Srikanth Reddy

DEVELOPMENT AND EVALUATION OF CONTROLLED
RELEASE MATRIX TABLETS CONTAINING PERINDOPRIL IN

THE TREATMENT OF HYPERTENSION
By
N. SRIKANTH REDDY
B. Pharm.
DISSERTATION SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BENGALURU, KARNATAKA.
IN PARTIAL FULFILLMENT
FOR THE AWARD OF THE DEGREE OF
MASTER OF PHARMACY
IN
PHARMACEUTICS
Under the Guidance of

Dr. SOMASHEKAR SHYALE
M.Pharm., Ph.D.
Professor
DEPARTMENT OF PHARMACEUTICS
V. L. COLLEGE OF PHARMACY
RAICHUR – 584103.
2011
i
‘I DEDICATE THIS BOOK TO MY DAD, MOM AND
DEAR SISTER’
‘TO GAYATHRI LAKSHMI.B WHO HAVE BEEN AN
IMMENSE SUPPORT AND BELIEVING IN ME’
ii
Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka.
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation entitled “Development and evaluation
of controlled release matrix tablets containing perindopril in the treatment of
hypertension” is a bonafide and genuine research work carried out by me under the
guidance of Dr. Somashekar Shyale, Professor, Department of Pharmaceutics, V.L.
College of Pharmacy, Raichur.
Date:
Place: Raichur (N.Srikanth Reddy)
iii
CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled “Development and evaluation
hypertension” is a bonafide research work done by Mr. N.Srikanth Reddy in partial
fulfillment of the requirement for the degree of Master of Pharmacy in
Pharmaceutics under my guidance at V.L. College of Pharmacy, Raichur.
Date: Dr. Somashekar Shyale

M.Pharm.,Ph.D.
Place: Raichur Professor, Dept. of Pharmaceutics,
V.L College of Pharmacy,
Raichur-584103.
iv
ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION
This is to certify that the dissertation entitled “Development and evaluation
hypertension” is a bonafide research work done by Mr. N.Srikanth Reddy under
the guidance of Dr. Somashekar Shyale at V.L. College of Pharmacy, Raichur.
Dr. Y. Anand Kumar Dr. S.M Shanta Kumar

M.Pharm., Ph.D. M.Pharm., Ph.D.
Professor & Head, Principal,
Dept. of Pharmaceutics, V.L. College of Pharmacy,
V.L. College of Pharmacy, Raichur -584103.
Raichur -584103.
Date: Date:
Place: Raichur Place: Raichur
v
COPYRIGHT
Declaration by the Candidate
I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka,
shall have the rights to preserve, use and disseminate this dissertation /thesis in print
or electronic format for academic /research purpose.
Date:
Place: Raichur (N.Srikanth Reddy)
© Rajiv Gandhi University of Health Science, Bengaluru, Karnataka.
vi
ACKNOWLEDGEMENTS
In the name of Lord Venkateshwara swamy, I bow myself to thank and acknowledge
the continued blessings showered on me to successfully complete my dissertation.
I deeply express my gratitude whole heartedly to my mother Smt. N. Aruna,
my Father Shri. N.Venkata Rami Reddy and my sister Miss N.padmaja for their
support and encouragement for the choices I have made, whom I owe in a substantial
measure and for which mere words cannot suffice. ‘You have given me a solid ground
for life’.
It gives me immense pleasure to acknowledge, the help rendered to me by a
host of people, to whom I owe gratitude for the successful completion of my M.Pharm
foremost amongst them are my uncle Mr. G.Venkata Rami Reddy, My aunty
Mrs.G.Tulasi for their constant encouragement, moral support and everlasting love
that have served as a source of inspiration, strength and determination at each and
every front of my life.
The research work embodied in this dissertation has been carried out at the
Department of Pharmaceutics V.L. College of Pharmacy, under the supervision of
esteemed and most respected Guide, Dr. Somashekar Shyale who gave me a chance
to work under his able guidance and for providing the necessary facilities and
pleasant working environment. I take this golden opportunity to thank and express my
sincere gratitude for his continuous encouragement, valuable suggestions, dynamic
guidance, moral support, keen interest to solve my queries, and blessings throughout
the period of this work.
vii
I hereby thank the most inspiring, charismatic and energetic Dr. S.M. Shanta
Kumar, Principal, V.L. College of Pharmacy Raichur, for his unconditional support
and encouragement.
I thank Dr. Y. Anand Kumar, Smt. K.M. Lokamatha Swamy, Dr. Ayesha
Shalam, Smt. Hafsa Mahamudi, Shri. P. Rajesh Kumar and Shri. Mallikaarjuna
Gowda, Department of Pharmaceutics, for their concern, co-operation and
encouragement throughout the duration of the course.
I thank respected Dr. K.M.K. Swamy, Dr. Srinivasalu, Shri. Zaheeruddin
and Shri. Manish Kumar Dept. of Pharmaceutical Chemistry, Dr. N. Venkat Rao
and Dr. Jeevan Mani Babu Dept. of Pharmacology, Dr. Hemant Kumar and Dr.
Pramod Kumar Dept. of Pharmacognosy, for their encouragement and moral
support.
I also acknowledge with heartfelt thanks the contributions of M/s Lupin
Pharmaceuticals Ltd. Pune and M/s Unichem Laboratories Ltd. Mumbai for
providing the polymers and excipients required for the present research.
I express my special thanks and regards to my roommates Mr. T.Rajesh, Mr.
A .Pavan kumar for filling competitive spirit in me through unending support and
encouragement.
I hereby acknowledge the cooperation and help rendered by my departmental
friends and well wishers, Mr. Syed Amezuddin Azhar, Mr. L. Prashanth Reddy,
Mr. Vivek Sood, Mr. Alluri Pavan Kumar, Mr. T. Rajesh, Mr. Suneel Kumar
viii
Batchu, Mr. Virupakshi Gouda, Mr. N. Abhilash, Mr. C S Arun Kumar, Miss.
Shashikala and Miss. Areefa .
I am also very grateful to my childhood friends and the closest friends from
the student days, especially Miss. Gayathri Lakshmi Bahumanyam,
Mr.P.V.BalaSubramanyam, Mr. Riaz basha, Mrs. Sujatha Reddy , Mr. Krishna
mohan , Miss.G.M.Sridevi, Mr. Ajay Babu, Mr. Alluri Pavan kumar. that they have
not forgotten me in spite of the long distance between us.
I am also thankful to my friends, Mr. Naga Venkat Dileep ,Mr. Shiv Patel,
Mr. Raghavendra Babu, Mr. Rajesh Pal, Mr. Sangram Deshmukh, Mr. Md. Bashir,
Mr. Rizwan Sheikh, Mr. Gajanan Dadge, Mr. Kapil Joshi, Mr. Mahesh Birajdar,
Mr. Manoj Kumar, Mr. Amol Phullari, , Mr. Fasih Ahmed, Mr. Mehboob, Mr.
Vinay, Mr. Uday, Miss Petricia, Miss Soumya, Miss Saritha, Miss Shwetha and
Miss Roopa for their co-operation and help.
I thank my seniors Miss. Anitha, Mrs. Bharthi, Mr. Srinivas, Mr. Sachin,
Mr. Srikanth, Mr. Hemanth, and others for their guidance and help.
I thank my juniors especially Miss Gayathri Lakshmi Bahumanyam Mr.
Bharath V , Mr. Viresh, Mr. Bharath D , Mr. Shyam , Mr. Uday, Mr. Kirtinidhi,
Mr. Amaregouda, Mr. Vinod, Mr. Aezaz, Miss. Bhanodaye Miss. Keerti Chandana,
Miss and for their cooperation and help.
I take this opportunity to thank all the teaching and non-teaching staff of V.L.
College of Pharmacy, Raichur, for their constant help and support. Also, I hereby
ix
express my gratitude to all the people involved directly or indirectly in the successful
completion of this dissertation work.
At last but not least I heartly thankful to my school Priyadarshini English
Medium High School, Banaganapalli ,Head mistress J.Shoba Rani and principal
J. kesarlingum sir school teachers Bhasa sir , Lakshmi teacher, Devi mam, where
motivate me to this position.
(Srikanth Reddy.N)
x
LIST OF ABBREVIATIONS USED
1. cm : Centimeter
2. conc. : Concentration
3. °C : Degree Celsius
4. DT : Disintegration Time
5. DC : Drug Content
6. ODT : Controlled Matrix Tablet
7. Fig : Figure
8. PE : Perindopril Erbumine
9. GIT : Gastro intestinal tract
10. gm : Grams
11. h : Hours
12. HCl : Hydrochloric Acid
13. ICH : International Conference on Harmonization
14. Kg : Kilogram
15. M : Molarity
16. mg : Milligram
17. min : Minutes
18. µg : Microgram
19. mL : Milliliter
20. mm : Millimeter
21. M.W : Molecular Weight
22. N : Normality
23. nm : Nanometer
24. pH : Negative logarithm of hydrogen ion concentration
25. r : Correlation Coefficient
26. RH : Relative Humidity
27. rpm : Revolutions per minute
28. SD : Standard Deviation
29. Sec : Seconds
30. U.V. : Ultra Violet
31. max : Wavelength Maxima
xi
32. WHO : World Health Organization
33. WT : Wetting Time
34. w/w : Weight by Weight
xii
ABSTRACT
Background and Objectives:
Perindopril Erbumine (PE) is an Ace inhibitor. It is effective in the treatment
of Hypertension and Blood pressure, has a half-life 0.8-1 h and oral bioavailability is
< 60 %. Perindopril erbumine shows promising pharmacokinetics and Physico-
chemical properties required for control release dosages. Therefore this drug was
selected as model drugs for this investigation.
The objectives of the present research work is to formulate and evaluate
controlled matrix tablets containing Perindopril Erbumine (PE) as a drug using
different ratios of polymers to avoid hepatic first pass metabolism and to increase
bioavailability of the drug.
Methods:
An UV Spectrophotometric method was developed to quantitate Perindopril
Erbumine either in bulk or in tablets and the method was validated for linearity,
accuracy and precision. Different matrix carriers like Xanthan gum, eudragit RL 100,
and almond gum were used to develop matrix tablets. Various rheological
characteristics of the powder bed like bulk density, tapped density, compressibility
index, and repose angle were evaluated and studied. Matrix tablets were compressed
on a 10 station pilot press using 6 mm flat faced punches (PPID, Chamunda, India)
and were all assessed for weight variation, hardness, thickness, friability, swelling
index, in vitro release of the drug by using USP XXIV dissolution testing apparatus.
The conditions were simulated and sink conditions were maintained. Further stability
xiii
studies of the Perindopril Erbumine formulations were conducted according to ICH
guidelines at 40°C/ 75 % RH for a period of 90 days.
Results:
The value of U.V. absorbance maxima (λ max) = 215.5 nm obtained during this
study corroborates with literature value 216 nm. Melting point was found to 126.5ºC
which corroborates with the literature value 1260C−1280C. Solubility of Perindopril
Erbumine was found to be 0.355 mg/mL in distilled water. The partition coefficient of
Perindopril Erbumine was found to be 0.464.
Bulk density was found to be between 0.293 gm/mL and 0.415 gm/mL for
all the formulations. Tapped density was found to be between 0.308 gm/mL and
0.498 gm/mL. The angle of repose ( ) was determined before adding the
lubricants/glidants and after adding lubricants/glidants. The repose angle before
incorporation of lubricants/glidants was found to be 21.800 to 27.120. After the
addition of lubricants/glidants the angle of repose was found to be 19.980 and
24.110. Carr’s Compressibility index was observed to be between 3.03 % and 12.6
% indicating that the powder bed is compressible.
Powder bed was compressed in 10 station rotary pilot press using 6 mm flat
faced punches. The weight of the matrix tablets was found to be fairly uniform
ranging between 100.0 ± 0.1 mg to 100.8 ± 0.2 mg for a 100 mg tablet (n=10). The
thickness of the tablets was determined using a micrometer (Mitutoyo, Japan). The
thickness of the tablets, were found to be between 3.008±0.0 mm to 3.010±0.002
(n=10). The hardness of the tablets were determined with a hardness tester (Pfizer,
xiv
India) and the hardness was found to be fairly consistent and uniform, ranging
between 3.26±0.115Kg/cm2 to 4.93±0.23Kg/cm2 (n=5).
Drug content of the all formulations were in the range of 3.806 mg to
3.94mg for matrix tablets. The friability of all the formulations were determined in a
friabilator operated for 5 min at 25 rpm, and the percent friability was found to be
0.16% to 1.1%.
The matrix tablets were found to swell gradually and the swollen tablet did
not lose its integrity for nearly 7 to 8 h. Increase in polymer content, increased
swelling index of the tablets.
In vitro release was studied by using USP XXIV dissolution apparatus, the
study was carried out in pH 7.4 and pH 6.8 buffer, at a constant temperature of 37 ±
0.5 0C stirred at 50 rpm for a period of 12 h. In vitro release data obtained was
statistically analyzed by ANOVA and a value of p<0.05 was considered to be
significant. The data was also subjected to regression analysis by least squares method
(r) to asses the linearity of the curve.
The release of Perindopril Erbumine from matrix tablets into the pH 6.8
buffer was found to be, F1 released 40.56%(r = 0.976 ), F2 released 42.53 % (r =
0.983), F3 released 45.11 % (r = 0.983 ), F4 released 44.39 % (r = 0.984), F5
released 45.18 % (r = 0.986), F6 released 44.78% (r = 0.982), F7 released 46.90 % (r
= 0.985), F8 released 47.58 % (r= 0.987), F9 48.08% (r = 0.986), respectively at the
end of 12h. Stability studies were conducted according to ICH guidelines for region
IV at 400C / 75 % RH. At regular intervals drug content was noted for 90 days and
also 90th day the matrix dosage form was subjected to dissolution.
xv
The flux from Perindopril Erbumine matrix tablets containing xanthun gum
(PE1, PE2, PE3) were found to be 0.119 mg /cm2 / h (r=0.976), 0.128 mg /cm2 / h
(r=0.983) and 0.136 mg /cm2 / h (r=0.983) respectively. The flux from Perindopril
Erbumine matrix tablets containing eudragit RL 100 (PE4, PE5, PE6) were found to
be 0.138 mg /cm2 / h (r=0.984), 0.14 mg /cm2 / h (r=0.986) and 0.137 mg /cm2 / h
(r=0.982) respectively. The flux from Perindopril Erbumine matrix tablets containing
xanthan gum (PE7, PE8, PE9) were found to be 0.147 mg /cm2 / h (r=0.985), 0.150
mg /cm2 / h (r=0.987) and 0.149 mg /cm2 / h (r=0.986) respectively.
Interpretation and conclusions:
The analytical method developed for Perindopril Erbumine was found to be
linear, accurate and precise. Melting point and λmax of the model drug determine in
this work, corroborates with previous reports, indicating the drug is pure. The
solubility of Perindopril Erbumine was found to decreasing with increase in pH. The
octanol: water partition coefficient of Perindopril Erbumine was found to be 0.464.
The drug content was found to be fairly uniform in the matrix tablets.
The thickness, diameter and weight of the tablets were found to be uniform
and consistent as indicated by their low SD values. The hardness of the compressed
tablets were determined using hardness tester (Pfizer, India) indicated that the tablets
are of adequate strength. The friability of the tablets was very low and therefore it was
understood that the tablets are of sufficient strength to withstand the stress of
transportation. Drug content of all tablet formulations was found to be uniform. All
the formulations containing matrix carriers swell considerably without losing the
shape or integrity of the tablet and also swelling increases with increase matrix
polymer content in the formulation.
xvi
In vitro release data showed that, matrix tablets containing xanthan gum
showed less release than the eudragit RL 100 and almond gum matrix tablets. To
ascertain the mechanism of release the data was plotted according to korsemeyer-
peppa equation. It was found that, the release from the tablet follows Super case II
transport owing polymer chain disentanglement and relaxation.
Stability studies data indicated no significant decrease in the drug content and
drug release . Periodic comparison of in vitro release profile during stability studies
indicated, there was a no significant difference between the profiles at p <0.05 for a
period of 90 days.
KEYWORDS: Controlled Matrix Tablets (CMTs); Perindopril Erbumine (PE);
Xanthan gum, Eudragit RL 100 and almond gum.
xvii
S.No Table of contents Page No.
1. Introduction 1 - 23
1.1. An overview of Controlled matrix drug delivery system 1
1.2. An overview of hypertension 1

