These are summarized as follows.

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 <1 as 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.



E.g. 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 (16 hours) in the sustained release floating capsules as

compared with conventional MICARD capsules (8 hours).

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, eg, Riboflavin and Furosemide.

E.g. Furosemide is primarily absorbed from the stomach followed by the duodenum.

It has been reported that a monolithic floating dosage form with prolonged gastric

residence time was developed and the bioavailability was increased. AUC obtained

with the floating tablets was approximately 1.8 times those of conventional

Furosemide tablets.

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.

Eg. A significantly 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%).



1.5. Evaluation 6

Gastro retention of the systems can be evaluated by X-ray or γ-scintigraphy. Modern

technique of γ-scintigraphy now makes it possible to follow the transit behaviour of

dosage form in human volunteers in a non-invasive manner.

1.6. Marketed Floating Formulations 5

Valrelease® - floating capsule of Diazepam

Madopar®

- Benserazide and L-dopa.

Liquid gaviscon® - floating liquid alginate preparation.

Almagate flot-coat®

- Antacid preparation.

The currently available polymer-mediated non-effervescent and effervescent FDDS,

designed on the basis of delayed gastric emptying and buoyancy principles, appear to

be an effective and rational approach to the modulation of controlled oral drug

delivery. This is evident from the number of commercial products and a myriad of

patents issued in this field.

1.7. OPTIMIZATION9,10

:

In today‟s industrialized society almost every product that eventually reaches the market

has a long lineage of testing and modification to its design before it sees the light of the

day. So “success is the most difficult commodity” to come out, especially with time frame

imposed, which is structured by a customer need or by a competitive threat. This leads to

experimenters or researchers to find the most efficient schemes of formulating, testing

and applying such schemes as broad a gamut of application required, to make a successful

product. The word „optimize‟ is defined as, to make as perfect, effective or functional as



possible and optimization may be interpreted as the way to find those values of the

dependent variable.

1.7.1. Terms used in Optimization:

Variables: These are the measurements, values, which are characteristics of the data.

There are two types of variables;

a. Dependent variables.

b. Independent variables.

Independent variables are the variables, which are not dependent on any other value

e.g., lubricants concentration, drug to polymer ratio, etc. Dependent variables are

dependent on the concentration of independent variable used.

Factor: Factor is an assigned variable such as concentration, temperature, lubricating

agent, drug-to-polymer ratio, polymer-to-polymer ratio or grade. A factor can be

qualitative or quantitative. A quantitative factor has a numerical value to it e.g.,

concentration (1%, 2%…… so on), drug to polymer ratio (1:1, 1:2……etc).

Qualitative factors are the factors, which are not numerical. For e.g., Polymer grade,

humidity condition, type of equipment, etc. These are discrete in nature.

Levels: The levels of a factor are values or designation assigned to the factor. For

e.g., concentration (factor) 1% will be one level, while 2% will be another level. Two

different plasticizers are levels of grade factor. Usually levels are indicated as low,

middle or high level. Normally for ease of calculation the numeric and discrete levels

are converted to –1 (low level) and +1 (high level).



Response: Response is mostly interpreted as the outcome of an experiment. It is the

effect, which we are going to evaluate i.e., disintegration time, duration of buoyancy,

thickness, t1/2

etc.

Effect: The effect of a factor is the change in response caused by varying the levels of

the factor. This describes the relationship between factors and levels.

Interaction: It is also similar to effect, which gives the overall effect of two or more

variables (factors) of a response. For example, the combined effect of lubricant

(factor) and glidant (factor) on hardness (response) of a tablet.

1.8. EXPERIMENTAL DESIGNS:

Experimental design is a statistical design that prescribes or advises a set of

combination of variables. The number and layout of these design points within the

experimental region depend on the number of effects that must be estimated.

Depending on the number of factors, their levels, possible interactions and order of

the model, various experimental designs are chosen. Each experiment can be

represented as a point within the experimental domain, the point being defined by its

co-ordinate (the value given to variables) in the space. The various experimental

designs are as follows;

1. Factorial Design

2. Plackett-Burman Design

3. Star Design

4. Central Composite Design



1.8.1. Factorial Design:

It is an experimental design, which uses dimensional factor space at the corner of the

design space. Factorial designs are used in experiments where the effects of different

factors or conditions on choice for simultaneous determination of the effect of several

factors and their interaction.

The simplest factorial design is the two factorial design, where two factors are

considered each at two levels, leads to four experiments, which are situated in 2-

dimensional factor space at the corners of a rectangle.

If there are three factors, each at two levels, eight experiments are necessary which

are situated at the corners of an orthogonal cube on a 3 dimensional space. The

number of experiments is given by 2n

, where „n‟ is the number of factors.

If the number of factors and levels are large, then the number of experiments needed

to complete a factorial design is large. To reduce the number of experiments,

fractional factorial design can be used (i.e., ½ or ¼ of the original number of

experiments with full factorial design).

The fitting of an empirical polynomial equation to the experimental result facilitates

the optimization procedure. The general polynomial equation is as follows:

Y = b0 + b1 X1 + b2 X2 + b12 X1 X2 + b11 X1 X1 + b22 X2 X2 …… 1

Where, Y is the response.

X1, X

2 are the levels (concentration) of the 1, 2, 3 factor.

b1, b

2, b

12, b

11, b

22 are the polynomial coefficient

b0

is the intercept (which represents the response when the level of all factors is low).



In the present work, an attempt has been made to formulate GFDDS of methyldopa using

hydroxy propyl methyl cellulose of different viscosity grades and sodium bicarbonate as

effervescent agent in order to prolong the drug release and to impart floating properties to

the matrix tablet formulations respectively.

After preliminary studies, optimization of designed GFDDS will be performed using 3²

full factorial design by conducting experiments to evaluate all the nine batches of

methyldopa GFDDS. The validity of the derived polynomial equations for the dependent

variables (dissolution parameters, floating lag time and floating time) will be verified by

designing and evaluating one extra check point formulations.

Chapter 2 Objectives


2. OBJECTIVES

Oral drug delivery system is the most popular delivery system due to its ease of

administration. In the past, oral route has been explored for the systemic delivery of

drugs through different types of dosage forms. However the drug or the active moiety

must be absorbed well throughout the GIT in order to produce an optimized

therapeutic effect. Absorption may be hindered, if there is a narrow absorption

window for drug absorption in the GIT or if the drug is unstable in the GI fluids. Thus

the real challenge is to develop an oral controlled release dosage form not only to

prolong the delivery but also to prolong the retention of the dosage form in the

stomach or small intestine until the entire drug is released.

One of the most important approaches to control the retention of drug delivery system

in the GIT is by adopting Gastro Retentive Drug Delivery Systems (GRDDS). Such

retention systems are important for drugs that are degraded in the intestine or for

drugs like antacids or certain antibiotics.8

Gastro Retentive Drug Delivery Systems offer several advantages over other

controlled drug delivery systems like site specific drug delivery, improved GI

absorption and bioavailability, better therapeutic efficacy with a possible reduction of

dose size and decrease in the side effects of drugs. This technology is particularly

suitable for drugs like Methyldopa which has low absorption window.

Methyldopa, an anti-hypertensive agent, has a half life of less than 2 hrs, and given

with a dose of 250 mg 3-4 times per day. In view of the above, the present work is

aimed at formulating and evaluating a Gastro Retentive Drug Delivery System



(GRDDS) of Methyldopa to prolong the drug release and drug retention at the site of

absorption, decrease the dosing frequency and to improve the patient compliance.

2.1. Specific Objectives of the Study

Evaluation of selected polymers for formulation of floating matrix tablet of

Methyldopa.

Optimization of the formulation using 32 full factorial design.

Formulation of floating matrix tablet by direct compression.

Evaluation of the developed formulation of Methyldopa.

Comparative evaluation of the best formulation with the available marketed

formulation.

2.2. Plan of work

1. Preparation of standard calibration curve for Methyldopa.

2. Selection of polymers and polymer concentrations.

3. Compatibility study between drug and selected polymers.

By Fourier Transform Infrared Spectroscopy.