1.2.1 Hypertension classification 2
1.2.2. Clinical classification of hypertension 2
1.2.3 Etiology and pathogenesis 3
1.2.4 Pathophysiology 6
1.2.5 Diagnosis 6
1.2.6. Treatment 6
1.2.7 Antihypertensive agents 7
1.2.8. Limitations of conventional dosage form 8
1.3. Rationale of controlled drug delivery system 9
1.3.1 Advantages of controlled drug delivery system 10
1.3.2 Disadvantages of controlled drug delivery system 10
1.4. Factors influencing the design of controlled release products 11
1.4.1. Physicochemical properties of drug 11
1.4.2. Route of administration 11
1.4.3. Acute/chronic therapy 12
1.4.4. Target sites 12
1.4.5. The patient 12
1.4.6. The diseased state 12

1.5. Oral controlled release system 13
1.5.1. Matrix Formulations 14
1.6. An overview on Perindopril Erbumine 19
1.7 Conventional methods 21
2. Aims and objectives of the Investigation 24-25
3. Review of literature 26-38
xviii
4. Methodology 39-74
4.1. Materials 39
4.2 Equipments 40
4.3 Profile of Perindopril Erbumine 41
4.4 Review of additives 46
4.4.1 Xanthan gum 46
4.4.2 Almond gum 49
4.4.3 Eudragit RL 100 52
4.4.4 Starch I.P 54
4.4.5 Magnesium Stearate 56
4.4.6 Talc 59
4.5 Analytical methods used for the estimation of Perindopril 62

Erbumine (PE) drug either in bulk, tablets or in dissolution
fluids
4.5.1 Method used to estimate Perindopril Erbumine 62
4.6 Methods used for characterization of the drug 65
4.6.1 Melting point determination 65
4.6.2 Solubility studies 66
4.6.3. Partition coefficient 66
4.6.4 Permeability coefficient 67
4.7. Preparation of Perindopril Erbumine Tablets 67
4.7.1. Method of preparation of granules 67
4.8 Evaluation of pre-compression characteristics of granule bed 68
4.9 Compression of tablets 69
4.10 Evaluation of post-compression characteristics of tablets 69
4.11 In vitro release study 73
xix
4.12 Stability studies 74
4.13 Statistics 74
5 Results 75-117
5.1 Characterization of Perindopril Erbumine 76
5.2 Development and evaluation of Controlled matrix tablets of 77

Perindopril Erbumine
5.3 In vitro studies 80
6. Discussion 118-122
7. Conclusion 123-126
8. Summary 127-128
9. Bibliography 129-137
xx
Table
List of tables Page No.
No.
1.1. Clinical classification of hypertension 3
1.2. In vivo performance of controlled release formulations 13
4.1. Materials used 39
4.2. Equipments used 40
4.3. Analysis of almond-tree gum 50
4.4. Spectrophotometric data for the estimation of Perindopril 62
Erbumine at 215.5 nm
4.5. Linearity studies of gemifloxacin 63
4.6. Accuracy and precision studies 64
4.7. List of the ingredients used in the formulae of different 74
Controlled Matrix tablets of Perindopril Erbumine
5.1. Various physico-chemical characteristics of Perindopril 90
Erbumine
5.2. Evaluation of rheological characteristics of CMT containing 91
5.3. Evaluation of physical characteristics of CMT containing 92
5.4. Swelling studies of controlled release matrix tablets of 93
5.5. In vitro release of Perindopril Erbumine from controlled 94
matrix tablets containing 20%w/w Xanthan gum
5.7. 98
In vitro release of Perindopril Erbumine from controlled

matrix tablets containing 20%w/w Eudragit RL 100
xxi
matrix tablets containing 20%w/w Almond gum
5.14. Drug content after 90 days of stability studies of controlled 112

release matrix tablets of Perindopril Erbumine (PE1, PE2,
PE3) at 400C/75% RH
PE6) at 400C/75% RH
PE9) at 400C/75% RH
5.17. In vitro release after 90 days of stability studies of controlled 115

PE3) at 400C/75% RH (n=3)
PE6) at 400C/75% RH (n=3)
PE9) at 400C/75% RH (n=3)
xxii
Fig. No. List of figures Page No.
1.1. Renin-angiotension activation 5
1.2. Schematically representation of a leaching-based release 16
mechanism.
4.1 Calibration curve of gemifloxacin 63
matrix tablets containing 20%w/w Xanthan gum (PE 1)
matrix tablets containing 25%w/w Xanthan gum(PE 2)
matrix tablets containing 30%w/w Xanthan gum(PE 3)
matrix tablets containing 20%w/w Eudragit RL 100 (PE 4)
matrix tablets containing 20%w/w Almond gum (PE 7)
xxiii
1. INTRODUCTION
1.1. An overview of Controlled matrix drug delivery system:
Cardiovascular diseases are one of the life threatening diseases of mankind
and hypertension is the most common cardiovascular disease, which requires constant
monitoring. It is well known that hypertension is a major factor for congestive cardiac
failure and coronary artery disease. Control of hypertension reverses the risk of
congestive cardiac failure; where as the risk of coronary disease is not
reversed rapidly.1 It is very much essential to control the hypertension and maintain
sufficient blood circulation to heart to reduce the morbidity and make the patient to
lead a near normal life. The conventional treatment of chronic illnesses like
diabetes, hypertension ironically sometimes disturbs the normal rhythm of the life.
The ultimate aim of every therapy is to restore the normalcy of life without causing
adverse effects or the therapy must be with minimum adverse effects. Conventional
dosages cause fluctuation of drug levels in the plasma and hence, certain adverse
affects are seen. Therefore the success of a therapy depends on the continuous
administration of the drug to maintain constant drug plasma levels.2
1.2. An overview of hypertension:
Hypertension is defined as a systolic blood pressure (SBP) ≥ 140 mmHg and a
diastolic blood pressure (DBP) ≥ 90 mmHg for persons up to 60 years of age and for
subjects with diabetes mellitus or familiar hypercholesterolemia and as a SBP ≥ 160
mmHg and a DBP ≥ 90 mmHg for persons of 60 years and older without diabetes
mellitus or familiar hypercholesterolemia. Hypertension is a risk factor for myocardial
infarction, stroke, congestive heart failure, end-stage renal disease, and peripheral
Department of Pharmaceutics, V.L.C.P, Raichur. 1
vascular disease. The World Health Organization reported that suboptimal blood
pressure (SBP > 115 mmHg) is responsible for 62% of all cerebrovascular diseases
and 49% of all ischemic heart diseases. In addition, suboptimal blood pressure is the
number one cause of death throughout the Western world.
1.2.1. Hypertension classification: 4, 5
1) Primary or essential hypertension in which definite cause for the increase in
blood pressure is unknown.
2) Secondary hypertension in which increase in blood pressure is secondary to renal
endocrine or vascular lesions. Secondary hypertension comprises 5-10% cases
of hypertension.
Both essential and secondary hypertension may be benign or malignant.
Benign hypertension is moderate elevation of blood pressure and the rise is slow
over the years. About 90% patients of hypertension have benign hypertension.
Malignant hypertension is marked and rapid increase of blood pressure to
200/140mm Hg. Or more and patients have papilloedema, retinal haemorrhages and
hypertensive encephalopathy. Less than 5% of hypertensive patients
develop malignant hypertension and life expectancy after diagnosis in these patients
is less than 2 years if not treated effectively.
1.2.2. Clinical classification of hypertension:
Although hypertension is rise blood pressure above the normal clinical
values,which can be mild to malignant and therefore classified clinically as
summarized below.

Category Systolic (mm of Hg) Diastolic (mm of Hg)
Normal >130 <85
High Normal 130-139 85-89
Hypertension
Mild stage (stage 1) 140-159 90-99
Moderate (stage 2) 160-179 100-109
Severe (stage 3) 180-209 110-119
Very sever (stage 4) >210 >120
Malignant hypertension >200 >140
1.2.3. Etiology and pathogenesis:
Normal blood pressure is regulated by two haemodynamic forces and factors
which alter these factors would cause hypertension.
1) Cardiac output
2) Total peripheral vascular resistance
For essential hypertension mainly three following factors are responsible
1) Genetic factors
2) Racial factors
3) Risk factors modifying the course
1) Genetic factors: The role of familial aggregation, occurrence in twins has long
been suspected.
2) Racial and environmental factors: higher incidence of essential
hypertension is in blacks than in whites. A number of environmental factors like

salt intake, obesity, skilled occupation, higher living standards and patients
in high stress have been implicated in the development of hypertension.
3) Risk factors: The essential hypertension that begins in the middle life is
modified by a number of factors.
a) Age
b) Sex
c) Smoking
d) Obesity
e) Excess of alcoholic intake
f) Diabetes mellitus
For secondary hypertension mainly four factors are responsible:
1) Hypertension due to renal problems
2) Hypertension due to endocrine problems
3) Hypertension associated with coarctation of aorta
4) Neurogenic causes
Renal hypertension is produced by one of the following three inter-related
mechanisms:
a) Activation of renin angiotensin system
b) Sodium and water retention
c) Decreased release of vasodepressor

Activation of renin angiotensin system is shown as follows
Renin
Angiotensin-I
Angiotensin-II
Angiotensin-III
Sodium retention
Increase in volume
Blood pressure
Fig: 1.1. Renin-angiotension activation
Sodium and water retention regulates blood volume and cardiac output.
Sodium concentration in the blood is regulated by the release of aldosterone,
reduction in glomerular filtration rate and release of atriopeptin hormone from atria
of heart.
Decreased release of vasodepressor agents like prostaglandins
counters the vasopressor effect of Angiotensin – II.
Endocrinal hypertension is due to a number of endocrinal diseases
like adrenocortical hyperfunction, hyperparathyroidism.

Coarctation of aorta causes systolic hypertension due to constriction and
diastolic hypertension results from changes in the circulation.
Neurogenic hypertension is due to disease like psychogenic, increase in
intracranial pressure.
1.2.4. Pathophysiology:
The pathogenesis of essential hypertension is still unknown. Earlier it was
suggested that renal sodium retention, expanded vascular volume, increasing cardiac
output which led to increased vascular resistance. Later, it was suggested that
sympathetic nervous system plays primary role. Syndrome X relationship gives that
hypertension is related to obesity, insulin resistance, glucose intolerance and
hyperinsulinemia..
1.2.5. Diagnosis:
The diagnosis of hypertension is based on repeated, reproducible
measurements of elevated blood pressure. It serves primarily as prediction of
consequences for the patient and includes a statement about the cause of hypertension.
Since hypertension is usually asymptomatic until organ damage is imminent its
diagnosis depends mainly on measurements of blood pressure and not on symptoms
reported by patients
1.2.6. Treatment: 6
The first step in treating hypertension may be non-phamacologic which
includes sodium restriction, weight reduction in overweight patients. Pharmacologic
management includes a single drug for mild hypertension while for moderate to serve
hypertension a combination of two or more drugs.

1.2.7. Antihypertensive agents: 7
Antihypertensive agents are the drugs which lower the blood pressure in
hypertensive patients.Proteins, peptides and recombinant drugs:
a. Classification of antihypertensives:
1. Diuretics
eg. Chlorthalidone, Clopamide, Indapamide
2. β Adrenergic blockers
eg.Acebutolol, Atenolol, Metoprolol, Propranolol, Timolol
3. α Adrenergic blockers
eg. Terazosin, Prazosin, Doxazosin
4. α + β Adrenergic blockers
eg. Labetalol, Carvedilol
5. Ace inhibitors
eg. Perindopril, Captopril, Enalapril, Lisinopril, Fosinopril,
trandolapril, benazepril etc.
6. Calcium channel blockers
eg. Amlodipine, Felodipine Nifedipine, Nimodipine, Verapamil
7. Vasodilators
eg. Hydralazine, Minoxidil, Sodium nitroprusside
8. Angiotension-II receptor antagonists
eg. Candesartan, Losartan, Valsartan
9. Central sympatholytics
eg. Clonidine, Methyldopa

In the past three decades, the treatment of an acute disease or a chronic illness
has been mostly accomplished by delivery of drugs to patients using various
conventional dosage forms like tablets, capsules, ointments, liquids, and injectables,
as drug carriers. This type of drug delivery system is known to provide a prompt
release of drug. Therefore, to achieve as well as to maintain the drug concentration
within the therapeutically effective range needed for treatment, it is often necessary to
take the conventional type of drug delivery systems several times a day. This results
in a significant fluctuation of drug levels in the body.8
1.2.8. Limitations of conventional dosage form :
Poor patient compliance; increased chances of missing the dose of a drug with
short half-life for which frequent administration is necessary.
A typical peak-valley plasma concentration-time profile is obtained which
makes attainment of steady–state condition difficult.
The unavoidable fluctuations in the drug concentration may lead to under
medication or overmedication as the Css values fall or rise beyond the
therapeutic range.
The fluctuating drug levels may lead to precipitation of adverse effects like
nausea, vomiting, gastric irritation and toxicity especially of a drug with small
9
therapeutic index whenever overmedication occurs.
Continuous I.V. infusion has been recognized as a superior mode of
systemic drug delivery that can be tailored to maintain a constant and sustained
drug levels within therapeutic window for as long as required for effective

treatment. It also provides a means of direct entry into the systemic
circulation of drugs that are subjected to hepatic first-pass metabolism and/or
suspected of producing gastrointestinal incompatibility. Unfortunately, such a
mode of drug administration entails certain health hazards and therefore
necessitates continuous hospitalization during treatment and requires close medical
supervision.10
To duplicate the benefits of intravenous drug infusion without its potential
hazards, several technical advancements have been made.
There are two ways to overcome the situation:
• Development of new, better and safer drugs with long half- lives and large
therapeutic indices, and
• Effective and safer use of existing drugs through concepts and techniques of
controlled drug delivery systems.
1.3. Rationale of controlled drug delivery system:
An ideal controlled drug delivery system is the one that delivers the drug at a
pre-determined rate, locally or systemically, for a specified period of time. Controlled
release is differs from sustained release systems which simply prolong the drug
release and hence plasma drug level for a longer period of time. Thus the objective of
most products should be controlled delivery to reduce dosing frequency to an extent
that once daily dose is sufficient for therapeutic management through a
uniform plasma concentration at steady state.

1.3.1. Advantages of controlled drug deliverysystem:
Controlled release drug delivery systems have received much attention in past
two decades as they overcome the disadvantages of conventional therapy and offer
some benefits like:
• Controlled administration of a therapeutic dose at the desired delivery rate.
• Constant blood levels of the drug, reduction of side effects.
• Minimization of dosing frequency.
• Enhancement of patient compliance.
• To obtain better therapeutic efficacy and diminished toxicity.
• Increased safety margin of high potency drugs due to control of
plasma levels.
• Maximum utilization of drug enabling reduction in total amount of
dose administered.
• Reductions in health care costs through improved therapy, shorter treatment
period, less frequency of dosing and reduction in personnel time to dispense,
administers and monitor the patients.
1.3.2. Disadvantages of controlled drug delivery system :
Decreased systemic availability in comparison to immediate release
conventional dosage forms, this may be due to incomplete release, increased
first pass metabolism, increased instability, insufficient residence time for
complete release, site-specific absorption, pH dependent solubility.
Poor in vitro-in vivo correlation.
Possibility of dose dumping due to food.

Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity
reactions.
Reduced potential for dosage adjustment of drugs normally administered in
varying strengths.
9
Higher cost of formulation.
1.4. Factors influencing the design of controlled release products:
The variables to be considered for design of controlled release products are,
1.4.1 Physicochemical properties of drug:
Physicochemical properties of drug such as solubility, partition
coefficient, protein binding, contribute in a major to the designing of controlled
release products.
1.4.2 Route of administration:
Some routes of administration exert a negative influence on drug
efficacy especially chronic administration and therefore route of application
should be considered. many physiological constraints imposed by the particular
route, that is GI motility, blood supply, first pass metabolism and sequestration
of small foreign particles by the liver and spleen influence the performance of
the controlled release systems.
1.4.3 Acute/chronic therapy:
Expected length of drug therapy to achieve cure or control of ailment
is important factor in design of controlled release product like development of one
year contraceptive implants represents a different case than does an antibiotic

treatment for acute microbial attack.
1.4.4 Target sites:
Side effects can be minimized by delivering the maximum fraction of
applied dose reaching the target site. this can be partially attained by localized
delivery or use of novel carriers.
1.4.5 The patient:
Condition of patient, ambulatory or bedridden, obese or gaunt, old or
young can effect the design of controlled design.
1.4.6 The diseased state:
Pathophysiological state of subject play important part in the design
of suitable controlled release delivery system, that is in hepatic failure oral
delivery of drug should be stopped.
The below table enlists the various drug related and biological
factors affecting the design and in vivo performance of controlled release
formulations.11

Drug related Aqueous Physiological
solubility Partition coefficient Prolonged drug absorption Variability in
Molecular size GI emptying and motility Gastrointestinal
Drug stability Protein blood flow
binding Pharmacokinetic
Biological Absorption Dose dumping first pass metabolism
Distribution Elimination variability of urinary pH effect on drug
Duration of action Margin of elimination enzyme induction/inhibition
upon multiple dosing pharmacological

safety Side effects Disease
changes in drug effect upon multiple
state
dosing sensitizing/tolerance
1.5 Oral controlled release system:
Oral controlled release dosage forms can be classified in different ways.
One way is to distinguish between single-unit dosage forms such as tablets and
capsules, and multiparticulate dosage forms such as pellets or beads. According to
Carmella et al oral sustained release technologies may be classified according to
different criteria including the type of release (e.g. continuous release, delayed
transit release, slow, prolonged, pulsed, repeat-action, etc.) the release
mechanism (e.g. diffusion, dissolution, etc.) or the type of technological
system. Combining the classification methodology used by Carmella et al and
controlled release products can be classified as follows:
Reservoir systems including enteric coated tablets, capsules, coated granules
and microcapsules.
Osmotic systems
Ion-exchange resins
Matrix systems
1.5.1 Matrix Formulations:
Matrix formulations are defined as a drug or other active ingredient
embedded in insoluble excipients in order to achieve release by a continuous
leaching of the drug from the inert matrix core.
Matrix systems can be divided into three types:
1. Monolithic matrix tablets
2. Gel forming hydrophilic matrix tablets
3. Erodable (hydrophobic) matrix tablets
Inert monolithic matrix tablets:
Probably the simplest method of obtaining controlled release of a drug from
an oral dosage form is incorporation of a drug in an inert matrix. In this inert
means noninteracting with the biological fluids. The main reason for its
popularity is that drug release from plastic matrix tablets is independent on the
state and condition of the digestive juices, which may show large inter- and intra
patient variability (pH, viscosity).
During its transit through the gastro-intestinal tract, the porous matrix
tablet does not disintegrate like conventional tablets, but remains intact and the
skeleton can be recovered in faeces. The materials used in the preparation of these
inert matrices are predominantly (insoluble) polymers and lipophilic compounds.

The first polymers to be used for the preparation of matrix tablets were (semi-)
synthetic polymers such as polyethylene, polyvinyl chloride, polymethyl
methacrylate, polystyrene, poly vinyl acetate, cellulose acetate and ethyl cellulose.
The fat compounds used included carnauba wax, hydrogenated castor oil, and
tristearin.
Major drawback of most of the inert polymeric matrix tablets were
their inherent first order drug release characteristics, their poor direct
compression characteristics and the problematic cleaning of agglomeration
equipment used for the preparation of agglomerates with the required compression
characteristics.
Mechanism of release of inert monolithic matrix tablets:
Release from inert matrix tablets occurs via leaching mechanism. Drug
particles dispersed in the polymer matrix dissolve in the penetrating gastro-
intestinal fluids and are released from the tablet by diffusion through the porous
network of already existing pores and pores that created by dissolution of the
drug particles. At drug loadings exceeding approximately 10-15 % volume, a
continuous structure connecting all drug particles exists (percolating drug
network). At considerably lower loadings, a particular fraction of the drug may
be completely surrounded by the polymer matrix (trapped fraction), which would
result in incomplete release.

Fig. 1.2. Schematically representation of a leaching-based release mechanism. 12
Solvent activated matrix tablets:
The use of solvent-activated matrix tablets as a method to obtain zero
order release i.e. constant release rates over an extended period was first
proposed by Hoffenberg. Solvent-activated drug delivery system is a collective
term comprising those systems in which the interaction between polymer and
water is responsible for achieving controlled release. The interaction with water
may include plasticization, swelling, dissolution, erosion or degradation of the
polymer. The two most important types of solvent activated matrix tablets are gel-
forming hydrophilic matrix tablets and erodable (hydrophobic) matrix tablets.
Gel-forming hydrophilic matrix tablets:
Gel-forming hydrophilic or swellable matrix systems are homogeneous
or heterogeneous systems in which the drug is dispersed in a swellable
hydrophilic polymer. These systems have been widely studied by researchers since
they offer the possibility to obtain a constant drug delivery over an extended
period of time. Drug release is a function of the polymer characteristics.

Upon swallowing gel-forming hydrophilic matrix tablets, the
hydrophilic polymer is plasticized by the aqueous gastro-intestinal due to
which undergoes macromolecular chain relaxation and volume expansion.
Consequently, upon penetration of the gastro-intestinal fluids into tablet, a sharp
front can be distinguished which separates a dry, glassy core from a hydrated and
rubbery gel layer. Release is governed by diffusion of the dissolved drug
through the swollen gel layer and generally shows a burst effect, caused by
dissolution and leaching of drug particles present at the surface prior to formation
of the release-controlling gel.
Other swellable polymers, which have been applied in swelling-
controlled oral drug delivery systems, which show solvent controlled release, are
guar gums, Xanthan gum, poly (ethylene oxide) (PEO), poly (vinyl alcohol),
ethylene-vinyl alcohol copolymers (EVA) and dextrans.
Erodable matrix tablets:
Erodable polymers such as polyanhydrides offer another interesting
material platform for z e r o -order drug r e l e a s e . Like several HPMC grades,
upon water penetration, polyanhydrides form a gel-layer, which erodes at a
specific rate. By choosing the right polymer composition the thickness of the gel-
layer may remain constant with time resulting in a constant release rate until
12
depletion of the drug.
In the last two decades, controlled-release dosage forms have made
significant progress in terms of clinical efficacy and patient compliance.
Preparation of drug- embedded matrix tablet that involves the direct

compression of a blend of drug, retardant material and additives is one of
the least complicated approaches for delivering drug in a temporal pattern into
the systemic circulation. The matrix system is commonly used for manufacturing
controlled rel ease dosage forms because it makes such manufacturing easy. A
wide array of polymers has been employed as drug retarding agents each of which
presents a different approach to the matrix concept. Polymers forming insoluble
or skeleton matrices constitute the first category of retarding materials, also
classed as plastic matrix systems.
The second class represents hydrophobic and water-insoluble materials,
which are potentially e r o d a b l e ; while t h e t h i r d g r o u p i n c l u d e s
p o l y m e r s t h o s e f o r m hydrophilic matrices.
Plastic matrix systems, due to their chemical inertness and drug
embedding ability, have been widely used for controlling the release of the
drug. Liquid penetration into the matrix is the rate-limiting step in such systems
unless channelling agents are us ed . The hydrophobic and waxy materials, on
the other hand, are potentially erodable and control the release of drug
through pore diffusion and erosion. Polymers belonging to hydrophilic matrix
systems, when exposed to an aqueous medium, does not disintegrate, but
immediately after hydration develops a highly viscous gelatinous surface barrier,
which controls the drug release from, and the liquid penetration into the centre of
13
the matrix system.
The use of hydrophilic polymers is actually the most used method in
controlling the release of drugs in the formulation of oral pharmaceutical

dosage forms. Hydroxypropyl methylcellulose has been extensively used since
the early 1960s as a rate-controlling polymer in oral extended-release dosage

14
forms.
Hydrophilic matrix systems are popular and versatile controlled release
system. Amongst polysaccharide derivatives used to produce such systems, these
are a range of cellulose ethers, e.g., Hydroxypropyl methylcellulose (HPMC) and
a diverse range of other materials, including sodium alginate, carrageenan,
chitosan, ands Xanthan gum
1.6. An overview on Perindopril Erbumine:
Numerous studies demonstrated the efficacy of perindopril in the therapy of
essential hypertension. Perindopril doses of 4 to 16 mg administered once daily are
more effective than placebo in the treatment of mild-to-moderate hypertension. Doses
greater than 8 mg offer no advantage in most patients; however, in some patients
doses of 12 or 16 mg daily provide greater therapeutic benefit. The antihypertensive
activity of perindopril is linear at doses up to 8 mg, with 2 mg doses having only
slight antihypertensive activity. Administration with hydrochlorothiazide,
indapamide, and nifedipine in patients demonstrating an inadequate response to
monotherapy has resulted in improved blood pressure control.
The long-term efficacy of perindopril was reported in the results of an open
trial evaluating 690 patients. Therapy was initiated with perindopril 4 mg once daily
and increased, if necessary, to 8 mg. If diastolic blood pressure remained greater than
90 mmHg on perindopril 8 mg, a diuretic was added, and then another
antihypertensive agent was added if necessary. After 1 year of therapy systolic and

diastolic blood pressure were reduced by 29 mmHg and 19 mmHg, respectively.
Perindopril monotherapy normalized blood pressure in 55% of the patients. Blood
pressure control was achieved in 78% of the patients. After 3 years, perindopril
monotherapy at 4 or 8 mg controlled blood pressure in 56% of the patients.
The efficacy of perindopril was demonstrated in several studies enrolling
elderly patients with essential hypertension. Perindopril doses of 2 to 8 mg daily
reduced systolic and diastolic blood pressure. In a double-blind study enrolling 34
patients with a mean age of 84 years, perindopril reduced systolic pressure 10% and
diastolic pressure 9%. Although this effect was greater than that observed in the
placebo group (5% and 4%, respectively), the difference was not significant. In a
follow-up open study enrolling 91 patients with mean age of 79.1 years, 6 months of
perindopril therapy reduced blood pressure in the 80 patients who completed the
study; systolic blood pressure was reduced by 36.7 mmHg and diastolic blood
pressure decreased by 18.2 mmHg. Blood pressure control (defined as blood pressure
< 160/95 mmHg) was achieved in 92.5% of patients (62.5% at the dosage of 2 mg per
day, 22.5% at 4 mg per day, 7.5% at 8 mg per day, and 5% at 8 mg per day plus 40
mg nifedipine). The efficacy of perindopril was evaluated in 2,927 elderly patients
(>70 years) in an open study. At initiation of therapy with perindopril 2 or 4 mg once
daily, diastolic blood pressure was between 94 and 115 mmHg. After 1 or 3 months
of therapy, the dose could be doubled or a diuretic added if the perindopril dose had
reached 8 mg in patients with diastolic blood pressure remaining above 90 mmHg.
Diastolic blood pressure was reduced to less than 90 mmHg in 69% of patients at 1
month, 86% of patients at 3 months (in patients on perindopril alone), and 94% at 6
months. At 6 months, diastolic blood pressure was lowered 28 mmHg and systolic

blood pressure 16.6 mmHg. At that time, 86% of the patients were on perindopril
alone and 14% were on perindopril plus a diuretic; perindopril doses were 2 mg in
6.7% of patients, 4 mg in 79.1%, and 8 mg in 14.2%.
The efficacy of perindopril was demonstrated in several groups of patients
with hypertension and concomitant disease including hyperlipidemia, Type II
diabetes, ischemic heart disease, cardiac arrhythmia, peripheral arterial occlusive
disease, nephropathy with proteinuria, and chronic obstructive pulmonary disease.
Efficacy was demonstrated in patients with hypertension receiving nonsteroidal anti-
inflammatory agents (Indomethacin or diclofenac). In all groups, perindopril 4 mg
once daily effectively reduced blood pressure without negatively affecting the
patient's concomitant disease state or therapy. Perindopril did not affect lipid or
apolipoprotein levels in patients with hyperlipidemia, did not affect glucose control in
diabetic patients, had an anti-ischemic and antianginal effect in those with ischemic
heart disease, and reduced urinary albumin excretion in patients with proteinuria.
Other studies have shown a lack of effect of perindopril on lipid or carbohydrate
metabolism. Several studies demonstrated the safety and efficacy of perindopril in the
treatment of hypertension in patients with diabetes or glucose intolerance. Perindopril
has not negatively affected glucose tolerance, insulin sensitivity, renal function, or
lipid profiles in diabetic patients treated long-term.
1.7. Conventional methods: 15
Conventional methods such as direct compression, dry granulation and wet
granulation methods can be adopted to produce Controlled matrix tablets. In
formulating CMTs, one of the important components is the Matrix carriers.