4. Pre-compressional evaluation studies.

Bulk Density

% Compressibility

Angle of Repose

5. Optimization by 32 full factorial design.

6. Formulation of tablets by direct compression method.



7. Post-compressional evaluation studies.

Weight variation

Hardness

Friability

Drug Content

Swelling studies

Erosion studies

Buoyancy

8. Selection of best formulations.

9. In-vitro dissolution studies.

10. Data analysis.

11. Stability Studies.

Chapter 4 Methodology


4. METHODOLOGY

Table 5: MATERIALS AND SOURCES

Sl.no Chemicals/Reagents Sources

1 Methyldopa Atoz Pharmaceuticals Pvt. Ltd.,

Tamil Nadu

Umedica Laboratories Pvt.Ltd., Gujarat

2 HPMC K4M Dr. Reddy’s Laboratories.

3 HPMC K15M Dr. Reddy’s Laboratories.

4 Sodium Bicarbonate Merck Specialities Pvt. Ltd., Mumbai

5 Ascorbic Acid Titan Biotech Ltd., Rajasthan

6 Di-Calcium phosphate dihydrate Finar Chemicals., Ahmedabad

7 Magnesium stearate Titan Biotech Ltd., Rajasthan

8 Talc Finar Chemicals., Ahmedabad

9 Concentrated Hydrochloric Acid Himedia Laboratories Pvt. Ltd., Mumbai

10 Propylene Glycol Meru Chem Pvt. Ltd., Mumbai

11 Methanol Himedia Laboratories Pvt. Ltd., Mumbai

12 Dichloromethane Rankem Fine Chemicals Ltd., Mumbai

13 Deionised water Millipore, India

http://www.tradeindia.com/Seller-2462181-ATOZ-Pharmaceuticals-Pvt-Ltd-/



Table 6: Instruments Used

Sl.no Equipments Manufacturer

1 Electronic Weighing balance Citizen, India

2 UV-1700 Spectrophometer Shimadzu, Japan

3

Electrolab-EF2 friabilator (USP) Servewell Instruments,

India

4 Remi Water bath shaker, RIS 163 Remi Instruments, India

5

Electro lab TDT 06PS Dissolution apparatus

(USP)

Servewell Instruments,

India

6 Electro lab ETD-1020 tap density tester (USP)

Servewell Instruments,

India

7 Tablet punching machine CIP, Ahmedabad

8 Bath sonicator Enertech electronics Ltd

9 FTIR Shimadzu 8700 Shimadzu, Japan

10 DSC Q2000 Diya Labs, Mumbai

11 Humidity control oven NEC 210R10

Newtronic Instruments,

India



4.1 Preformulation Studies

Drug-excipients compatibility studies

Excipients are integral components of almost all pharmaceutical dosage forms. The

successful formulation of a stable and effective solid dosage form depends on the

careful selection of the excipients, which are added to facilitate administration,

promote the consistent release and bioavailability of the drug and protect it from

degradation.

Infra Red (IR) Spectroscopy38

IR spectroscopy deals with the study of absorption of IR region, which extends from

the red end of the visible spectrum to the microwave region. An IR radiation is

absorbed by a molecule when the applied IR frequency is equal to the natural

frequency of vibration of the molecule. Absorption of IR radiation brings a change in

the dipole moment of the molecule.

Figure 2: Schematic representation of IR studies.



Procedure

Integrity of the drug in the formulation was checked by taking an IR spectrum of the

selected formulation along with the drug and other excipients. The spectra obtained

were compared using Shimadzu FTIR 8400 spectrophotometer. In this study

pelletization of potassium bromide (KBr) was employed. Crystals of potassium

bromide was completely dried at 100°C for 1 hr and was thoroughly mixed with the

sample in the ratio of 1 part of sample and 100 parts of KBr. The mixture was

compressed to form a disc using dies. This disc was placed in the sample chamber and

a spectrum was obtained through the software program which was further subjected to

interpretation.

4.2. STANDARD CALIBRATION CURVE OF METHYLDOPA

A simple, fast and precise UV spectrophotometric method for estimation of

methyldopa was carried out. A very dilute solution of the drug (100µg/ml) in 0.1N

HCl was subjected to UV scanning and the λmax was found to be 280 nm (Figure: 1).

Absorbance was read at 280 nm using 0.1N HCl as blank. Beer’s range was obeyed

between 2-20 µg/ml.

4.2.1. Preparation of stock solution

Accurately weighed 10 mg of methyldopa was dissolved in small amount of 0.1N HCl

and the volume was then made up to 100 ml with the same to obtain a concentration

of 100µg/ml.

4.2.2. Preparation of working standard solution

From the above solution aliquots of 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, and 2.0 ml

were transferred to a series of 10 ml volumetric flask and diluted up to the mark with



0.1N HCl. Absorbance was measured spectrophotometrically at 280nm against blank

using Shimadzu UV spectrophotometer.

4.3. FORMULATION OF FLOATING TABLETS

4.3.1. Study of hydrocolloids for buoyancy and matrix integrity39

:

Hydrophillic polymers such as HPMC, SCMC, ethyl cellulose, methyl cellulose,

carboxy methyl cellulose and carbopol were studied for buoyancy and matrix

integrity. 100 mg of each hydrocolloid was filled in a hard gelatin capsules (No.1) and

placed in beaker containing 100 ml of stimulated gastric fluid (pH 1.2) at room

temperature. Periodic observations were made for buoyancy and matrix integrity.

4.3.2. Optimization of polymer ratio:

On the basis of buoyancy studies and matrix integrity HPMC was selected and

optimized. Two grades of HPMC (K15M and K4M) were selected for the formulation

of floating tablets. Formulation H1 to H5 were prepared with different ratios of

HPMC K15M and HPMC K4M viz., 0.5:1, 1:0.5, 1:1, 1:1.5 and 1.5:1 respectively.

The prepared formulations were evaluated for the floating lag time and floating

duration. In all the formulations ascorbic acid (0.1%) was added as a stabilizer except

formulation H0.



Table 7: Optimization of ratio of polymers

Ingredients H0 H1 H2 H3 H4 H5

Methyldopa 250 250 250 250 250 250

HPMC K 15M 22.5 22.5 45 45 45 67.5

HPMC K 4M 45 45 22.5 45 67.5 45

Sodium bicarbonate 60 60 60 60 60 60

Ascorbic Acid (0.1%) - 0.4 0.4 0.4 0.4 0.4

Dicalcium Phosphate 16.5 16.1 16.1 - - -

Magnesium Stearate (0.5%) 2 2 2 2 2 2

Talc (1%) 4 4 4 4 4 4

Total wt of the tablet 400 400 400 406.4 428.9 428.9

* Weight in milligrams

4.3.3. Optimization of variables using factorial design40

:

A 32 randomized full factorial design was used in this study. Two factors were

evaluated, each at 3 levels, and experimental trials were performed at all 9 possible

combinations. The ratio of polymers HPMC K15M and HPMC K4M (X1) and the

amount of Sodium bicarbonate (X2) were selected as independent variables. The

floating lag time and in-vitro dissolution studies at 12 hrs were selected as dependent

variables.



Table 8: Optimized formulations prepared by 32 full factorial design

* Weight in milligrams

Step-wise backward linear regression analysis was used to develop polynomial equations

for the dependent variables by using PCP Disso 2000 V3 software. The validity of the

developed polynomial regression equations was verified by preparing check point

formulations (C1and C2), as shown in table 35.

Table 9: Factorial Design Batches of Methyldopa.

Variables

Batches

F1 F2 F3 F4 F5 F6 F7 F8 F9

X1 -1 -1 -1 0 0 0 +1 +1 +1

X2 -1 0 +1 -1 0 +1 -1 0 +1

Ingredient F1 F

2 F

3 F

4 F

5 F

6 F

7 F

8 F

9

Methyldopa 250 250 250 250 250 250 250 250 250

HPMC K15M 22.5 22.5 22.5 45 45 45 67.5 67.5 67.5

HPMC K4M 45 45 45 45 45 45 45 45 45

Sodium

bicarbonate 40 60 80 40 60 80 40 60 80

Di-calcium

phosphate 36.1 16.1 - 13.6 - - - - -

Ascorbic acid

(0.1%) 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4

Magnesium

stearate (0.5%) 2 2 2 2 2 2 2 2 2

Talc (1%) 4 4 4 4 4 4 4 4 4



Table 10: Coded Values and Actual Values for the Independent Variables.

Coded Values

Actual Values

X1 X2 (%)

–1 0.5:1 10

0 1:1 15

+1 1.5:1 20

A statistical model incorporating interactive and polynomial terms was used to

evaluate the response (Equation 1)41

.

Y = b0 + b1 X1 + b2 X2 + b12 X1 X2 + b11 X1 X1 + b22 X2 X2 …… 1

Where, Y is the response.

X1, X

2 are the levels (concentration) of the 1, 2, 3 factor.

b1, b

2, b

12, b

11, b

22 are the polynomial coefficient

b0

is the intercept (which represents the response when the level of all factors is low).

4.3.4. Method of preparation of tablets42

The floating tablets were prepared by direct compression method. Drug and the

selected polymers were accurately weighed and geometrically blended in a mortar and

pestle for 15 mins, then other excipients such as sodium bicarbonate, talc and

magnesium stearate were added. The mixed powder blend was passed through # 60

mesh. The powder was then subjected to pre-compressional evaluation such as angle

of repose, % compressibility, flow rate, etc. Tablets were compressed on a 10 station

rotary CIP tablet punching machine using 10 mm flat round punches to obtain tablets



weighing around 400mg. Finally the post-compressional evaluations such as hardness,

floating lag time, buoyancy, friability, weight variation, drug content, and in-vitro

release studies were carried out.