a) Direct Compression: 16
In this technique, tablets are compressed directly from the mixture of the drug
and excipients without modifying the physical nature of the materials. This method is
applicable for crystalline chemicals having good compressible characteristics and
flow properties such as potassium salts, chlorate, chloride, bromide etc.
The processing steps involved are:
Raw materials → weighing → screening → Mixing → Compression
b) Dry granulation technique: 16
Slugging may be used to form granules if the tablet ingredients are sensitive to
moisture and/or unable to withstand elevated temperature during drying. This method
is referred to as dry granulation. Compression granulation involves the compaction of
the components of a tablet formulation by means of a flat punch. These compact
masses, called slugs, are then milled and screened to produce granules. Specially
designed machines called roller compactors are used on a large scale.
Raw material → Weighing → Screening → Mixing → Slugging → Milling →
Screening → Mixing → Compression
c) Wet granulation method: 16
This is the most widely used method of tablet preparation. The active
ingredient, diluent and disintegrants are mixed or blended well. For large scale
production twin shell blenders, planetary mixers, sigma blade mixers, ribbon blade
mixers are used commonly used. Moist materials from wet milling step are placed on

large trays and placed in drying chambers with a circulating air current and
thermostable heat controller. After drying granulation, the lubricant or glidant is
added as fine powder to promote flow of granules. These granules are then
compressed to get tablets.
Raw material → Weighing → Screening → Wet massing → Sieving/Milling →
Drying → Screening → Mixing → Compression

2. AIMS AND OBJECTIVES OF THE INVESTIGATION
Hypertension confers an increased risk of heart attacks and strokes. Elevated
arterial pressure causes pathological changes in the vasculature and hypertrophy of
the left ventricle. As a consequence, hypertension is the principal cause of stroke,
leads to disease of the coronary arteries with myocardial infarction and sudden cardiac
death, and is a major contributor to cardiac failure, renal insuffiency, and dissecting
aneurysm of the aorta.1 Perindopril is a ACE inhibitor prodrug of Perindoprilet which
has been successfully used in the treatment of hypertension either alone or in
combination with other antihypertensive agents. When administered orally it is only
36 % available as a conventional medication.
However, some of the technologies used for the manufacture of CMTs have
disadvantages, pertaining to specialized equipment required , such as freeze-driers and
specially molded tableting machines, apart being a costly affair.
Since, Perindopril Erbumine CMT are not having Prominent significance in
the commercial market for use, an attempt was made to formulate and evaluate
Controlled matrix tablet(CMT) containing Perindopril Erbumine(PE), which can be
manufactured by commonly used production methods and equipment, with the
following objectives:
1. To carry out Preformulation studies on pure drug, pre-compressional
characterization of physical mixture of drug and excipients.

2. To evaluate tablets for various physico-chemical parameters such as hardness,
diameter, friability, weight variation, drug content, swelling index, in vitro
disintegration time, in vitro dissolution.
3. To study the influence of excipients on drug release from such tablets and to
improve the rate of release of drug from the CMT.
4. To carryout stability studies on selected fast dissolving tablets as per ICH
guidelines.
The work plan was outlined to fulfil the above objectives for different
formulation variables. Various methods were used for evaluation of the tablets to
qualify CMT requirements and the results obtained and the stability studies are all
discussed in the following chapters.

3. REVIEW OF LITERATURE
The literature from various text books, pharmacopoeias, journals, and World
Wide Web were thoroughly studied and understood. The references that were found
to be relevant to the current investigation have been cited appropriately, the following
abstracts of the previous reports would give an insight of the investigation that has
been undertaken:
Shirwaikar A.A.et.al.,17 studied Rosin, a natural resin, as an insoluble matrix
material for the release of diltiazem HCI, as a model drug. The granules prepared
were flowing with good compressibility. The tablets prepared were flat faced, which
retained their shape throughout. The method of preparation of matrix system and its
concentration were found to have a pronounced effect on the release of diltiazem HCI.
Various physical parameters of granules and the tablets were evaluated. The release
mechanisms and the release rate kinetics of the tablets were examined using different
models. The release was found to follow both the first order kinetics and Fickian
diffusion. Marked differences in the release rate of the drug from different
formulations were observed when % cumulative release was plotted against time. The
drug delivery was analyzed using the paddle method according to USP XXIII. All the
studies were done in distilled water.
Nevin Erk18 developed a new sensitive, simple, rapid and precise reversed-
phase high performance liquid chromatographic (HPLC) and two spectrophotometric
methods to resolve binary mixture of Perindopril and indapamide in the
pharmaceutical dosage forms. The first method is based on HPLC on a reversed-phase
column using a mobile phase of phosphate buffer pH 2.4 and acetonitrile (7:3 v/v)

was used. Linearity range for Perindopril and indapamide was 5.0–70.0 and 8.0–35.0
g ml−1. In the second method, the first derivative Spectrophotometry with a zero-
crossing technique of measurement is used for the simultaneous quantitative
determination of Perindopril and indapamide in binary mixtures without previous
separation step. Linear calibration graphs of first derivative values quantitative
determination of Perindopril and indapamide in binary mixtures at 225.7 and 255.4
nm for Perindopril and indapamide, respectively. The third method is based on ratio
derivative spectrophotometry, the amplitudes in the first derivative of the ratio spectra
at 226.5 and at 255.3 nm were selected to determine Perindopril and indapamide in
the binary mixture. All the proposed methods showed good linearity, precision and
reproducibility. The proposed methods were successfully applied to the
pharmaceutical dosage forms containing the above-mentioned drug combination
without any interference by the excipients.
Prameela Rani.A.etal.,19 developed A new high performance liquid
chromatographic (HPLC) method was developed and validated for the determination
of Perindopril Erbumine (PE) in pharmaceutical formulations. Optimum separation
was achieved in 10 min using C18 column (250 mm × 4.6 mm, i.d., particle size 5
mm), and elution was accomplished using a mobile phase (1ml/min). Detection was
carried out using a UV detector set at 215 nm. A linear relationship between mean
peak area and concentration of PE was observed in the range 4-20 μg/ml, with a
detection limit of 2 μg /ml and a quantization limit of 7.0 μg/ml. Intra-day and Inter-
day precision, and accuracy of the methods have been established according to the
current ICH guidelines. The developed method was successfully applied to the
determination of PE in pharmaceutical formulations. The results were statistically

compared with those of the reference method (UV method) by applying Student‟s t-
test and F-test. Accuracy, evaluated by means of the recovery method, was in the
range 99.00 - 100.5 %, with precision (RSD) 0.865%. No interference was observed
from the co formulated substances. The proposed method was successfully employed
for the determination of PE in various pharmaceutical preparations
The drug release behaviour of xanthan gum matrix tablets were studied by
Talukdar MM.et al., using three drugs having different properties, i.e., caffeine as a
soluble neutral drug, indomethacin as an insoluble acidic drug, and the sodium salt of
indomethacin as a soluble acidic drug. Swelling was ascertained by measuring the
axial and the radial expansion of matrix tablets following exposure to media of
physiological ionic strength. The mean drug dissolution time and swelling rate were
calculated from dissolution and swelling experiments, respectively, and were used as
responses for comparison under different experimental conditions. The dependence of
drug release on the swelling of the polymer matrix and on the type of the drugs added
was established. The former is mainly influenced by the ionic strength and buffer
concentrations. The latter is affected by the solubility of the drug. The mechanism of
matrix swelling follows Case I diffusion, whereas drug release from this polymer
matrix conforms to Case II diffusion.
Sarojini.S.etal.,20 Developed effect of natural almond gum as a binder in the
formulation of diclofenac sodium tablets. The study was undertaken to find out the
potential of gum from Almond gum to act as a binder and release retardant in tablet
formulations. The effect of almond gum and pvp on the release of diclofenac sodium
was studied. Seven formulations were prepared by wet granulation method containing
Microcrystalline cellulose as diluents, diclofenac sodium as model drug using

2%,4%,6%,8% and 10% w/v of almond gum solution and 2%,4% w/v of pvp gum
solution. This was carried out to find out the difference between synthetic and natural
gum and whether synthetic gum can be replaced by natural gums. The drug release
increased with almond gum when compared to synthetic gum concentration of 2%
and 4%. The values of release exponent were found to be less than 0.5. This implies
that the release mechanism is non-fickian diffusion. Tablet at 2% w/v binder
concentration showed optimum results as tablet binder. The Almond gum was found
to be useful for the preparation of uncoated tablet dosage form.
K S Lakshmi.etal.,21 A Validated HPTLC Method for Simultaneous
Determination of Losartan and Perindopril in Tablets. A Simple, fast and precise high
performance thin layer chromatographic method has been developed for the
simultaneous determination of Losartan and perindopril in tablet. Separation was
carried out on precoated TLC plates, coated with silica gel 60 F 254. The separation
was done using a mobile phase toluene: acetonitrile: formic acid (5:5:0.3 v/v/v). After
development, the chromatoplates were scanned at 215 nm. The Rf value of losartan
and perindopril was found to be 0.55 and 0.27 respectively. The results of the analysis
have been validated statistically and by recovery studies.
T. Raja sekharan.etal.,22 Formulation and Evaluation of Theophylline
Controlled Release Matrix Tablets using Xantham gum. Controlled release matrix
tablets of Theophylline were prepared with hydrophilic polymer xantham gum and
evaluated. Controlled release matrix tablets of Theophylline were prepared by wet
granulation technique by varying polymer ratios (1:1 and 1:2) and hardness (5, 6 and
7 kg/cm2). Tablets were prepared by wet granulation technique. The granules are
subjected for Preformulation studies. Compressed tablets were evaluated for hardness,
uniformity of weight, friability, drug content, thickness and diameter. All the
formulation showed compliance with pharmacopoeial standards. IR spectroscopy
revealed that there was no interaction between the drug and the polymer used in the
formulation. In vitro dissolution studies were performed using Disso 2000 (paddle
type). Among all formulations F6 showed controlled 73.18 + 1.55 % after 10 hr. The
kinetic treatment showed that the drug release followed higuchi model. F-6
formulation was subjected to stability studies at three different temperatures for
6months period. It was found to be stable. From this study it was proved that the
release of theophylline from matrix tablets was influenced by both polymer ratio and
hardness.
Bhanja Satyabrata.et al.,23 Design and in vitro Evaluation of Mucoadhesive
Buccal Tablets of Perindopril Prepared by Sintering Technique The aim of the present
study was to prepare and evaluate a mucoadhesive buccal tablet containing
antihypertensive drug i.e. Perindopril to avoid the first pass metabolism and to
improve its bioavailability with reduction in dose and also dose related side effects.
The half life of Perindopril is approximately 0.8 to 1 hrs. The tablets were prepared by
direct compression method containing polymer Polyethylene oxide and carnauba wax.
The prepared tablets were sintered at various temperatures like 600 C and 700C for 1.5
hr and 3 hr. The sintered tablets were tested for weight variation, hardness, surface
pH, drug Content Uniformity, swelling index, bio adhesive strength sand in-vitro drug
dissolution study. FTIR studies showed no evidence on interactions between drug,
polymers, and excipients. The Invitro release of Perindopril was performed under sink
conditions (Phosphate buffer PH 6.8, at 37±0.50C and 50 rpm) using USP-XXIV
dissolution apparatus. The sintering times and the sintering temperature markedly

affected the drug release properties of Perindopril buccal tablets. It is notable that the
release rate of Perindopril from buccal tablets was inversely related to the time of
sintering and the sintering temperature. This is may be due to increase in extent and
firmness of sintering which compacts the mass further, so that the drug release is
affected. The best in-vitro drug release profile was achieved with the formulation F4
A (sintered at 600c for 1.5 hr.) which contain the drug, polyethylene oxide and
carnauba wax in the ratio of 1:15:10.The surface pH, bio adhesive strength and
swelling index of formulation F4 A was found to be 6.27, 34.8 gm and 179.31 (after
12 hr). The tablets (formulation F4 A) containing 4 mg of Perindopril exhibited 8 hrs
sustained drug release (98 %) with desired therapeutic concentration. The drug release
followed diffusive mechanism with first order release kinetics. The stability studies
showed that optimized formulation was considered to be highly.
Ranjith Kumar Mamidala.et al,.24 Factors Influencing the Design and
Performance of Oral Sustained/Controlled Release Dosage Forms. Of all drug
delivery systems, oral drug delivery remains the most preferred option for
administration for various drugs. Availability of wide variety of polymers and
frequent dosing intervals helps the formulation scientist to develop
sustained/controlled release products. Oral Sustained release (S.R) / Controlled
release (C.R) products provide an advantage over conventional dosage forms by
optimizing bio-pharmaceutic, pharmacokinetic and pharmacodynamic properties of
drugs in such a way that it reduces dosing frequency to an extent that once daily dose
is sufficient for therapeutic management through uniform plasma concentration
providing maximum utility of drug with reduction in local and systemic side effects
and cure or control condition in shortest possible time by smallest quantity of drug to

assure greater patient compliance. This review describes the various factors
influencing the design and performance of sustained/controlled release products along
with suitable illustrations.
Thawatchai Phaechamud.et al,.25 Controlled Release of Propranolol HCl from
Chitosan-Lactose-Xanthan Gum Matrix Tablets. The application of low molecular
weight Materials chitosan as matrix component for controlled propranolol HCl
release prepared by direct compression was studied. The effect of the additives on
drug release from matrix tablets containing chitosan was investigated an
incorporation of xanthan gum into chitosan tablet could prolong the drug release
rather than that containing single polymer. The drug release could be modified by
addition of lactose. The drug release was gradually enhanced as the greater
amount of the lactose was added into the matrix. Most of drug dissolution profiles
could be well fitted with first order kinetic release.
Harry GB et.al.,26 characterized the two polymorphic modifications of
fosinopril sodium to their differences in melting behaviour, powder X-ray diffraction
patterns, fourier transform infrared spectra(FTIR),and solid state 31P- and 13C-NMR
specta. The polymorphs were found to be enantiotropically related based upon
melting point, heat of fusion, and solution mediated transformation data. Analysis of
solid state FTIR and 13C-NMR data indicated that the environment of the acetal side
chain of the fosinopril sodium differd in two polymorphs, and that there might be cis-
trans isomerization about the C6-N peptide bond. These conformational
differences are postulated as the origin of the observed polymorphism.