4.3.5. Coating of methyldopa floating tablets:

The prepared floating tablets were physically stabilized by applying a coating layer of

hydrophillic polymer by Dip coat method. The method involves dipping the tablet

vertically into the coating solution and then pulling out the tablet slowly at low speed.

The coated tablets were then dried to get uniformly coated tablets43,44

.

The coating solution was prepared by using HPMC 15cps as polymer,

methanol:dichloromethane in the ratio of 2:1 as solvent system and propylene glycol

as plasticizer. This mixture was then stirred. Prepared coating solution was then

applied to methyldopa tablets by dip coating method.

Table 11: Formula for coating solution

S.No. Ingredient Quantity

1. Hydroxy propyl methyl cellulose (15 cps) 8 gm

2. Propylene Glycol 2.4 ml

3. Methanol 90 ml

4. Dichloromethane 45ml



4.4. Pre-Compressional Evaluation parameters45,46

4.4.1. Bulk Density

It is a ratio of mass of powder to bulk volume. The bulk density depends on particle

size distribution, shape and cohesiveness of particles. Accurately weighed quantities

of powder mixture were poured into graduated measuring cylinder through large

funnel and volume was measured. The measuring cylinder was then tapped 3 times on

a hard surface from height of 2-3 inches at 2 second interval till a constant volume

was obtained.

It was expressed in gm/ml and given by

Bg

WgBD

where, BD = Bulk Density

Wg = Weight of granules

Bg = Bulk volume of granules

4.4.2. Carr’s Consolidation Index (% Compressibility)

Carr’s Index explains flow properties of the tablet powder. It is expressed in

percentage and given by

100Density Tapped

Density Untapped-Density TappedIndex ion Consolidat X



Table 12: Consolidation Index

S. No. Consolidation Index % Flow

1. 5 – 12 Excellent

2. 13 – 16 Good

3. 17 – 21 Fair

4. ≥ 40 Poor

4.4.3. Angle of Repose

It is defined as the maximum angle possible between the surface of the pile of the

powder and horizontal plane. To determine angle of repose fixed funnel method was

used. A funnel was fixed with its tip at a given height of 2 inches above a flat

horizontal surface to which a graph paper was placed. The powder blend was

carefully poured through a funnel till the apex of the conical pile just touches the tip

of the funnel. The ‘r’ was calculated from the circumference obtained on the graph. θ

was then calculated using the formula

Tan θ = h/r

where,

θ = Angle of Repose

h = Height of Pile

r = Radius of the base of the pile



Table 13: Angle of Repose

S. No. Angle of Repose ( 0 ) Flow

1. < 25 Excellent

2. 25 – 30 Good

3. 30 – 40 Fair

4. > 40 Poor

4.5. Post-Compressional Evaluation

4.5.1. Hardness

The Pfizer hardness tester was used to determine the tablet hardness. The tablet was

held between affixed and moving jaw. Scale was adjusted to zero; pressure was

gradually increased until the tablet fractured. The pressure at that point gives the

measure of the hardness of tablet. Hardness was expressed in Kg/ cm2.

4.5.2. Friability

Friability was determined using Roche Friabilator. Twenty tablets were weighed (W)

and placed in the friabilator and then operated at 25 rpm for four mins. The tablets

were then dedusted and weighed (W0). Friability limit should be < 1%.

The difference in the two weights is used to calculate friability.

)1(1000W

WXFriability

where,

W0 = Initial weight

W = Final weight



4.5.3. Weight Variation Test

Twenty tablets were weighed individually and average weight was calculated. The

individual weights were then compared with average weight. The tablet passes the test

if not more than two tablets fall outside the percentage limit and none of tablet differ

by more than double percentage limit.

100XW

WWPD

avg

indavg

where, PD = Percentage Deviation

Wavg = Average Weight of Tablet

Wind = Individual Weight of Tablet

Table 14: Weight Variations

S. No. Average Weight % Deviation

1. 0.12g or less ± 10

2.

More than 0.12g but less than

0.3g

± 7.5

3. 0.3g or more ± 5

4.5.4. Drug Content

Drug content was determined to check dose uniformity in the formulations. 10 tablets

were randomly selected, weighed and powdered. A quantity equivalent to 100 mg of

methyldopa was added in to a 100 ml volumetric flask and dissolved in distilled water

and made up the volume and filtered. An aliquot of 10 ml was pipetted out into 100



ml volumetric flask and made up the volume with distilled water. Absorbance was

read at 280nm using distilled water as a blank.

4.5.5. Buoyancy studies47,48

The time taken by the tablet to emerge on to the surface of the medium is called the

floating lag time and the total time for which the tablet floats on the media surface is

the buoyancy time. Buoyancy studies were carried out in glass beakers containing

100ml of 0.1N HCl. Lag time and floating time were noted. (Table: 21 and 22)

4.5.6. Swelling Index49

Swelling of hydrophilic polymer such as HPMC greatly depends upon the contents of

the stomach and the osmolarity of the medium. These eventually influence the release,

slowing action and the residence time. The swelling index of tablets was determined

in 0.1N HCl at room temperature by gravimetric method. The swollen weight of the

tablet was determined at predefined time intervals over a period of 24 hrs. The

swelling index was calculated using following formula

100 W

W-WIndex Swelling

0

0i X

Where,

W1=Weight of dry tablet,

W0= Weight of swollen tablet

4.5.7. In-vitro Release studies

In-vitro release studies were carried out in USP XXIII dissolution test apparatus Ι

using pH 1.2 buffer as dissolution medium at 370 ± 0.5

0C and rotational speed of 75



rpm for 24 hrs. 5 ml of sample was withdrawn at different time intervals and 1 ml was

taken, volume made up to 10 ml with 0.1N HCl and then estimated

spectrophotometrically at 280nm against blank treated in similar manner.

Dissolution mechanism of the formulations was analyzed by plotting drug release

versus time plot.

4.6. Data Analysis50

:

The results of in-vitro release studies obtained for F1 to F9 were analyzed by

following models

4.6.1. Zero Order Kinetics: A zero-order release would be predicted by the

following equation.

At = A

0 – K

0t …1

Where:

At = Drug release at time ‘t’

A0

= Initial drug concentration

K0

= Zero-order rate constant (hr-1

).

When the data is plotted as cumulative percent drug release versus time, if the plot is

linear then the data obeys zero-order release kinetics, with a slope equal to K0.

4.6.2. First Order Kinetics: A first-order release would be predicted by the

following equation

Log C = Log C0

– 303.2Kt …2

Where,

C = Amount of drug remained at time ‘t’



C0

= Initial amount of drug

K = First-order rate constant (hr-1

).

When the data is plotted as log cumulative percent drug remaining versus time yields

a straight line, indicating that the release follows first-order kinetics. The constant ‘K’

can be obtained by multiplying 2.303 with slope values.

4.6.3. Peppas Model

In order to understand the mode of release of drug from swellable matrices, the data

were fitted to the following equation

Ktn M

Mt....3

Where,

Mt / Mσ = the fraction of drug released at time t.

K = Constant incorporating the structural and geometrical

characteristics of the drug / polymer system.

n = Diffusion exponent related to mechanism of the release.

Above equation can be simplified by applying Log on both sides, we get.

tLogn K Log M

MtLog

When the data is plotted as log of drug released versus log time, yield a straight line

with a slope equal to n and k can be obtained from Y- intercept.

4.7. Erosion studies51

: Erosion studies for the best formulation F3 were performed

using the method described by Reynold et al. Weighed tablets (H1) were taken in



basket and placed in dissolution flask, containing 900ml of acidic buffer (pH 1.2) at

37⁰C. At different time intervals tablets were withdrawn and the wet tablets were

dried in an oven at 40⁰C until constant mass was achieved, then placed in desiccators

and finally weighed as residual weight (H2). The degree of erosion is calculated using

the formula,

Percentage Erosion = 100 (H1 – H2) /H1

Where,

H1=Initial weight of tablet,

H2= Residual weight of tablet

4.8. DRUG-FORMULATION COMPATIBILITY STUDIES

Excipients are integral components of almost all pharmaceutical dosage forms. The

successful formulation of a stable and effective dosage form depends not only on the

careful selection of the excipients but also on the formulation process which includes

temperature effect, compression force effects etc. Pure drug and best formulation

were subjected to Differential scanning colorimetry and FTIR to check if there is any

interaction.

4.8.1. Differential Scanning Calorimetry

DSC is a thermo analytical technique in which the difference in the amount of heat

required to increase the temperature of a sample and reference are measured as a

function of temperature. Both the sample and reference are maintained at nearly same

temperature throughout the experiment



Figure3: Schematic diagram of DSC.

Procedure:

DSC (Perkin-Elmer Thermal Analysis) experiments were carried out in order to

characterize the physical state of the drugs. Samples of formulation were placed in

aluminium pans and thematically sealed. The heating rate was 10°C per min using

nitrogen as the purge gas. The DSC instrument was calibrated for temperature using

Indium. In addition, for enthalpy calibration Indium was sealed in aluminium pans

with sealed empty pan as a reference.

4.9. Stability Studies52

Stability is defined as the extent to which a product retains the contents within

specified limit and throughout its period of storage and use i.e. shelf life, the same

properties that it possesses at the time of manufacture. These studies were designed to

increase the rate of chemical or physical degradation of the drug substance or product

by using accelerated storage conditions.



4.8.1. Method:

Selected formulations and pure drug were stored at RT and accelerated conditions

(45⁰C, 75% RH) for 3 months in Newtronic, Temperature / humidity control oven

NEC 210R10. The samples were withdrawn at monthly intervals and drug content

was analyzed spectrophotometrically for methyldopa at 280nm. Physical changes,

buoyancy lag time and drug content were observed.

Chapter 5 Results

Al-Ameen College Of Pharmacy, Bangalore. Page 67

RESULTS

5.1 Preformulation Studies

5.1.1 Compatibility Analysis

FTIR studies conducted on pure drug and physical mixtures showed that there is no

marked interaction between drugs and selected polymers.

IR spectra of pure drug and physical mixtures are shown in Figure 4 to Figure 5.

Figure 4: IR spectra of pure drug.

Figure 5: IR spectra of physical mixture.

500 750 1000 1250 1500 1750 2000 2500 3000 3500

4000 1/c

m

-20

-10

0

10

20

30

40

50

60 %T

3477.42 3477.42 3215.11

2941.24 2839.02

2584.44

2365.53

2048.26

1884.32

1643.24

1527.52 1447.48 1402.1

5 1287.40

F5

500 750 1000 1250 1500 1750 2000 2500 3000 3500 4000 1/cm

5

10

15

20

25

30

35 %T

3478.38 3214.15

3054.07

2583.47

2048.26

1643.24

1527.52 1487.98 1401.19

1371.29 1287.40 1253.64 1211.21

F6

Chapter 5 Results


5.1.2 Standard graph of Methyldopa by UV-Visible spectrophotometry:

A simple, fast and precise UV spectrophotometric method for estimation of

methyldopa was carried out. Absorbance was read at 280 nm using 0.1N HCl as

blank. Beer’s range was obeyed between 2-20 µg/ml.

Table 15: Standard graph of Methyldopa by UV-Visible spectrophotometry

S.No

Concentration

(μg/ml)

Absorbance *Average

absorbance 1 2 3

1 2 0.024 0.023 0.024 0.0236±0.0005

2 4 0.046 0.042 0.047 0.045±0.0026

3 6 0.068 0.069 0.067 0.068±0.001

4 8 0.091 0.089 0.091 0.0903±0.0011

5 10 0.11 0.112 0.111 0.111±0.001

6 12 0.138 0.135 0.137 0.1366±0.0015

7 14 0.159 0.159 0.161 0.1596±0.0011

8 16 0.179 0.177 0.176 0.1773±0.0015

9 18 0.201 0.2 0.201 0.2006±0.0005

10 20 0.229 0.227 0.228 0.228±0.001

*n=3

Chapter 5 Results


Figure 6: Standard graph of Methyldopa UV Spectrophotometry

5.2. Formulation of Tablets

5.2.1. Study of hydrocolloids for buoyancy and matrix integrity:

Hydrocolloids were selected based on their property of buoyancy and retention of

matrix integrity as shown in (Table 16)

Table 16: Selection of hydrocolloids

Sl. No. Polymer Floating Time (hrs)

Buoyancy

Matrix Integrity

1. MC 6 hours +++

2. SCMC 20 hours +++

3. HPMC (K4M) 24 hours ++++

4. HPMC (K15M) 30 hours ++++

5. EC 3 hours ++

6. CMC 4 hours +++

7. Carbopol 8 hours +++

++++ = Excellent +++ = Good ++ = Not good + = Poor

y = 0.011xR² = 0.999

0

0.05

0.1

0.15

0.2

0.25

0 5 10 15 20 25

Concentration (μg/ml)

Ab

sorb

ance

Chapter 5 Results


5.2.2. Optimization of ratio of polymers:

On the basis of buoyancy studies and matrix integrity of hydrocolloids, two grades of

HPMC (K15M and K4M) were selected for further studies. In order to optimize the

ratio of two hydrocolloids 6 different formulations viz H0 to H5 were prepared and

evaluated for floating time and buoyancy.

Table 17: Evaluation of prepared batches of trial formulations

Formulation Code Floating lag time(sec) Buoyancy(hrs)

H0 100 24

H1 85 24

H2 120 24

H3 80 24

H4 110 24

H5 90 24

Optimization of variables using factorial design:

A 32 randomized full factorial design was used in this study. Two factors were

evaluated, each at 3 levels, and experimental trials were performed at all 9 possible

combinations. The ratio of polymers HPMC K15M and HPMC K4M (X1) and the

amount of Sodium bicarbonate (X2) were selected as independent variables. Based on

factorial design, nine different formulations were prepared and evaluated.

Chapter 5 Results


5.3. Pre Compressional Evaluation Parameters:

The powder blend of the nine optimized formulations (F1 to F9) was evaluated for the

flow properties such as untapped, tapped density, % compressibility and angle of

repose.

Table 18: Evaluation of flow properties of tablet blend:

Sl.No Formulation

code

*Untapped

density (g/cc)

*Tapped

density (g/cc)

*%

Compressibility *Angle of repose

1 F1 0.361 ± 0.003 0.419 ± 0.005 13.85 ± 0.983 20⁰24' ± 0.9529

2 F2 0.387 ± 0.004 0.438 ± 0.005 11.61 ± 0.130 21⁰09' ± 0.2663

3 F3 0.402 ± 0.004 0.458 ± 0.006 12.08 ± 0.141 22⁰36' ± 0.3751

4 F4 0.270 ± 0.003 0.287 ± 0.002 5.85 ± 0.707 20⁰42' ± 0.3137

5 F5 0.300 ± 0.006 0.322 ± 0.005 6.98 ± 0.726 22⁰13' ± 0.3525

6 F6 0.335 ± 0.003 0.372 ± 0.004 10.05 ± 0.979 22⁰42' ± 0.3213

7 F7 0.372 ± 0.004 0.419 ± 0.005 11.18 ± 0.121 22⁰20' ± 0.5250

8 F8 0.379 ± 0.004 0.413 ± 0.004 8.22 ± 1.050 22⁰09' ± 0.6438

9 F9 0.355 ± 0.003 0.397 ± 0.004 10.65 ± 0.108 21⁰63' ± 0.254

*n=3

Chapter 5 Results


5.4. Post compressional evaluation parameters: The tablets were prepared by direct

compression method using 10 station rotary CIP tablet punching machine using 10

mm flat round punches. The prepared floating tablets were evaluated for hardness,

friability, drug content, lag time and buoyancy.

Table 19: Post compressional evaluation parameters

*n=3

5.4.1. Swelling Index: The swelling index of tablets was determined in 0.1N HCl at

room temperature by gravimetric method. The swollen weight of the tablet was

determined at predefined time intervals over a period of 24 hrs. The results for

swelling index are shown in the table no 20 and figure 7 to 9.

Formulation

Code

*Hardness

Kg/cm2

*Friability

(%)

*Avg wt (mg)

± SD

*Drug

content

%

*Lag

time

(sec)

*Buoyancy

(hrs)

F1 2.62 0.55 401.06 ± 0.996 96.83 105 24

F2 3.20 0.61 399.12 ± 0.621 97.09 85 24

F3 2.71 0.68 402.34 ± 0.544 97.57 45 24

F4 2.93 0.53 401.08 ± 0.875 96.15 150 24

F5 3.00 0.65 404.64 ± 1.003 95.07 80 24

F6 2.86 0.69 421.50 ± 0.752 94.49 60 24

F7 2.59 0.57 405.31 ± 0.703 95.42 200 24

F8 3.1 0.62 423.04 ± 0.348 95.78 90 24

F9 3.12 0.64 446.11± 0.817 96.55 80 24

Chapter 5 Results


Table 20: Swelling index of optimized formulations (F1 to F9)

Formulation

code Swelling Index (%)

0.25 hr 0.5 hr 1 hr 2 hr 3 hr 6 hr 10 hr 12 hr 24 hr

F1 47.5 95 107.5 125 140 145 157.5 180 210

F2 50 95 105 120 142.5 165 177.5 200 275

F3 58.5 95.1 107.3 121.9 139 160.9 165.9 187.8 253.7

F4 47.5 105 120 135 150 157.5 182.5 202.5 272.5

F5 51.3 97.4 112.8 138.5 151.3 156.4 169.2 184.6 284.6

F6 58.9 107.7 117.9 133.3 151.3 158.9 174.4 182.1 287.2

F7 45 110 122.5 145 155 180 197.5 222.5 322.5

F8 46.2 125.6 141.0 158.9 169.2 176.9 197.4 212.8 366.7

F9 46.2 107.7 123 143.6 161.5 182 192.3 235.9 335.9

*n=3

Chapter 5 Results


Figure 7: Comparison graph for Swelling Index of F1 to F3


0

50

100

150

200

250

300

0 5 10 15 20 25 30

F1

F2

F3

SI

0

50

100

150

200

250

300

350

0 5 10 15 20 25 30

F4

F5

F6

Chapter 5 Results



5.4.2. In-vitro drug release: In-vitro release studies were carried out in USP XXIII

dissolution test apparatus Ι using pH 1.2 buffer as dissolution medium at 370 ± 0.5

0C

and rotational speed of 75 rpm for 24 hrs. The dissolution profiles for the nine

formulations are shown in the tables 21 to 29 and figures 10 to 12.