Basak SC et.al., 27 prepared propranolol hydrochloride matrix tablets with
hydroxypropyl methylcellulose polymer to control the release of drug with a view to
develop twice daily sustained release dosage for. The resulting matrix tablets prepared
with hydroxypropyl methylcellulose K4M fulfilled all the official requirements of
tablet dosage forms. The in vitro drug release was measured in aqueous solutions for a
total period of 12 h using 1.2 pH buffer for first 1 h and pH 7.5 buffer for the rest of
period. The drug release was within the limits of predetermined set vis-a-vis USP
requirements.
Sunil Jambhekar et.al.,28 made an effort to improve the bioavailability of the
insoluble drug indomethacin, three complexes were prepared with Indomethacin and
the soluble complexing agents β-hydroxyethyl and hydroxypropyl β-cyclodextrin. The
indomethacin content was similar among the complexes (P ≤ 0.05). To confirm
complex formation, each complex was characterized by ultraviolet, infrared, nuclear-
magnetic resonance, powder X-ray diffraction, and differential-scanning calorimetry
techniques. Powder diffraction studies show the β-cyclodextrin complex was
polycrystalline, and the hydroxyethyl and hydroxypropyl β-cyclodextrin complexes
were amorphous. Phase-solubility analysis confirmed the formation of complexes and
suggested the three complexes were bound similarly. Solubility studies show
complexation increased indomethacin solubility, and the hydroxyethyl and
hydroxypropyl- β-cyclodextrin complexes were more soluble than the β-cyclodextrin
complex in 0.1N hydrochloric acid and distilled water. Dosage forms were prepared
by encapsulating the complexes without the addition of excipients. Dissolution studies
show the encapsulated β- and hydroxyethyl- β-cyclodextrin complexes had superior
dissolution when compared to the hydroxypropyl- β-cyclodextrin and Indocin® (50

mg) capsules. Bioavailability studies were performed by administering the
indomethacin complex or Indocin capsules to male-albino, New Zealand rabbits.
Indomethacin plasma-time concentration data fit best to a compartment-independent
model for all capsule formulations. Bioavailability comparisons by ANOVA show no
significant difference (P ≤ 0.10) in the peak-plasma time and peak concentration
among the capsule formulations. The area-under-the-curve for the β-cyclodextrin
complex capsules was found to be significantly higher (P ≤ 0.10) than all other
capsule formulations. In conclusion, the bioavailabilty of indomethacinwas improved
by complexation with only β-cyclodextrin No correlations were found among the
bioavailability, solubility, and dissolution results.
Medenica.M et.al.,29 Evaluation of impurities level of perindopril tert-
butylamine in tablets Perindopril tert-butylamine is a new member of angiotensin-
converting enzyme inhibitors group used in the treatment of hypertension and heart
failure. In this paper, the evaluation of reversed-phase high-performance liquid
chromatographic method (RP-HPLC) for the determination of impurities level of
perindopril tert-butylamine in tablets was done. The chromatograms were recorded
using a Hewlett Packard 1100 chromatographic system with DAD detector.
Separations were performed on a YMC-Pack C8 column (250mm×4.6 mm; 5 _m
particle size) at 50◦C column temperature. Mobile phase was a mixture of
acetonitrile–potassium phosphate buffer (0.05 M) (37:63, v/v) (pH 2.5). pH of the
mobile phase was adjusted with orthophosphoric acid. Mixture of acetonitrile–water
(40:60, v/v) was used as a solvent. Injection volume was 50 _l, flow rate 1.7 ml
min−1 and UV-detection was performed at 215 nm. The developed method subjected
to method validation and parameters in terms of selectivity, linearity, precision,

accuracy, limit of detection, limit of quantitation and robustness were defined. The
validated method is suitable for the simultaneous determination of perindopril tert-
butylamine as well as its impurities in pharmaceuticals.
Hisham E. Abdellatef et.al.,30 Two sensitive, spectrophotometric and atomic
absorption spectrometric procedures are developed for the determinationof ramipril
and perindopril. Both methods are based on the formation of a ternary complex,
extractable withchloroform, between copper(II), eosin and the two cited drugs.
Spectrophotometrically under the optimum condition, the ternary complexes showed
an absorption maximum at 535 nm, with apparent molar absorptivities of 6.55
and4.00_103 mol_1cm_1 and Sandell‟s sensitivities of 5.80_10_2 and 1.04_10_1mg
cm_2 for perindopril andramipril, respectively. The solution of ternary complex
obeyed Beer‟s law in concentration ranges 10–60 and 20–100 mg ml_1 for
perindopril and ramipril, respectively. The proposed method was applied to the
determination of the two cited drugs in pharmaceutical tablets. The atomic absorption
spectrometric method, directly through the quantitative determination of copper
content of the organic extract of the complex, was also investigated for the purpose of
enhancing the sensitivity of the determination. The spectrophotometric and atomic
absorption spectrometric procedures hold their accuracy and precision well when
applied to the determination of ramipril and perindopril dosage forms.
Hisham E. Abdellatef et.al.,31 Simple, rapid, accurate and sensitive
spectrophotometric methods are described for the determination of perindopril. The
methods are based on the reaction of this drug as n-electron donor with 2,3-dichloro-
5,6-dicyano-p-benzoquinone(DDQ)-7,7,8,8-tetracyanoquinodimethane (TCNQ),
tetracyanoethylene (TCNE), chloranil (CL) and p-chloranilic acid (p-CA) as p-

acceptors to give highly coloured complex species. The coloured products are
measured spectrophotometrically at 588, 843, 419, 550 and 520 nm for DDQ, TCNQ,
TCNE, CL and p-CA, respectively, optimization of different experimental conditions
is described. Beer‟s law is obeyed in the range of 20–200 mg ml_1 and colours were
produced in non-aqueous media and were stable for at least 1 h. Application of the
suggested methods to perindopril tablets are presented.
Kenneth I. Ozoemenaa.et al.,32 Construction of enantioselective,
potentiometric membrane electrodes based on carbon-paste impregnated with and
cyclodextrin as chiral selectors for the assay of S-perindopril is described. Response
characteristics showed that the proposed electrodes could be reliably applied in the
assay of S-perindopril raw material and its pharmaceutical formulation. The best
enantioselectivity and time-stability were exhibited by and cyclodextrin based
electrodes.
33
Yeole PG et.al., made an attempt to increase therapeutic efficacy, reduce
frequency of administration, and improve patient compliance, by developing
sustained release matrix tablets of diclofenac sodium. Sustained release matrix tablets
of diclofenac sodium, were developed by using different drug: polymer ratios, such as
F1 (1:0.12), F2 (1:0.16), F3 (1:0.20), F4 (1:0.24) and F5 (1:0.28). Xanthan gum was
used as matrix former, and microcrystalline cellulose as diluent. All the lubricated
formulations were compressed using 8 mm flat faced punches. Compressed tablets
were evaluated for uniformity of weight, content of active ingredient, friability,
hardness, thickness, in vitro dissolution using basket method, and swelling index. All
the formulations showed compliance with pharmacopoeial standards. Among
different formulations, F1 showed sustained release of drug for 12 hours with 89.67%
release. The effect of other parameters like addition of release modifier (PEG 6000),
gum concentration, pH of dissolution medium, rotation speed and dissolution by
paddle method, were also studied. Selected formulation (F1) was subjected to stability
studies for three months at 0-4°, room temperature (28°), and 45° with RH 75±5%,
and showed stability with respect to release pattern. The kinetic treatment showed that
the release of drug follows zero order kinetic (R2 = 0.9758). Korsmeyer and Peppas
equation gave value of n = 0.9409 which was close to one, indicating that the drug
was released by zero order kinetic. Thus, Xanthan gum can be used as an effective
matrix former, to extend the release of diclofenac sodium.
34
Reynolds D, et al., investigated polymer erosion of matrices of similarly
substituted hydroxy propyl methylcellulose (HPMC) polymers was examined, and
drug release in terms of diffusion and erosion contributions was characterized,
focusing on matrices containing either polymer alone or a drug content of 25% level
with no added excipient A novel approach was utilized to separate diffusion and
erosional contributions to drug release. Diffusion drug release was determined by
fitting release data versus (time) 0.45, and the drug release due to erosion was
quantified by subtracting the percent predicted for diffusion drug release from the
total drug release at each specific time point. Drug release resulting from polymer
erosion was linear versus time and was found to be a function of the number average
Molecular weight of the polymer. In contrast, diffusion release rates were comparable
for all HPMC grades studied and, thus, were independent of number average
molecular weight of the polymers studied. Under stirring conditions of 10 - 100 rpm
as well as static condition, the detachment of individual polymer chains at the matrix
surface occurred at a faster rate relative to diffusion away from the matrix surface.

The erosion study indicated that polymer diffusion of the HPMC polymer chains
through the aqueous diffusion layer was the rate-limiting step for polymer erosion. In
general, polymer erosion was found to be inversely related to the polymer number
average molecular weight. A scaling law was used to relate polymer erosion rate with
the respective polymer number average molecular weight. Similar relationships were
obtained for matrices with and without drug at a stirring rate of 100 rpm.
35
Lutfi Genc et al., prepared controlled release dosage forms of
dimenhydrinate with different polymers as MC, HEC, Carbopol 934,Eudragit RLPM
and Eudragit NE 30 D at different concentrations 2.5–10%. Direct compression DC
and wet granulation WG techniques were used to prepare the tablets. Magnesium
stearate was the lubricant while starch gel was the binder. When the branched
polymer is in contact with synthetic gastric liquid, this polymer turns into a gel,
because of the liquid transfer into the polymer. On the other hand, a release of the
drug is observed, which does not follow a classical kinetic equation, as the kinetics is
partially controlled by diffusion. This study shows that the diffusion release
mechanism in a matrix system comprising an insoluble hydrophobic and a hydrophilic
gel-forming part depends greatly on the wettability of the added drug. Furthermore,
with wettable and water soluble drug, the matrix swells and release is mainly achieved
by diffusion due to dissolution of the gel formed

4. METHODOLOGY
4.1. Materials
The materials used for the formulation and evaluations are listed below:
S. No. Materials Source
Complimentary sample from Lupin drugs

1. Perindopril Erbumine
Ltd, Pune
2. Xanthan gum S.d. Fine chemicals limited, Mumbai
3. Almond gum INR Chemicals, Mumbai
4. Eudragit RL100 S.d. Fine chemicals limited, Mumbai
5. Starch I.P S.d. Fine chemicals limited, Mumbai
6. Talc S.d. Fine chemicals limited, Mumbai
Magnesium Stearate S.d. Fine chemicals limited, Mumbai

7.

4. 2. Equipments
S. No Name of the Equipment Supplier / Manufacturer
Digital balance
1. Afcoset electronic balance, Mumbai.
2. Hot air oven Spencers, Delhi.
10 station PP1D, Chamunda pharma,

3. Tablet compression machine
Ahmedabad.
Tablet Dissolution tester USP

4. DBK Instruments, Mumbai.
XXII
5. Disintegration apparatus Campbell electronics, Mumbai.
6. Friability test apparatus Konark instruments.Ambala,Haryana.
7. pH meter Systronics, Mumbai.
UV-visible
spectrophotometer
8. Shimadzu Corporation, Japan.
(UV-1700)
9. Hardness tester Pfizer hardness tester, India.
10. Blender Konark instruments.Ambala,Haryana.
11. Bulk density apparatus Konark instruments.Ambala,Haryana.
12. Rotary Shaker Konark instruments.Ambala,Haryana.
13. Vernier Calipers Mitutoyo, Japan

4.3. Profile of Perindopril Erbumine: 38-46
Perindopril Erbumine is a dipeptide monoacid monoester with a
perhydroindole group and no sulphydryl radical; chemical name, tert-butylammonium
(2S, 3aS, 7aS)-1-(N-[(S)-1-ethoxycarbonyl butyl]-L-alanyl) perhydroindole-2-
carboxylate and used for the treatment of patients with hypertension and symptomatic
heart failure.
Physical and chemical properties:
Empirical Formula : C19H32N2O5 , C4H11N
Molecular weight : 368.46 g/mol
Melting point : 126 -128 C
Category : Antihypertensive
Description : White crystalline powder, slightly hygroscopic
odourless, bitter in taste.
Solubility : The Perindopril Erbumine is soluble in water,
methanol, ethanol, acetic acid and ethyl acetate, very
slightly soluble in ether, chloroform and benzene.
Chemical Nature : Perindopril Erbumine dipeptide monoacid monoester
with a perhydroindole group and no sulphydryl
radical.

Structure:
Chemical name: Tert-butylammonium (2S, 3aS, 7aS)-1-(N-[(S)-1-ethoxycarbonyl
butyl]-L-alanyl) perhydroindole-2-carboxylate
Pharmacokinetics:
Absorption : well absorbed after oral administration.
Route of administration : Oral
Protein Binding : 10 - 20%
Bioavailability : 65% - 75 %
Metabolism : Hepatic.
Half life : 1.2 h
Excretion : Renal.