0

50

100

150

200

250

300

350

400

0 5 10 15 20 25 30

F7

F8

F9

Chapter 5 Results


Table 21: Dissolution Profile for F1:

Time(hrs) Absorbance

at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration

in 900ml Loss in 5ml

Cummulative

loss

Amount

release *% CPR

0.5 0.0255 2.276786 22.76786 20491.07 0 0 20.49107 8.196429

1 0.0345 3.080357 30.80357 27723.21 113.8393 113.8393 27.83705 11.13482

2 0.0625 5.580357 55.80357 50223.21 154.0179 267.8571 50.49107 20.19643

3 0.078 6.964286 69.64286 62678.57 279.0179 546.875 63.22545 25.29018

4 0.105 9.375 93.75 84375 348.2143 895.0893 85.27009 34.10804

5 0.12 10.71429 107.1429 96428.57 468.75 1363.839 97.79241 39.11696

6 0.146 13.03571 130.3571 117321.4 535.7143 1899.554 119.221 47.68839

8 0.168 15 150 135000 651.7857 2551.339 137.5513 55.02054

10 0.208 18.57143 185.7143 167142.9 750 3301.339 170.4442 68.17768

12 0.231 20.625 206.25 185625 928.5714 4229.911 189.8549 75.94196

18 0.262 23.39286 233.9286 210535.7 1031.25 5261.161 215.7969 86.31875

24 0.277 24.73214 247.3214 222589.3 1169.643 6430.804 229.0201 91.60804

*n=3

Chapter 5 Results



Time (hrs) Absorbance

at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration


Cummulative

loss

Amount

release *% CPR

0.5 0.0315 2.8125 28.125 25312.5 0 0 25.3125 10.125

1 0.043 3.839286 38.39286 34553.57 140.625 140.625 34.6942 13.87768

2 0.069 6.160714 61.60714 55446.43 191.9643 332.5893 55.77902 22.31161

3 0.093 8.303571 83.03571 74732.14 308.0357 640.625 75.37277 30.14911

4 0.123 10.98214 109.8214 98839.29 415.1786 1055.804 99.89509 39.95804

5 0.147 13.125 131.25 118125 549.1071 1604.911 119.7299 47.89196

6 0.164 14.64286 146.4286 131785.7 656.25 2261.161 134.0469 53.61875

8 0.21 18.75 187.5 168750 732.1429 2993.304 171.7433 68.69732

10 0.239 21.33929 213.3929 192053.6 937.5 3930.804 195.9844 78.39375

12 0.253 22.58929 225.8929 203303.6 1066.964 4997.768 208.3013 83.32054

18 0.272 24.28571 242.8571 218571.4 1129.464 6127.232 224.6987 89.87946

24 0.288 25.71429 257.1429 231428.6 1214.286 7341.518 238.7701 95.50804

*n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration

in 900ml Loss in 5ml Cummulative loss

Amount

release *% CPR

0.5 0.05 4.464286 44.64286 40178.57 0 0 40.17857 12.345

1 0.066 5.892857 58.92857 53035.71 223.2143 223.2143 53.25893 18.0987

2 0.082 7.321429 73.21429 65892.86 294.6429 517.8571 66.41071 26.56429

3 0.098 8.75 87.5 78750 366.0714 883.9286 79.63393 31.85357

4 0.127 11.33929 113.3929 102053.6 437.5 1321.429 103.375 41.35

5 0.153 13.66071 136.6071 122946.4 566.9643 1888.393 124.8348 49.93393

6 0.176 15.71429 157.1429 141428.6 683.0357 2571.429 144 57.6

8 0.21 18.75 187.5 168750 785.7143 3357.143 172.1071 68.84286

10 0.238 21.25 212.5 191250 937.5 4294.643 195.5446 78.21786

12 0.271 24.19643 241.9643 217767.9 1062.5 5357.143 223.125 89.25

18 0.285 25.44643 254.4643 229017.9 1209.821 6566.964 235.5848 94.23393

24 0.296 26.42857 264.2857 237857.1 1272.321 7839.286 245.6964 98.27857

* n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration

in 900ml

Loss in

5ml

Cummulative

loss

Amount

release *% CPR

0.5 0.03 2.678571 26.78571 24107.14 0 0 24.10714 9.642857

1 0.037 3.303571 33.03571 29732.14 133.9286 133.9286 29.86607 11.94643

2 0.055 4.910714 49.10714 44196.43 165.1786 299.1071 44.49554 17.79821

3 0.078 6.964286 69.64286 62678.57 245.5357 544.6429 63.22321 25.28929

4 0.094 8.392857 83.92857 75535.71 348.2143 892.8571 76.42857 30.57143

5 0.114 10.17857 101.7857 91607.14 419.6429 1312.5 92.91964 37.16786

6 0.13 11.60714 116.0714 104464.3 508.9286 1821.429 106.2857 42.51429

8 0.157 14.01786 140.1786 126160.7 580.3571 2401.786 128.5625 51.425

10 0.195 17.41071 174.1071 156696.4 700.8929 3102.679 159.7991 63.91964

12 0.209 18.66071 186.6071 167946.4 870.5357 3973.214 171.9196 68.76786

18 0.237 21.16071 211.6071 190446.4 933.0357 4906.25 195.3527 78.14107

24 0.270 24.10714 241.0714 216964.3 1058.036 5964.286 222.9286 89.17143

*n=3

Chapter 5 Results



Time

(hrs)

Absorbance

at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration

in 900ml

Loss in

5ml

Cummulative

loss

Amount

release *% CPR

0.5 0.033 2.946429 29.46429 26517.86 0 0 26.51786 10.60714

1 0.064 5.714286 57.14286 51428.57 147.3214 147.3214 51.57589 20.63036

2 0.081 7.232143 72.32143 65089.29 285.7143 433.0357 65.52232 26.20893

3 0.096 8.571429 85.71429 77142.86 361.6071 794.6429 77.9375 31.175

4 0.112 10 100 90000 428.5714 1223.214 91.22321 36.48929

5 0.135 12.05357 120.5357 108482.1 500 1723.214 110.2054 44.08214

6 0.163 14.55357 145.5357 130982.1 602.6786 2325.893 133.308 53.32321

8 0.189 16.875 168.75 151875 727.6786 3053.571 154.9286 61.97143

10 0.213 19.01786 190.1786 171160.7 843.75 3897.321 175.058 70.02321

12 0.231 20.625 206.25 185625 950.8929 4848.214 190.4732 76.18929

18 0.256 22.85714 228.5714 205714.3 1031.25 5879.464 211.5938 84.6375

24 0.278 24.82143 248.2143 223392.9 1142.857 7022.321 230.4152 92.16607

*n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration


Cummulative

loss

Amount

release *% CPR

0.5 0.021 1.875 18.75 16875 0 0 16.875 6.75

1 0.026 2.321429 23.21429 20892.86 93.75 93.75 20.98661 8.394643

2 0.031 2.767857 27.67857 24910.71 116.0714 209.8214 25.12054 10.04821

3 0.045 4.017857 40.17857 36160.71 138.3929 348.2143 36.50893 14.60357

4 0.071 6.339286 63.39286 57053.57 200.8929 549.1071 57.60268 23.04107

5 0.111 9.910714 99.10714 89196.43 316.9643 866.0714 90.0625 36.025

6 0.129 11.51786 115.1786 103660.7 495.5357 1361.607 105.0223 42.00893

8 0.189 16.875 168.75 151875 575.8929 1937.5 153.8125 61.525

10 0.227 20.26786 202.6786 182410.7 843.75 2781.25 185.192 74.07679

12 0.247 22.05357 220.5357 198482.1 1013.393 3794.643 202.2768 80.91071

18 0.263 23.48214 234.8214 211339.3 1102.679 4897.321 216.2366 86.49464

24 0.285 25.44643 254.4643 229017.9 1174.107 6071.429 235.0893 94.03571

*n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration


Amount

release *% CPR

0.5 0.015 1.339286 13.39286 12053.57 0 0 12.05357 4.821429

1 0.019 1.696429 16.96429 15267.86 66.96429 66.96429 15.33482 6.133929

2 0.022 1.964286 19.64286 17678.57 84.82143 151.7857 17.83036 7.132143

3 0.04 3.571429 35.71429 32142.86 98.21429 250 32.39286 12.95714

4 0.048 4.285714 42.85714 38571.43 178.5714 428.5714 39 15.6

5 0.072 6.428571 64.28571 57857.14 214.2857 642.8571 58.5 23.4

6 0.111 9.910714 99.10714 89196.43 321.4286 964.2857 90.16071 36.06429

8 0.132 11.78571 117.8571 106071.4 495.5357 1459.821 107.5313 43.0125

10 0.147 13.125 131.25 118125 589.2857 2049.107 120.1741 48.06964

12 0.162 14.46429 144.6429 130178.6 656.25 2705.357 132.8839 53.15357

18 0.214 19.10714 191.0714 171964.3 723.2143 3428.571 175.3929 70.15714

24 0.267 23.83929 238.3929 214553.6 955.3571 4383.929 218.9375 87.575

*n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration


Amount

release *% CPR

0.5 0.013 1.160714 11.60714 10446.43 0 0 10.44643 4.178571

1 0.031 2.767857 27.67857 24910.71 58.03571 58.03571 24.96875 9.9875

2 0.042 3.75 37.5 33750 138.3929 196.4286 33.94643 13.57857

3 0.073 6.517857 65.17857 58660.71 187.5 383.9286 59.04464 23.61786

4 0.084 7.5 75 67500 325.8929 709.8214 68.20982 27.28393

5 0.115 10.26786 102.6786 92410.71 375 1084.821 93.49554 37.39821

6 0.149 13.30357 133.0357 119732.1 513.3929 1598.214 121.3304 48.53214

8 0.169 15.08929 150.8929 135803.6 665.1786 2263.393 138.067 55.22679

10 0.196 17.5 175 157500 754.4643 3017.857 160.5179 64.20714

12 0.229 20.44643 204.4643 184017.9 875 3892.857 187.9107 75.16429

18 0.252 22.5 225 202500 1022.321 4915.179 207.4152 82.96607

24 0.273 24.375 243.75 219375 1125 6040.179 225.4152 90.16607

*n=3

Chapter 5 Results




at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration


Amount

release *% CPR

0.5 0.021 1.875 18.75 16875 0 0 16.875 6.75

1 0.028 2.5 25 22500 93.75 93.75 22.59375 9.0375

2 0.048 4.285714 42.85714 38571.43 125 218.75 38.79018 15.51607

3 0.079 7.053571 70.53571 63482.14 214.2857 433.0357 63.91518 25.56607

4 0.101 9.017857 90.17857 81160.71 352.6786 785.7143 81.94643 32.77857

5 0.146 13.03571 130.3571 117321.4 450.8929 1236.607 118.558 47.42321

6 0.163 14.55357 145.5357 130982.1 651.7857 1888.393 132.8705 53.14821

8 0.194 17.32143 173.2143 155892.9 727.6786 2616.071 158.5089 63.40357

10 0.224 20 200 180000 866.0714 3482.143 183.4821 73.39286

12 0.232 20.71429 207.1429 186428.6 1000 4482.143 190.9107 76.36429

18 0.246 21.96429 219.6429 197678.6 1035.714 5517.857 203.1964 81.27857

24 0.281 25.08929 250.8929 225803.6 1098.214 6616.071 232.4196 92.96786

*n=3

Chapter 5 Results


Figure 10: Comparison Graph for dissolution profile of F1 to F3


0

20

40

60

80

100

120

0 5 10 15 20 25 30

F1

F2

F3

Time(hrs)

%C

PR

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30

F4

F5

F6

Chapter 5 Results



5.4.3. Mathematical modelling of in-vitro release kinetics:

The results of in-vitro release studies obtained for F1 to F9 were subjected to

mathematical modelling using different models such as zero order, first order, Matrix,

Hixson crowell and Korsemeyer- Peppas model. The results are shown in table 30 and

31.

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30

F7

F8

F9

Chapter 5 Results


Table 30: Release kinetics of floating tablets of Methyldopa:

Formula

tion

Code

Matrix Zero-order First-order Korsemeyer-Peppas Hixson Crowell

cube root law Best fit model

Slope R2

Slope R2

Slope R2

n Slope R2

Slope R2

F1 20.9642 0.9912 3.9278 0.9567 -0.0457 0.9955 0.6798 0.6798 0.9980 -0.1124 0.9947 Korsemeyer-Peppas









Chapter 5 Results


Table 31: Comparison of Dissolution efficiency, % Drug release, Mean

Dissolution time and T 50% and T90% drug release of the optimised

formulations.

Formulation Code % DE24hrs % R24hrs MDT T50% T90%

F1 62.44 91.608 7.66 8 24

F2 60.85 95.508 9.23 8 18

F3 65.95 98.278 7.95 5 12

F4 50.00 89.171 8.65 8 24

F5 47.68 92.166 9.80 7 22

F6 62.21 94.035 7.98 7 20

F7 62.77 87.575 7.78 11 > 24

F8 42.27 90.166 8.94 6 24

F9 43.06 92.967 9.12 6 24

Where %DE24hrs = Dissolution efficiency at 24hrs, %R24hrs = Percent drug

released at 24hrs, MDT= Mean dissolution time, T50% (hrs) = Time taken for 50%

drug released and T90% (hrs) = Time taken for 90% drug release.

5.4.4. Erosion studies for formulation F3:

On the basis of swelling studies and in-vitro release studies F3 was further evaluated

for various parameters viz, erosion studies, drug-polymer interaction and stability

studies.

Chapter 5 Results


Table 32: Result of erosion study of the formulation F3

S.No Time (hrs) Initial wt Residual wt *% Erosion

1 1 0.4 0.38 5

2 2 0.4 0.35 12.5

3 3 0.4 0.31 22.5

4 6 0.41 0.27 34.14

5 8 0.41 0.21 48.78

6 10 0.39 0.17 56.41

7 12 0.4 0.09 77.5

8 24 0.41 0.06 85.36

*n=3

Figure 13: Graph for erosion study of the formulation F3.

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

%erosion

Time(hrs)

% E

rosi

on

Chapter 5 Results


5.4.5. Comparison of the marketed formulation (Alphadopa) with the final formulation F3:

Table 33: Dissolution for the Marketed formulation

Time

(hrs)

Absorbance

at 280nm

Concentration

(μg/ml)

Concentration

in 10ml

Concentration

in 900ml

Loss in

5ml

Cummulative

loss

Amount

release

*% CPR

5 0.221 19.73214 197.3214 177589.3 0 0 177.5893 71.03571

10 0.269 24.01786 240.1786 216160.7 98.66071 98.66071 216.2594 86.50375

15 0.309 27.58929 275.8929 248303.6 120.0893 218.75 248.5223 99.40893

*n=3

Chapter 5 Results


Figure 14: Comparison Graph for dissolution profile of marketed formulation

and F3

5.5. Results of Optimization by 32 full factorial design:

Figure 15: Response surface plot showing effect of factorial variables on floating

lag time.

0

20

40

60

80

100

120

0 5 10 15 20 25 30

F3

marketed formulation

% C

PR

Time

1

0.5

0-0.5

-1

1

0.50

-0.5-1

0

20

40

60

80

100

120

140

160

180

200Y

1

Polymer Ratio Amount of

Gasgenerating Agent

180-200

160-180

140-160

120-140

100-120

80-100

60-80

40-60

20-40

0-20

Chapter 5 Results


Figure 16: Response surface plot showing effect of factorial variables on drug

release at 12 hrs.

Table 34: Evaluation parameters for the check points C1 and C2

Batch Code

Variable

level in coded

form

Drug release at 12hrs

(%CPR) Floating lag time

X1 X2 Actual

value

Predicted

value

Actual

value

Predicted

value

*C1 +0.5 +0.5 72.42 74.67 89 93

*C2 -0.5 -0.5 74.17 73.62 75 77

*C1& C

2 check point batches.

X1

(Polymer ratio): –0.5= 0.75:1, +0.5= 1.25:1,

X2(Gas generating agent): –0.5= 12.5%, +0.5= 17.5%

All the batches contained 250 mg of methyldopa, 1% talc and 0.5% magnesium

stearate.

1 0.5 0 -0.5 -1

1

0.4

-0.2

-0.80

10

20

30

40

50

60

70

80

90

100

Y1

Polymer ratio

Gas generating

Agent

90-100

80-90

70-80

60-70

50-60

40-50

30-40

20-30

10-20

0-10

Chapter 5 Results


5.6. DRUG-FORMULATION COMPATIBILITY STUDIES:

5.6.1. FTIR: FTIR studies conducted on pure drug, physical mixture and final

formulation F3 showed that there is no marked interaction between drugs and selected

polymers. IR spectra of pure drug and physical mixtures are shown in Figure 17 to 19.