Volume of Distribution : Approx. 140-160L/kg ;
Clearance : 219 – 362 mL/min.
Dissociation Constant (Pka): 2.6
Elimination Half life : 0.8-1 hr
Mechanism of Action:
Perindopril erbumine inhibits ACE in human subjects and animals, while the
principle mechanism of perindopril is blood pressure reduction is believed to be
through the renin-angiotension- aldoserone system.
There are two isoforms of ACE the somatic isoform, which exists as a
glycoprotein comprised of a single polypeptide chain of 1277 and the testicular
isoform, which has a lower molecular mass and is thought to play a role in sperm
maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two
functionally active domains, N and C, which arise from tandem gene duplication.
Although the two domains have high sequence similarity, they play distinct
physiological roles. The C-domain is predominantly involved in blood pressure
regulation while the N-domain plays a role in haematopoietic stem cell differentiation
and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but
have much greater affinity for and inhibitory activity against the C-domain.
Perindoprilet, the active metabolite of perindopril, competes with ATI for binding to
ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels
in the body decreases blood pressure by inhibiting the pressor effects of ATII as
described in the Pharmacology section above. Perindopril also causes an increase in

plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on
the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Adverse effects:
Upper respiratory infection, asthenia, rhinitis, diarrhoea, oedema, pharyngitis,
urinary tract infection, abdominal pain, sleep disorder, chest disorder, chest pain,
tinnitus, flatulence, malaise, cold/hot sensation, angioedema, gastro enteritis,
bronchitis, rhino rhea, vaginitis, ventricular extra systole, myocardial infraction
vasodilation, gout, pruvitus, conjunctivitis, arthralgia.
Contraindications:
Diuretics reduce the bioavailability of perindopril erbumine, Pregnancy:
contraindicated.
Interactions:
Perindopril Erbumine is known to interact with other drugs like Fluorouracil,
Lithium, Phenobarbitone, Phenytoin (Na), Warfarin (Na), Digoxin, Azathioprine,
Aspirin. These interactions are sometimes beneficial and sometimes may pose threats
to life.
Indications:
The drug is effective in the treatment of Hypotension, Anaphylactic reactions
during desensitization, membrane exposure, Intestinal angioedema, Neutropenia.
Dosage:
For Adult dose; 4-8 mg as a single dose for 1 day.

Commercial dosage: Aceon 4mg (Solvey pharma.)
Conversyl 4mg ( Aurobindo Pharma)
Warnings / Precautions:
Alcoholic drinks and alcohol containing medicines should be avoided during
Perindopril Erbumine treatment. Do not administer to subjects with a history of blood
dyscrasia.
Specification : 4mg
Storage : Keep tightly closed and Store in a dry place,
Protect from direct light.
Package : tablets × 1 blister in PVC/aluminium blister packaging.
Shelf life : 24 months.

4.4. Review of additives:
4.4.1. Xanthan Gum:47-49
Chemical name : Xanthan gum
Empirical formula : (C35H49O29)n
Molecular weight : (933) n Daltons
Chemical Structure :
H
H OH H H OH H H
H
OH 4
O OH
O HO
HO 1 O HO OH
O H
H 1 O
HO 1 HO O 3
1 OH
OH H OH H H H HO
H H H n
H OH
2 H
H O
O H
O O O
H 6 OH H 1
OH
O O 6
O O
4
O 4 H O OH
1 O OH H H
CH 3 H
HO HO
H H O
H H CH 3
Xanthan is an anionic bacterial polysaccharide composed of a U-(1)-D-
Gle(1)-beta-D-GLC (cellulosic) backbone with a trisaccharide side chain linked to
C3 of every second glucose residue. The side chain is U-D-Man-(1)-U-D-Gle A-
1(/2)-6-O-acetyl-alpha-D-Man-(1/beta-D-Glca-((12)-alpha-D with
approximately 60% of the terminal mannose units being pyruvylated and 90% of the
proximal mannose units substituted at C6 with O-acetyl groups. It has side chains of 2
mannose and 1 gluconic glucoronic acid group.

Xanthan gum is an exocellular polysaccharide reduced by fermentation of the
bacteria Xanthomonas campestris.
Description:
Xanthan gum is off white granular powder. In cold water, it is dispersed to
form pseudo plastic mixtures. It is highly water soluble.
Melting point: 270 °C
Viscosity (dynamic): 1200–1600 mPas (1200-1600 cP) for 1% w/v aqueous solution
at 25°C.
Salt solutions: Compatible and stable in solutions with high salt concentrations.
Others:
It has unique enzyme resistance. Upon heating it may increase or maintain
viscosity. It is affected by shear but recovers hence, is thixotropic gelling agent. It
stabilizes solid, liquid, and gaseous dispersions, viscosity dispersions are highly
pseudo plastic, Xanthan exhibits pseudo plasticity on the basis of its helical structure.
Stability and Storage:
Xanthan gum is a stable material Aqueous solutions are stable over a wide pH
range (pH 3–12), although they demonstrate maximum stability at pH 4–10 and
temperatures of 10–60°C. Xanthan gum solutions of less than 1% w/v concentration
may be adversely affected by higher than ambient temperatures: for example,
viscosity is reduced. Solutions are also stable in the presence of enzymes, salts, acids,
and bases.

Applications in pharmaceutical formulation or technology:
Gum provides visibly clear solutions even at higher concentrations; it exhibits
less gummy mouth-feel than gums with more Newtonian characteristics. Xanthan
gum is commercially available in both clarified and non clarified forms. Clarified
Xanthan gives visibly clear solutions even at high concentrations, while unclarified
Xanthan gums are opaque. It acts as an emulsion stabilizer, holds water, enhances
freeze-thaw stability, inhibits starch retro gradation improves shelf-life and serves to
bring about stabilization dispersions, suspension, and emulsion, and thickeners.
Although primarily used as a suspending agent, Xanthan gum has also been used to
prepare sustained-release matrix tablets. Controlled-release tablets of diltiazem
hydrochloride prepared using Xanthan gum have been reported to sustain the drug
release in a predictable manner and the drug release profiles of these tablets were not
affected by pH and agitation rate.

4.4.2 Almond Gum :50-53
Synonym : Peach gum, Cedo gum. A kind of amylose natural
gum secreted from peach trees.
Structure:
H
O
H
O
O N
H
O O
O O O
H
H H
O O
O
H
Chemical name:
2-phenyl-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4S,5S,6R)-3,4,5-
trihydoxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyacetonitrile.
Molecular Formula : C20H27NO11, 3H2O
Molecular Weight : 511.27 Daltons
pH : 6-7 (15 % w/v solution)

Chemistry:
Amygdalin, C20H27NO11, 3H2O, is the glucoside of d-phenylglycollic acid, and
is obtained from bitter almonds, or the seeds of other rosaceous plants. It is neutral in
reaction and laevorotatory ([α] D = -35.5°).By the action of emulsin, it is decomposed
into dextrose, benzaldehyde, and hydrocyanic acid this decomposition also occurs
under the influence of dilute acids.
Composition of Almond tree Gum :
The following table embodies the results obtained in the analysis of almond-
tree gum.
Table.4.3. Analysis of almond-tree gum
Almond - tree
Gum Form
(hard) (elastic)
Soluble in Water calculated 21.06 8.90
on Dry Substance %
Insoluble in water % 78.94 91.10
Moisture % 15.76 25
Ash % 2 .34 ----
Galactans as Galactose % 23.70 ----
Pentosans as Arabinose % 54.60 ----
Total Sugars 85 91

Melting point : It melts at about 200°C, after darkening in colour, and sets to
glassy mass, which melts at 125° C to 130°C.
Description : It occurs as a brownish, odorless, granular powder.
Solubility : Soluble in water or alcohol; insoluble in ether.
Applications:
Thickening agent and Stabilizer in foodstuff and cosmetics, auxiliary in ink
and pigment, Excipient, Gooey, etc.
Medicinal Uses:
As well as being a tasty addition to the diet, almonds are also beneficial to the
overall health of the body, being used especially in the treatment of kidney stones,
gallstones and constipation. Externally, the oil is applied to dry skins and is also often
used as carrier oil in aromatherapy. The seed is demulcent, emollient, laxative,
nutritive and pectoral. When used medicinally, the fixed oil from the seed is normally
employed. The seed contains 'laetrile', a substance that has also been called vitamin
B17.This has been claimed to have a positive effect in the treatment of cancer, but
there does not at present seem to be much evidence to support this. The pure
substance is almost harmless, but on hydrolysis it yields hydrocyanic acid, a very
rapidly acting poison - it should thus be treated with caution. In small amounts this
exceedingly poisonous compound stimulates respiration, improves digestion and
gives a sense of well-being. The leaves are used in the treatment of diabetes. The
plant contains the antitumor compound taxifolin.

4.4.3.Eudragit RL 10054-55
Chemical name: Polymethacrylate
Chemical Structure:
CH3 CH3 CH3 CH3

CH2 CH2 CH2 CH2
O O O O
O O O O
H CH3 H CH3
n
Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl
methacrylates, methacrylic acid and methacrylic acid esters.
Molecular weight: 1, 50,000.
Form: Granular form.
Colour: colourless.
Odour: Faint like amine odour.
Density: Relative density 0.816 - 0.836 g /c3.
Functional category: Film former, tablet binder, tablet diluent.
Solubility: Eudragit RL 100 is soluble in ethanol, methanol, isopropyl alcohol,
dichloro methane, acetone and ethyl acetate.
Viscosity: Eudragit RL 100 is having viscosity range of 15 mPas.

Stability and storage: Dry powder polymer forms are stable at temperature less than
30 oC. Above this temperature, powders tend to form clumps, although this does not
affect the quality of the substance and the clumps can readily be broken up. Dry
powders are stable for atleast 3 years if stored in tightly closed containers at less than
30 oC.
Incompatibilities: Interaction between polymethacrylates and some drugs can occur,
although solid polymethacrylates and organic solutions are generally more compatible
than aqueous dispersions.

4.4.4. Starch I.P :56
Chemical name : Starch.
Empirical formula : (C6H10O5)n where n = 300–1000.
Structural formula : Starch consists of amylose and amylopectin, two
polysaccharides based on α-glucose.
Structure :
Starch is the mixture of two polymers, amylase,- a linear (1→4) α-D-Glucan
and amylopectin, a branched D-Glucan with mostly α-D (1→4) and approximately
4% α-D (1→6) linkages.

Solubility:
It is practically insoluble in cold ethanol (95%) and in cold water. Starch
swells instantaneously in water by about 5–10% at37°C. Polyvalent cations produce
more swelling than monovalent ions, but pH has little effect.
Description:
Starch is a white-colour, odourless fine powder, comprising very small
spherical or ovoid granules, whose size and shapes are characteristic for each
botanical variety.
Functional category: Binder, Diluent, Disintegrant.
Applications in pharmaceutical formulation or technology:
Starch is one of the most commonly used tablet disintegrant at concentrations
of 3–15 % w/w. It is utilized as a binder, diluent. Unmodified starch does not
compress well and tends to increase tablet friability and capping if used in high
concentrations. Starch is also used in topical preparation and is used as a protective
covering in ointment formulations applied to the skin. Starch mucilage has also been
applied to the skin as an emollient, has formed the base of some enemas, and has
been used in the treatment of iodine poisoning. Starch has been investigated as an
excipient in novel drug delivery systems for nasal, oral, periodontal, and other site-
specific delivery systems.

4.4.5. Magnesium Stearate: 57,58
Synonym: Magnesium octadecanoate, octadecanoic acid, stearic acid, magnesium
salt.
Chemical Name: Octadecanoic acid magnesium salt
Empirical Formula: C36H70MgO4
Structural Formula:
[CH3 (CH2)16COO] 2Mg
-
H3C O 2+
Mg
-
H3C O
Molecular Weight: 591.34
Melting Point: 117-150 °C (commercial samples); 126-130 °C (high purity)
Solubility: Practically insoluble in ethanol, ethanol (95%), ether and water; slightly
soluble in warm benzene and warm ethanol (95%).
Description: Magnesium stearate is a very fine, light, white, precipitated or milled,
impalpable powder of low bulk density, having a faint odour of stearic acid and a
characteristic taste. The powder is greasy to the touch and readily adheres to the skin.

Typical Properties:
Crystalline forms : High-purity magnesium stearate has been isolated as a
trihydrate, a dihydrate, and an anhydrate.
Density (bulk) : 0.159 g/cm3
Density (tapped) : 0.286 g/cm3
Density (true) : 1.092 g/cm3
Flow ability : poorly flowing, cohesive powder.
Melting range : 117–1500C (commercial samples)
Solubility : Practically insoluble in ethanol, ether and water;
slightly soluble in warm benzene and warm ethanol.
Specific surface area : 1.6–14.8 m2/g
Incompatibilities:
Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with
strong oxidizing materials. Magnesium stearate cannot be used in products containing
aspirin, some vitamins, and most alkaloidal salts.
Applications in Pharmaceutical Formulation or Technology: Magnesium stearate
is widely used in cosmetics, foods, and Pharmaceutical formulations. It is primarily

used as a lubricant in capsule and tablet manufacture at concentrations between 0.25%
and 5.0% w/w. It is also used in barrier creams.
Functional Category: Tablet and capsule lubricant.
Stability and Storage Conditions: Magnesium stearate is stable and should be stored
in a well closed container in a cool, dry place.
Safety: Magnesium stearate is widely used as a pharmaceutical excipient and is
generally regarded as being non toxic following oral administration. However, oral
consumption of large quantities may produce a laxative effect or mucosal irritation.

4.4.8. Talc: 59
Synonyms: Hydrous magnesium calcium silicate, hydrous magnesium silicate,
magnesium hydrogen metasilicate, powdered talc, Purtalc, soap stone, steatite.
Chemical Name: Talc
Structural Formula: Mg6 (Si2O5)4(OH) 4
Empirical Formula: Talc is a purified, hydrated, magnesium silicate, approximating
to the formula Mg6 (Si2O5)4(OH)4. It may contain small, variable amounts of
aluminium silicate and iron.
Molecular Weight: 379.27 gm
Solubility: Talc is practically insoluble in dilute acids and alkalis, organic solvents,
and water.
Description: Talc is a very fine, white to greyish-white, odourless, impalpable,
unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and
free from grittiness.
Typical Properties:
Moisture content : Talc absorbs insignificant amounts of water at
2580C and relative humidity‟s up to about 90%.
Particle size distribution : varies with the source and grade of material.

Refractive index : nD20 = 1.54–1.59
Solubility : Practically insoluble in dilute acids and alkalis,
organic solvents, and water.
Specific gravity : 2.7–2.8
Specific surface area : 2.41–2.42m2/g
Storage Conditions : Talc should be stored in a well-closed container
in a cool, dry place.
Incompatibilities : Incompatible with quaternary ammonium
compounds.
Applications in Pharmaceutical Formulation or Technology: Talc is used in oral
solid dosage formulations as a glidant and lubricant (1-10%) and diluent (5-30%), as a
dissolution retardant in the development of controlled-release products, as an
adsorbent, as a dusting powder in topical preparations (90-99%).
Functional Category : It is used as an anti caking agent, glidant, tablet and capsule
diluent, tablet and capsule lubricant.
Storage Conditions: Talc should be stored in a well-closed container in a cool, dry
place.
Safety: Talc is not absorbed systemically following oral ingestion and is therefore
regarded as an essentially non toxic material. However, intranasal or intravenous

abuse of products containing talc can cause granulomas in body tissues, particularly
the lungs.
4.5. Analytical methods used for the estimation of Perindopril Erbumine (PE)
drug either in bulk, tablets or in dissolution fluids: 36,37
4.5.1. Method used to estimate Perindopril Erbumine:36
a) Preparation of Stock Solution:
100 mg of pure Perindopril erbumine was dissolved in 100 mL of distilled
water to obtain 1 mg /mL solution. This solution was further diluted with distilled
water till 10 μg/mL solution was obtained.
b) Analytical Methods:
The UV Spectrophotometric analytical method was developed for Perindopril
erbumine drug using a UV double beam Spectrophotometer (UV Pharmaspec 1700,
Shimadzu, Japan).
1) Determination of λ max:
10 μg/mL solution of Perindopril erbumine prepared as above was scanned for
absorbance in UV double beam spectrophotometer (UV Pharmaspec 1700, Shimadzu,
Japan) between range 200 to 400 nm, against distilled water as blank. It was found
that the solution showed absorbance maxima of 215.5 nm.
2) Estimation of Drug:
In present work, Spectrophotometric method was adopted using double beam
UV spectrophotometer (UV Pharmaspec 1700, Shimadzu, Japan).