Figure 17: F Figure 18: FTIR for physical mixture

Figure 18: FTIR for physical mixture

Figure 17: FTIR for pure drug

Figure 18: FTIR for physical mixture

500 750 1000 1250 1500 1750 2000 2500 3000 3500 4000 1/cm

-20

-10

0

10

20

30

40

50

60

%T

3477.42 3477.42 3215.11

2941.24 2839.02

2584.44

2365.53

2048.26

1884.32

1643.24 1527.52

1447.48 1402.15

1287.40

F5

500 750 1000 1250 1500 1750 2000 2500 3000 3500 4000 1/cm

5

10

15

20

25

30

35

%T

3478.38 3214.15

3054.07

2583.47

2048.26

1643.24

1527.52 1487.98 1401.19

1371.29 1287.40

1253.64 1211.21

F6

Chapter 5 Results


Figure 19: FTIR for final formulation

5.6.2. Differential Scanning Colorimetery:

Figure 20: DSC graph for the pure drug

500

750

1000

1250

1500

1750

2000

2500

3000

3500

4000 1/c

m

10

15

20

25

30

3

5

40

3477.42 3396.4

1

3216.08

2918.1

0

2850.5

9

2585.40

2363.60

2048.2

6

1643.24

1488.94

1403.12

1375.1

5 1287.4

0

1214.11

1123.46

F7

Chapter 5 Results


Figure 21: DSC for physical mixture

Figure 22: DSC for the final formulation F3

Chapter 5 Results


5.7. Stability studies:

Stability studies for best formulation were carried out. Physical and chemical stability

was determined for a period of 3 months. No significant changes were observed in the

physical appearance, lag time and drug content of the formulations kept both at RT

and accelerated conditions (45⁰C, 75% RH) for 3 months.

Chapter 5 Results


Table 35: Stability data for the final formulation F3

*n=3

*Physical appearance *Drug content (%) *Lag time (secs)

0

1st

month

2nd

month

3rd

month

0 1st month

2nd

month

3rd

month

0

1st

month

2nd

month

3rd

month

Storage at

45⁰C, RH

75%

No

change

No

change

No

change

No

change

97.43 ±

0.134

97.06 ±

0.112

96.65 ±

0.094

96.32 ±

0.013

45 ±

0.165

46 ±

0.234

50 ±

0.220

58 ±

0.172

Room

temperature

No

change

No

change

No

change

No

change

97.52 ±

0.097

96.89 ±

0.129

95.75 ±

0.237

95.22 ±

0.065

50±

0.221

49±

0.307

56 ±

0.213

60 ±

0.313

Chapter 5 Results


Figure 23: In-Vitro Buoyancy studies of the Best formulation F3:

a) Zero secs b) 45 sec

Chapter 6 Discussion


DISCUSSION

6.1. Selection of Drug:

In the present study an attempt was been made to formulate and evaluate floating

tablets of Methyldopa. Methyldopa is an anti hypertensive agent widely used in the

treatment of gestational hypertension as it showed no toxicity to the mother and

foetus. It is a competitive inhibitor of the enzyme DOPA decarboxylase which

converts L-DOPA into dopamine, and subsequently norepinephrine and epinephrine.

Methyldopa shows variable absorption throughout the GIT. It has a bioavailability of

50%, plasma half life of 1-2 hrs and largely excreted through urine by glomerular

filtration.

6.2. Selection of Dosage form:

Gastro retentive dosage forms have potential for use as controlled release drug

delivery systems. The use of floating dosage form is one method to achieve prolonged

gastric residence time, providing opportunity for both local and systemic drug action.

The floating tablets of Methyldopa were prepared to increase its gastric retention,

improve absorption and sustain the drug release.

6.3. Screening of polymers:

Hydrophilic polymers such as HPMC, SCMC, ethyl cellulose, methyl cellulose,

carboxy methyl cellulose and carbopol were studied for buoyancy and matrix

integrity. The polymers which showed the best buoyancy and matrix integrity were

selected for further studies.

http://en.wikipedia.org/wiki/Enzyme

http://en.wikipedia.org/wiki/DOPA_decarboxylase

http://en.wikipedia.org/wiki/L-DOPA

http://en.wikipedia.org/wiki/Dopamine

http://en.wikipedia.org/wiki/Epinephrine



Formulation of the floating tablets:

On the basis of polymer screening HPMC viz., K4M and K15M were selected for the

formulation of floating tablets. Six different formulations (H0 to H5) were prepared

using varying ratios of polymer combination (K4M and K15M) and a gas generating

agent such as Sodium bi-carbonate. The floating tablets were prepared by direct

compression method. The formulation H0 prepared without ascorbic acid showed

pink colouration due to atmospheric oxidation of the drug which was overcome by

incorporation of ascorbic acid in the remaining five formulations H1 to H5.

Optimization was been carried out using 3² full factorial design after evaluating the

preliminary data obtained from six batches of formulations (H0 to H5). The ratio of

polymers HPMC K15M and HPMC K4M (X1) and the amount of Sodium

bicarbonate (X2) were selected as independent variables. The floating lag time and in-

vitro dissolution studies at 12 hrs were selected as dependent variables. The two

factors were evaluated, each at 3 levels and experimental trials were performed at all

9 possible combinations. Polynomial equations were derived for floating lag time and

drug release at 12 hrs by backward stepwise linear regression analysis using ‘PCP

Disso 2000 V3 software’. Validity of the derived equations was verified by preparing

two check point formulations of intermediate concentrations (C1

and C2). The

prepared tablets were further coated with HPMC by dip coating method to improve

the physical stability.



6.4. Flow properties:

Flow properties play an important role in pharmaceuticals especially in tablet

formulation. The tapped and the untapped density of the powder blend were found to

be in the range of 0.287 to 0.458 g/cc and 0.270 to 0.402 g/cc respectively. The angles

of repose and % compressibility were in the range of 20⁰24 to 22

⁰42 and 5 to 13%

respectively which indicates excellent flow properties.

6.5. Pre-compressional evaluation:

The prepared floating tablets were evaluated for hardness, friability, uniformity of

weight, uniformity of drug content, swelling index, floating lag time, in-vitro floating

time, in-vitro dissolution, stability study and drug-polymer interaction. The hardness

of the prepared floating tablets was found to be in the range of 2.5 to 3.2 Kg/cm². The

friability of all tablets was less than 1% i.e., in the range of 0.51 to 0.69%. The

percentage deviation from the mean weights of all the batches of prepared floating

tablets was found to be within the prescribed limits as per IP. The values of the drug

content were in the range of 94 to 97 % in all the prepared batches as observed from

the data given in table-19.

In-vitro floating studies were performed by placing the tablets in glass beakers

containing 100ml of 0.1N HCl. The floating lag time and buoyancy time were noted

visually. The results are given in tables 17 and 19. For all (trial and factorial)

formulations, lag time was in the range of 45 to 200 secs. With formulations

containing the same amount of polymer of the same grade, floating lag time decreased

with increase in concentration of sodium bicarbonate. Formulation F3 comprising of

polymer-polymer ratio (HPMC K4M and K15M) of 0.5:1 and sodium bicarbonate



(20%) showed the lowest lag time of 45 secs, while formulation F7 comprising of

polymer-polymer ratio of 1.5:1 and NaHCO3 (10%) showed highest lag time of 200

secs. All the designed formulations remained intact and buoyant more than 24 hrs.

The swelling index of the tablets increases with an increase in the polymer content

and the content of gas generating agent (NaHCO3), as can be seen from the data given

in table 20.

6.6. In-vitro drug release study:

In-vitro drug release study was performed using USP XXIII dissolution test apparatus-I at

75 rpm using 900 ml of pH 1.2 maintained at 37 ºC ± 0.5ºC as the dissolution medium.

The results were shown in tables 21 to 29. From the obtained data, it was evident that as

the proportion of polymer in the formulation increases, cumulative percent drug release in

12 hrs decreases and as the proportion of the gas generating agent increases, the drug

release increases. F3 having lowest polymer-polymer ratio (0.5:1) and highest amount of

gas generating agent (20%) showed maximum release of 98.27% for 24hrs whereas F7

having highest polymer-polymer ratio (1.5:1) and the lowest amount of gas generating

agent (10%) showed a release of 87.57% for 24hrs.

6.7. Drug Release Kinetics:

In-vitro drug release data of all the optimized formulations was subjected to kinetic study

by linear regression analysis according to zero order and first order kinetic equations,

Korsmeyer–Peppas and Hixson Crowell models to ascertain the mechanism of drug

release. The results of linear regression analysis including regression coefficients are

summarized in tables 30 and 31.



From the kinetic data of factorial formulations, it is evident that all nine optimized

formulations have shown drug release by Korsmeyer-Peppas kinetics. The values of ‘R’

for Hixson Crowell cube root law of factorial formulations range from 0.94 to 0.99 and

those of ‘n’ values of Peppas equation range from 0.54 to 0.84. This data reveals that drug

release follows non-Fickian diffusion mechanism i.e., release is by diffusion and polymer

erosion.

6.8. Erosion study:

On the basis of swelling studies, floating lag time, in-vitro drug release and release

kinetics, formulation F3 was selected as the best formulation which was further

subjected to erosion study. F3 showed approximately 85.36% of polymer erosion for

24hrs. The best formulation F3 was then compared with the marketed formulation.

The release profile showed that F3 sustained the drug release for 24 hrs whereas the

marketed formulation released 99.4% of drug within 15 mins. The comparison of the

drug release of F3 and marketed formulation is shown in figure-14.

6.9. Factorial Design:

Based on the composition of H3 formulation, we have fixed the constraints for the levels

of independent variables (X1

and X2) i.e., 1:1 polymer-polymer ratio (X

1) and 15%

NaHCO3

(X2) in designing the formulations by 3² full factorial design.

In this 3² full factorial design, two factors (proportion of matrix polymers and gas

generating agent) were evaluated, each at three levels and experiments were performed on

all nine possible combinations. Floating lag time and drug release for 12 hrs were selected

as dependent variables. From the data obtained after evaluation, it was evident that



formulation F3 showed highly satisfactory values for floating lag time and released

approximately 98.27% drug in 24 hrs.

6.10. Development of Polynomial Equations:

From the buoyancy study and drug release data obtained for factorial formulations F1 to

F9, polynomial equations for two dependent variables (floating lag time and drug release

at 12hrs) have been derived using “PCP Disso 2000 V3 software’. Polynomial equation

for 3² full factorial design is:

Y = b0 + b1 X1 + b2 X2 + b12 X1 X2 + b11 X12 + b22 X2

2…1

where Y is dependent variable, b0

arithmetic mean response of nine batches and b1

estimated coefficient for factor X1. The main effects (X

1 and X

2) represent the average

result of changing one factor at a time from its low to high value. The interaction term

(X1X

2) shows how the response changes when two factors are simultaneously changed.

The polynomial terms (X12, X2

2) are included to investigate non-linearity.

The equation derived for floating lag time is:

Y1 = 83.827 + 28.58 X1 – 45 X2 – 16.48 X1X2 + 22.83 X2

2 …2

The negative sign for coefficient of X2

indicated that as the concentration of gas

generating agent (NaHCO3) increased, lag time decreased. The polymer ratio had a

positive impact on the lag time whereas X22 represents the non-linearity.

The equation derived for drug release at 12 hrs is:

Y2 = 74.146 – 9.140 X1 + 8.091 X2 …3



The negative sign for coefficient of X2

indicated that as the concentration of NaHCO3

increased, drug release for 12 hrs decreased whereas the polymer ratio shows a positive

impact on drug release.

Validity of the above equations was verified by designing two check point formulations

(C1 and C

2) and studying the lag time and drug release profiles. The closeness of predicted

and observed values for the lag time and drug release at 12 hrs indicated validity of

derived equations for the dependent variables.

The computer generated response surfaces for the dependent variables are shown in

figures 15 and 16.

6.11. Drug-formulation compatibility studies

6.11.1. FTIR:

IR spectrum of Methyldopa exhibited characteristic peaks at 3473.42 cm–1

and 1643.24

cm–1

due to N–H stretching and C=O stretching of carboxyl group respectively. The peaks

at 3215.11 cm–1

were due to phenolic –OH group. The C–H absorption frequency was

noticed at 2839.02 cm–1

in confirmation of presence of alkyl moieties. IR spectrum of

physical mixture and final formulation F3 showed peaks at 3478.38 cm–1

, 3477.42 cm–1

due to N–H stretching and at 1642.04 cm–1

, 1643.24 cm–1

due to C=O stretching of the

carboxyl group respectively. The peaks at 3214.15 cm–1

and 3216.08 cm–1

in the physical

mixture and final formulation F3 respectively represent the phenolic –OH group. The

presence of above peaks confirmed undisturbed drug in the formulation. Hence, there

were no drug-carrier interactions.



6.11.2. DSC Studies:

DSC thermograms (Figures 20-21) for pure drug, physical mixture and final

optimized formulation F3 were obtained. The thermogram of pure drug exhibited the

single endothermic peak at around 314°C as the drug melting point lies around 307-

314°C. In case of physical mixture of drug with excipients, the drug peak was shifted

to lower temperature of 307.8°C with reduced intensity which may be due to baseline

shift and an additional peak at 126.5°C was observed due to presence of excipients.

Baseline shifts may be caused by changes in sample weight, heating rate or the

specific heat of the sample. A change in specific heat often occurs after the sample

has gone through a transition such as crystallization or melting. Similar peaks were

observed for final optimized formulation F3 with increased intensity that may have

occur due to punching of tablets.

6.12. Stability Studies:

Stability study was performed on the best formulation F3 by storing the samples at RT

and 45⁰C, RH 75% for 3 months. The samples were tested for any changes in physical

appearance, drug content and floating lag time at monthly intervals. The results as shown

in table 36 indicated that there were no significant changes in physical appearance, lag

time and drug content of the formulation during the storage.

Chapter 7 Conclusion


CONCLUSION

Floating tablets of Methyldopa with shorter lag time can be successfully prepared

by direct compression method using HPMC (K4M and K15M) and NaHCO3

as

gas generating agent. All the prepared tablet formulations were found to be good

without capping and chipping. As the amount of polymer in the tablet formulation

increased, the drug release rate decreased and as the concentration of gas

generating agent (NaHCO3) increased, the drug release rate increased. The

incorporation of Ascorbic acid (0.1%) prevented the atmospheric oxidation of

Methyldopa and hence stabilized the optimized formulations. The designed

formulations of Methyldopa displayed Korsemeyer-Peppas kinetics, and drug

release followed non-Fickanian diffusion mechanism. From the results of

buoyancy, drug release, erosion studies and mathematical modelling, formulation

F3 containing Methyldopa 250mg, HPMC (K15M and K4M) in the ratio of 0.5:1

and NaHCO3

20% evolved as the optimized formulation and it released 98.27%

drug in 24 hrs.

Stability studies of optimized formulation F3 indicated that there were no

significant changes in the physical appearance, lag time and drug content after

storage for 3 months both at RT and accelerated conditions (45⁰C, 75% RH)

for 3 months. IR spectroscopic and DSC studies indicated that there were no drug

excipient interactions in the optimized formulation.

The optimized formulation F3 can thus be considered as a promising gastro

retentive drug delivery system of Methyldopa sustaining the drug release to 24hrs.

Chapter 8 Summary


8. SUMMARY

The aim of the present work was to formulate Gastro Retentive Delivery Systems of

Methyldopa in order to prolong its release in the GIT and achieve sustained release.

Floating tablets of Methyldopa were prepared by effervescent technique. HPMC, a

hydrocolloid gelling agent was chosen as the polymer as it swells in contact with

gastric fluid after oral administration, achieves bulk density of < 1 and helps in

floatation of the tablets. Also, the gel structure acts as a reservoir for sustained drug

release.

In the effervescent tablets along with the HPMC, effervescent component such as

sodium bicarbonate was used. CO2 liberated by the effervescent agent produced an up

thrust of the dosage form and maintained its buoyancy due to decrease in specific

gravity.

Initially, compatibility between the drug and the polymers were assessed by IR

studies. IR spectra of the pure drug and the physical mixture indicated the

compatibility between the drug and polymers.

Six batches of preliminary trial formulations consisting two different viscosity grades

of HPMC (K15M and K4M) used in combination at different ratio were designed and

from the results of evaluation data, the constraints for independent variables X1

(polymer ratio) and X2

(amount of gas generating agent) were fixed. The floating

tablets were prepared by direct compression method. The formaulations were

incorporated with ascorbic acid to overcome the problem of discolouration of the

prepared floating tablets. A 32

full factorial design was applied to get nine optimized

Chapter 8 Summary


formulation. Further the prepared tablets were coated by dip coating method to

improve the physical stability of the drug.

Tablet powder was evaluated for their Bulk Density, % Compressibility and Angle of

Repose and they were found to have excellent flow properties as indicated by their

values.

The optimised formulations were also evaluated for weight variation, hardness and

friability. Further, the tablets were studied for buoyancy. As the viscosity of HPMC

increased in the formulations, the buoyancy time also increased. (HPMC K15M >

HPMC K4M). All the nine formulations showed a buoyancy of 24 hrs or more. All

the selected formulations were subjected to dissolution studies at pH of 1.2 by basket

method for a period of 24 hrs. The dissolution was prolonged for 24 hrs in case of

effervescent formulations. The drug was analyzed from the dissolution media at 280

nm by UV spectrophotometer. The Best formulation sustained the drug release to 24

hrs when compared to marketed formulation which completely released the drug

within 15 mins.

The mechanism of drug release was found to be diffusion controlled. The drug release

followed Kosmeyer-Peppas kinetics. The mechanism of diffusion was found to be

non-Fickian as seen by their n value of more than 0.5 calculated by Kosmeyer Peppas

equation.

The Best formulation F3 showed no drug - excipient interactions when subjected to

compatibility studies such as FTIR and DSC. It was found to be stable on storage both

at RT and accelerated conditions (45⁰C, 75% RH) for 3 months.

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