3) Calibration curve of Perindopril erbumine:
Procedure:
Different aliquots were taken from stock solution in a series of 10 mL
volumetric flask and diluted with distilled water to prepare a series of concentration in
the range of 2-10 μg/mL. The solutions were scanned on spectrophotometer in the UV
range (200-400 nm) and the absorbance was measured at 215.5 nm using distilled
water as a blank.
The absorbance so obtained was tabulated in table 4.3. Calibration curve was
constructed and is shown in figure 4.1.
Later, the method was validated for linearity (table 4.4.), accuracy and
precision (table 4.5.). The results of validation study are presented in the following
tables.
Table 4.4. Spectrophotometric data for the estimation of Perindopril erbumine at

215.5 nm:
Concentration
Sl. No Absorbance*
(µg/mL)
1 0. 00 0.000
2 2. 00 0.032
3 4. 00 0.064
4 6. 00 0.099
5 8. 00 0.128
6 10. 00 0.160
*Average of three determinations

The linear regression analysis was done on absorbance data points. A straight-
line equation (Y = mx + c) was generated to facilitate the calculation of amount of
drug. Absorbance = slope x concentration + Intercept
y = 0.016 x - 0.00015
0.200
Absorbance (nm)
0.150
0.100
0.050
0.000
0 2 4 6 8 10 12
Concentration (µg)
Fig 4.1 Calibration Curve of Perindopril erbumine
4) Validation of analytical method developed in the study:
Table 4.5. Linearity studies of Perindopril erbumine:
S.No. Concentration ((µg/mL)) Absorbance (nm) Regression Data
1. 0.032
0. 00
2. 0.064
2. 00
c= -0.000124
m=0.0157
r= 0.9997
3. 0.098
4. 00
4. 0.131
6. 00
*
*
5. 0.160
8. 00
6. 0.032
10. 00
*m = slope; *c= intercept;* r = regression.

Table.4.6. Accuracy and precision studies:
Amount of Amount of
Drug Drug
Formulation Accuracy Precision
Drug added recovered
(mg/mL) (mg/mL)
PE1 4 3.80 95.51 0.001
PE2 4 3.85 96.30 0.003
PE3 4 3.84 96.14 0.001

Perindopril erbumine
PE4 4 3.92 98.02 0.001
PE5 4 3.94 98.54 0.001
PE6 4 3.93 98.38 0.002
PE7 4 3.93 98.43 0.001
PE8 4 3.91 97.91 0.002
PE9 4 3.90 97.70 0.0005
4.6. Methods used for characterization of the drug:
4.6.1. Melting point determination:
Melting point of the drug was determined by taking a small quantity of drug
in a capillary tube closed at one end which was placed in theil‟s melting point
apparatus. The temperature at which the drug melts was noted using liquid paraffin
as a solvent. Average of triplicate readings was recorded.

4.6.2. Solubility studies:
The solubility of the drug was determined in distilled water and different
solvents according to the method proposed by Diez et al. 63 Triplicate readings were
taken and average was calculated.
An excess amount of the drug was taken and dissolved in a measured
amount of distilled water in a volumetric flask to get a saturated solution. The
solution was shaken intermittently to assist the attainment of equilibrium with the un-
dissolved drug particles. Then measured quantity of the filtered drug solution was
withdrawn after 24 hours and successively diluted with distilled water suitably and
the concentration was measured in a UV spectrophotometer at their respective
absorbance maxima. Similarly the solubility of drug was determined in different
buffers, viz., pH 1.2, pH 2.2, pH 6.9, pH 7.0, pH 8.0, pH 9.0.
4.6.3. Partition coefficient:
The partition coefficient of the drug was determined by taking equal volumes
of n-octanol and aqueous phases in a separating funnel. Drug solution of 1mg/mL
was prepared, and 1mL of the prepared solution was added to n-octanol: water
(50:50) taken in a separating funnel and subsequently shaken for 10 minutes and
allowed to stand for 2 h. Both the phase was separated, centrifuged for 10 min at
2000 rpm. The aqueous and n-octanol phase was assayed before and after
partitioning using UV Spectrophotometer to get partition coefficient. Triplicate
readings (n=3) were taken and average was calculated.

4.6.4. Permeability coefficient:60
The permeability coefficient of drug was calculated by “Potts & Guy
equation”.
Log kp = − 2.7 + 0.71 × Log Ko/w − 0.0061 × Molecular weight
Where,
Log kp = Permeability coefficient
Ko/w = Partition coefficient
4.7. Preparation of Perindopril Erbumine Tablets
4.7.1 Method of preparation of granules:
Granules of Perindopril erbumine were prepared by wet granulation
technology. All the ingredients as per the formulae mentioned in table no. 4.6 were
weighed and grinded to fineness in a mortar and pestle. The powder blend was then
passed through sieve # 120. The powder was then kneaded with a clean and dry
pestle using starch paste. The wet mass so obtained was passed through mesh # 16.
The particles were then subjected to drying for 2-3 h in an oven at 40 °C. The dried
granules were then passed through mesh # 20. Fine particles to an extent of 20 %
were blended thoroughly with the particles of #16/20 and this powder blend was used
for further processing.
4.8. Evaluation of pre-compression characteristics of granule bed:

Granules prepared by wet granulation technology were evaluated for various
rheological properties like bulk density, tapped density, compressibility index, flow
properties (angle of repose) by using standard procedures. All studies were carried
out in triplicate (n=3) and average values were reported.
4.8.1. Bulk density (Db): 61
Bulk density was determined (bulk density apparatus, Konark instruments,
India) by taking accurately weighed quantity of the dried granules in a measuring
cylinder and recording the volume and weight of the total granules. Bulk density is
expressed in gm/mL and is given by,
Db = M / Vo
Db = Bulk density (gm/mL)
M is the weight of granules (gm)
Vo is the bulk volume of granules (mL)
4.8.2. Tapped Density (Dt): 61
Tapped density was determined (Tapped density apparatus, Konark
instruments, India) by taking accurately weighed quantity of the dried granules in a
measuring cylinder and recording the volume of granules after 100 tapping and
weight of the total granules.
Dt = M / V
Where, Dt = Tapped density (gm/mL)
M is the weight of granules (gm)

V is the tapped volume of granules (mL)
4.8.3. Compressibility index: 61
Compressibility index was determined by placing the dried granules in a
measuring cylinder and the volume (V0) was noted before tapping, after 100 tappings
again volume (V) was recorded.
Compressibility index = (1- V/ V0) X 100
V0 = volume of powder/granules before tapping.
V = volume of powder/granules after 100 tappings.
4.8.4. Angle of repose (θ): 61
It is defined as the maximum angle possible between the surface of pile of the
powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed
with its tip at a given height (h), above a flat horizontal surface on which a graph
paper was placed. Powder was carefully poured through a funnel till the apex of the
conical pile just touches the tip of funnel. These studies were carried out before and
after incorporating lubricant/glidant. The angle of repose (θ) was then calculated.
θ = tan-1(h/r)
Where, θ = angle of repose
h = height of pile,
r = radius of the base of the pile.

4.9. Compression of tablets:
After adding lubricant (talc) and anti-adherent (magnesium stearate) to the dry
granule bed and subsequent blending, the granules were compressed into tablets on a
pilot press machine (PP1D, Chamunda Pharma, India) using 6 mm diameter, flat
faced punches at a pressure of approximately 5 kg /cm2.
4.10. Evaluation of post-compression characteristics of tablets:
Tablets were evaluated for their thickness, weight uniformity, hardness,
friability, disintegration time and dissolution profiles by using standard procedures.
4.10.1. Thickness and diameter: 62
Control of physical dimensions of the tablet such as thickness and diameter is
essential for consumer acceptance and tablet uniformity. The thickness and diameter
of the tablet was measured using Vernier callipers (Mitutoyo, Japan). The
measurements were in mm. Average of three readings were taken and the results were
tabulated (n = 3).
4.10.2. Hardness test: 62
Prepared tablets were evaluated for their hardness by using Pfizer hardness
tester. Scale was adjusted to zero; load was gradually increased until the tablet

fractured. The value of the load at that point gives a measure of hardness of the tablet.
Hardness was expressed in Kg/cm2. Triplicate readings were taken and average was
computed.
4.10.3. Weight uniformity: 62
Randomly selected ten tablets were weighed individually and together in a
single pan balance. The average weight was noted and standard deviation and
percent coefficient of variance was computed.
4.10.4. Friability test (F): 62
Tablet friability was tested using Roche Friabilator. Pre-weighed tablets were
allowed for 100 revolutions (4 min), taken out and dedusted. The percentage weight
loss was calculated by reweighing the tablets. The % friability was then calculated
by,
4.10.5. Disintegration time: 62
Disintegration test was performed for the prepared tablets in 900 mL, 0.1N
HCl at 37±2 oC by using USP disintegration apparatus. Time was noted with a digital
chronometer. Triplicate readings were taken and average was computed.
4.10.6. Swelling index: 64

The swelling properties of the tablets were evaluated by determination of
percent of swelling. Each tablet was weighed (W1) and immersed in a simulated
saliva fluid at pH6.8 for predetermined times. After immersing the formulation for
specified time, the tablets were wiped off to remove excess of surface water by using
filter paper and weighed (W2).
%Swelling = (W2) – (W1)/ (W1) X 100
Where,
W 1 is the initial weight of the tablet.
W2 is the weight of the tablet after the particular swelling time interval.
R = 100 (Wa - Wb) / Wb
4.10.7. Drug content uniformity: 62
From each batch three randomly selected tablets were weighed accurately and
powdered in a clean and dry glass mortar with pestle. Powder equivalent to 100 mg
of drug was transferred into 100 mL volumetric flask containing distilled water; the
remaining volume was made up to 100 mL with distilled water. Shaken
intermittently for 24 h and the solution was filtered, make up desired dilutions and
analysed for drug content at max 215.5.5 nm, using a distilled water as a blank.
Triplicate readings were taken and average was computed.
4.11 In vitro release study: 65

Apparatus : USP XXII (Type 2) Dissolution apparatus
Dissolution medium : 900 mL 0.1 N HCl (pH 1.2)
Temperature : 37± 0.5 °C
RPM : 50
Volume withdrawn and replaced : 1 mL
λ max : 215.5 nm
Blank solution : 0.1 N HCl
Procedure:
In-vitro drug release studies were carried out using USP XXII dissolution
apparatus type II (Campbell electronics, Mumbai) at 50 rpm. The dissolution medium
consisted of 900 mL of 0.1 N HCl, maintained at 37 + 0.5 °C. The drug release at
different time intervals was measured using a double beam UV spectrophotometer
(UV Pharmaspec 1700, Shimadzu, Japan) at 215.5 nm. The study was conducted in
triplicate.
4.12. Stability studies: 66
The stability experiments were conducted to investigate the influence of
temperature and relative humidity on the drug content and dissolution profile of
various fast dissolving tablets.
The formulations were exposed to a temperature of 40 °C and also a relative
humidity of 75 % RH. The sample was removed from the oven at the end of 24 hours
and analysed for drug content for 90 days. At the end of 90 days the tablets of each
formulation were subjected to dissolution as outlined in sec 4.11.8. Average of

triplicate readings was taken. The observations were tabulated. The dissolution
profiles were compared with dissolution profile performed on tablets kept at ambient
conditions.
4.13. Statistics: 67-68
The in vitro data was subjected to regression analysis by least squares method.
The standard deviation was calculated and reported. In vitro data was analysed by
ANOVA, a value of p< 0.05 was considered to be statistically significant.

Table.4.7. List of the ingredients used in formulae of different Fast dissolving tablets containing Perindopril erbumine.
S.No Ingredients (mg/tab) PE1 PE2 PE3 PE4 PE5 PE6 PE7 PE8 PE9
4 4 4 4 4 4 4 4 4
1. Perindopril erbumine
Starch (as 10% w/w) 15%w/w 15 15 15 15 15 15 15 15 15

2.
Xanthan gum
20 25 30 -- -- -- -- -- --
3.
(25%, 30% & 35% w/w)
Almond gum (25%,30% & 35%) -- -- -- 20 25 30 -- -- --

4.
Eudragit RL 100
-- -- -- -- -- -- 20 25 30
5.
(25%,30% & 35%)
Micro crystalline cellulose

59 54 49 59 54 49 59 54 49
6.
(diluent)
2 2 2 2 2 2 2 2 2
7. Talc and Mg stearate(2:1) 1.5%w/w
100 100 100 100 100 100 100 100 100

Total Tablet Weight (mg)

5. RESULTS
To maintain constant drug release, a drug delivery system should be able
to with stand a variety of physiological variables which may influence gastric
retention such as food, position of body and volume fluid intake; food related dose
dumping is also major concern.
Development of oral controlled release system has been a challenge to
a formulator because of their in ability to restrain and localize the system in the
targeted area of the GIT. Oral delivery of drugs is by far, the most referable
route of drug delivery due to the ease of administration and patient compliance.
There has been a tremendous progress in research and patent, from immediate
release tablet to controlled release tablets.
An ideal controlled drug delivery system is the one that delivers the drug
at a pre-determined rate, locally or systemically, for a specified period of time.
Controlled release is differs from sustained release systems which simply
prolong the drug release and hence plasma drug level for a longer period of time.
Thus the objective of most products should be controlled delivery to reduce
dosing frequency to an extent that once daily dose is sufficient for therapeutic
management through a uniform plasma concentration at steady state.
Hence drugs whose absorption window is in stomach or proximal
small intestine are incompletely absorbed and most of it is lost. It is also understood
that, as the solubility of the drug decreases the time available for drug dissolution
becomes less adequate and transit time becomes a significant factor affecting

the drug absorption, hence controlled drug delivery dosages are effective in
delivery of water soluble drugs like Perindopril erbumine. The objective of the study
was to formulate and evaluate controlled matrix tablets of Perindopril erbumine.
In this light of information the drug Perindopril erbumine was initially
characterized for its various physico-chemical properties. The results obtained from
various experiments, for the purpose of developing a suitable controlled matrix tablet,
are discussed below.
5.1. Characterization of Perindopril Erbumine:
The pure drug obtained was characterised for its melting point, solubility and
Partition coefficient. Melting point of the drug was found to be 126.5 C (n=3) which
corroborates with the previous report 126 to 128 C. Partition coefficient of the pure
drug was determined in n-Octanol: Water (50:50), and it was found to be 0.464 (n=3).
Later, an analytical method for the quantification of Perindopril erbumine was
developed using a double beam UV spectrophotometer. U.V. absorption maxima of
Perindopril Erbumine (PE) in water was found to be 215.5 nm (n=3) which is nearly
same as literature value 215 nm36. the analytical method was validated for linearity,
accuracy and precision. The results are given in tables 5.1. to 5.4.
Later, solubility of Perindopril Erbumine in distilled water, acidic and alkaline
pH buffers was studied. A saturated solution of the drug was prepared in respective
solvents and shaken, under ambient conditions, for 24 h. At the end of 24 h, 1mL of
the solution was pipetted out and the concentration (mg/mL) was determined using a

double beam UV spectrophotometer. The solubility was found to be 0.355 mg/mL in
distilled water. Similarly, the solubility of the drug in different buffers was also
determined. It was found that the solubility of Perindopril Erbumine is 0.555 mg/mL
in pH 1.2, 0.501 mg/mL in pH 2.2, 0.315 mg/ mL in pH 7.0, 0.098 mg/ mL in pH 8.0
and 0.066 mg/mL in pH 9.0. Average of triplicate readings was taken (n=3) and the
results obtained were tabulated and are summarized in table 5.1.
5.2. Development and evaluation of Controlled matrix tablets of Perindopril
Erbumine:
Perindopril Erbumine tablets were prepared by Wet granulation method using
different ratios of polymers like xanthun gum, eudragit RL 100, almond gum and
15% starch, microcrystalline cellulose. 15 % w/w of Starch paste (10 % w/w) was
used as binder in all formulations. All the powders were weighed and grounded to
fineness in a clean and dry mortar and pestle. The powder blend was than passed
through a sieve # 120. The powder was then kneaded with a clean and dry pestle
using starch paste prepared in distilled water as granulating fluid. The wet mass was
then passed through a mesh # 16. The particles were allowed to dry for 2-3 h in an
oven at 400C. The dried granules were then passed through a mesh # 18. Fine particles
to an extent of 20 % w/w were blended thoroughly with the particles of #16/18 and
than to this powder blend was added talc and magnesium stearate at 2:1 ratio and used
for further processing.

The dried granules of Perindopril Erbumine were characterized for rheological
properties. after mixing when granules are ready for punching then compressed into
tablets into 100 mg tablets on a pilot press machine (PP1D, Chamunda Pharma, India)
using 6 mm diameter, flat faced punches at a pressure of approximately 5-6 kgs /cm2.
Totally 9 formulations (PE1-PE9) were developed and studied.
The tablets were studied for compressional properties, Swelling index. In vitro
dissolution studies were carried out in USP XXIV dissolution apparatus and the
tablets were stored at 40°C / 75 % RH (ICH guidelines) to study the stability profile of
the drug.
5.2.1. Evaluation of pre-compression and compression characteristics of powder
bed of Perindopril Erbumine:
The compression powder bed were studied for their rheological behavior by
determining, angle of repose ( ), bulk density (gm/mL), tapped density (gm/mL),
and compressibility index (%), by adopting standard techniques described in Sec 4.8,
and the results are presented in the following paragraphs.
Carr‟s Compressibility index was found to be less than 15 % for all the 9
formulations. The index was observed to be between 3.03 % and 12.6 % indicating
that the powder bed is compressible.
Bulk density was found to be between 0.293 gm/mL and 0.415 gm/mL for
all the formulations. Tapped density was found to be between 0.308 gm/mL and
0.498 gm/mL. The angle of repose ( ) was determined before adding the

lubricants/glidants and after adding lubricants/glidants. The repose angle before
incorporation of lubricants/glidants was found to be 21.800 to 27.120. After the
addition of lubricants/glidants the angle of repose was found to be 19.980 and
24.110. These results indicate that, the powder beds of all the formulations are freely
flowable and easily compressible. The results, average of thee readings, was
computed and are given in table no 5.2.
Compressed tablets of Perindopril Erbumine were evaluated for several
compressional characteristics like thickness, diameter, weight uniformity, drug
content, swelling index, drug release profiles and stability studies . The weight of
the tablets was found to be fairly uniform ranging between, 100.8 ± 1.54 mg to
105.4 ± 6.32 mg for a 100 mg tablet (n=10). The thickness of the tablets was
determined using a micrometer (Mitutoyo, Japan). The thickness of the tablets, were
found to be between 3.008±0.0 mm to 3.010 ±0.002 (n=10). The hardness of the
tablets were determined with a hardness tester (Pfizer, India) and the hardness was
found to be fairly consistent and uniform, ranging between 3.26 ±0.115Kg/cm2 to
4.93 ±0.23Kg/cm2 (n=5). Drug content of the all formulations were in the range of
3.806 mg to 3.94mg for controlled matrix tablets. The friability of all the
formulations were determined in a friabilator operated for 5 min at 25 rpm, and the
percent friability was found to be 0.16% to 1.1%..
Further swelling behavior of the matrix tablets of Xanthan gum, eudragit
RL100 and almond gum were studied at pH6.8. The swelling index was computed as
discussed in section 4.10.6. The tablets of formulation from PE 1 to PE 7 were found

to loose their integrity and shape at the end of 8 h and similarly the tablets of PE 8 to
PE 9 lost their integrity at the end of 8 h. Hence the study was discontinued either
after 8 h or 6 h. The observations are presented in table.
It was also found that, increase in polymer content increases the swelling
index of the tablet formulations containing xanthun gum and the order of swelling
was found to be PE3 > PE2> PE1.
It was found that, increase in polymer content increases the swelling index of
the tablet formulations containing chitosan and the order of swelling was found to be
PE6> PE5> PE4. The study revealed that, amount of matrix carriers in the
formulation influences the swelling behavior rather than the amount of diluent. Also,
all the formulations containing matrix carriers swell considerably without losing the
shape or integrity of the tablet.
5.3. In vitro studies:
5.3.1. In vitro release studies of formulations PE1, PE2 and PE3:
The formulations PE1, PE2 and PE3 were prepared with 20% w/w, 25% w/w
and 30 % w/w of xanthun gum as polymer. Each of the tablet in all the formulations
contain 4 mg of Perindopril Erbumine, microcrystalline cellulose and 15% starch
paste as diluent and matrix binders .
The in vitro release data of formulation PE 1, containing 20 % w/w xanthun
gum as matrix carrier, is given in table 5.5 (n=3). The study was conducted in pH 7.4

for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h. „PE 1‟
formulation released nearly 40.56 %. The tablet was observed to be swelling and the
shape of the tablet was not distorted and it remained intact. When dissolution was
continued in buffer of pH 6.8 up to 24 h the formulation released nearly 83.49 % of
drug. Averages of triplicate readings were taken. The raw data obtained was subjected
to regression analysis by least squares method (r). The data was also analyzed
statistically by ANOVA, a value of p< 0.05 was considered to be significant. A high
regression coefficient (r= 0.978), indicating the percentage cumulative drug release vs
time curve is linear. There was no significant difference observed between the „p‟
values of any two readings of the same sampling interval. Plot percentage cumulative
drug release (%) vs time (h) is shown in figure 5.1 showed the curve obtained is linear
with an r = 0.978.
The swollen tablet left at the end of dissolution was carefully lifted and
collected on a blotting paper to drain any moisture present, The amount released in
dissolution study and the amount remaining in the tablet is found to be same as the
drug content of the tablet formulation. The tablet when further examined periodically
with naked eye showed no significant changes up to 8 h. After 8 h, small particles
were seen dissolution media (pH 6.8) for up to 24 h. After 24 h of dissolution, intact
gel mass remained in the basket but of reduced dimensions.
The results of controlled matrix tablets PE 2 containing 25 % w/w xanthun
gum as matrix carrier were tabulated as in table 5.6 (n=3). The study was conducted
in pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h. PE

25 formulation released nearly 42.53 % of the drug in dissolution media. The tablet
was observed to be swelling and the shape of the tablet was not distorted and it
remained intact. When dissolution was continued in buffer of pH 6.8 upto 24 h the
formulation released 84.18 % (approx) of drug. Averages of triplicate readings were
taken. The raw data obtained was subjected to regression analysis by least squares
method (r). The data was also analyzed statistically by ANOVA, a value of p< 0.05
was considered to be significant. A high regression coefficient (r= 0.984), indicating
the percentage cumulative drug release vs time curve is linear.
There was no significant difference observed between the „p‟ values of any
two readings of the same sampling interval. Plot of percentage cumulative drug
release (%) vs time (h) is shown in figure 5.2 showed the curve obtained is linear with
an r = 0.984. The swollen tablet left at the end of dissolution was carefully lifted and
collected on a blotting paper to drain any moisture present, than remaining drug
content was quantified as described. The amount released in dissolution study and the
amount remaining in the tablet is found to be same as the drug content of the tablet
formulation.
The results of in vitro release data of formulation PE 3, containing 30% w/w
xanthun gum as matrix carrier, is given in table 5.7 (n=3). The study was conducted in
pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h of study
and later the study was continued in pH 6.8 buffer up to 24 h. „PE 3‟ formulation
released nearly 45.11%. The tablet was observed to be swelling and the shape of the
tablet was not distorted and it remained intact. When dissolution was continued in

buffer of pH 6.8 up to 24 h the formulation released nearly 90.22 % of drug, Averages
of triplicate readings were taken. The raw data obtained was subjected to regression
analysis by least squares method (r). The data was also analyzed statistically by
ANOVA, a value of p< 0.05 was considered to be significant. A high regression
coefficient (r= 0.984), indicating the percentage cumulative amount drug release vs
time curve is linear.
two readings of the same sampling interval. Plot of the percentage cumulative amount
with an r = 0.984. The swollen tablet left at the end of dissolution was carefully lifted
and collected on a blotting paper to drain any moisture present, than remaining drug
content. The amount released in dissolution study and the amount remaining in the
tablet is found to be same as the drug content of the tablet formulation.
5.3.2. In vitro release studies of formulations PE4, PE5 and PE6:
and 30 % w/w of Eudragit RL 100 as polymer. Each of the tablet in all the
formulations contain 4 mg of Perindopril Erbumine, microcrystalline cellulose and
15% starch paste as diluent and matrix binders .
The in vitro release data of formulation PE 4, containing 20 % w/w Eudragit
RL 100 as matrix carrier, is given in table 5.8 (n=3). The study was conducted in pH
7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h. „PE 4‟

with an r = 0.986.
The results of controlled matrix tablets PE 5 containing 25 % w/w Eudragit
RL 100 as matrix carrier were tabulated as in table 5.9 (n=3). The study was
conducted in pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to
12 h. PE 25 formulation released nearly 45.18 % of the drug in dissolution media. The

tablet was observed to be swelling and the shape of the tablet was not distorted and it
remained intact. When dissolution was continued in buffer of pH 6.8 upto 24 h the
formulation released 90.18 % (approx) of drug. Averages of triplicate readings were
taken. The raw data obtained was subjected to regression analysis by least squares
method (r =0.987). The data was also analyzed statistically by ANOVA, a value of p<
0.05 was considered to be significant. A high regression coefficient (r= 0.987),
indicating the percentage cumulative drug release vs time curve is linear.
formulation.
Eudragit RL 100 as matrix carrier, is given in table 5.10 (n=3). The study was
conducted in pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to
12 h of study and later the study was continued in pH 6.8 buffer up to 24 h. „PE 3‟
formulation released nearly 44.76%. The tablet was observed to be swelling and the

drug, Averages of triplicate readings were taken. The raw data obtained was subjected
regression coefficient (r= 0.983), indicating the percentage cumulative amount drug
release vs time curve is linear.
5.3.3. In vitro release studies of formulations PE7, PE8 and PE9 :
and 30 % w/w of Almond gum as polymer. Each of the tablet in all the formulations
contain 4 mg of Perindopril Erbumine, microcrystalline cellulose and 15% starch
paste as diluent and matrix binders .
The in vitro release data of formulation PE 7, containing 20 % w/w Almond
gum as matrix carrier, is given in table 5.11 (n=3). The study was conducted in pH 7.4
for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h. „PE 7‟

with an r = 0.986.
The results of controlled matrix tablets PE 8 containing 25 % w/w Almond
gum as matrix carrier were tabulated as in table 5.12 (n=3). The study was conducted
in pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h. PE 8
formulation released nearly 47.58 % of the drug in dissolution media. The tablet was
observed to be swelling and the shape of the tablet was not distorted and it remained

intact. When dissolution was continued in buffer of pH 6.8 upto 24 h the formulation
released 92.18 % (approx) of drug. Averages of triplicate readings were taken. The
raw data obtained was subjected to regression analysis by least squares method (r
=0.987). The data was also analyzed statistically by ANOVA, a value of p< 0.05 was
considered to be significant. A high regression coefficient (r= 0.987), indicating the
percentage cumulative drug release vs time curve is linear.
formulation.
Almond gum as matrix carrier, is given in table 5.13 (n=3). The study was conducted
in pH 7.4 for first 6 h and the media was replaced with pH 6.8 buffer up to 12 h of
study and later the study was continued in pH 6.8 buffer up to 24 h. „PE 9‟
formulation released nearly 48.02%. The tablet was observed to be swelling and the
drug, Averages of triplicate readings were taken. The raw data obtained was subjected

regression coefficient (r= 0.986), indicating the percentage cumulative amount drug
release vs time curve is linear.
Stability studies were conducted according to ICH protocol at 400 C
/75% RH for a period of 90 days. The data of stability indicates that there was no
decrease in the drug content and In vitro drug release was observed over a period of
90 days and data is given in table 5.14 to5.19

Table: 5.1. Various physico-chemical characteristics of Perindopril Erbumine.
Solubility mg/ml Solubility mg/ml in Buffer pH

SL. Melting point Partition Log
Drug Name 0
No C coefficient KP
Water pH 1.2 pH 2.2 pH 7.0 pH 8 pH 9.0
Perindopril
126.50C 0.355 0.555 0.501 0.315 0.098 0.066 0.464 -0.3334
1 Erbumine

Table: 5.2 Evaluation of rheological characteristics of controlled release matrix
tablets of Perindopril Erbumine. (n=3).
Angle of repose ( º θ)
Bulk Tapped
Formulation Compressibility
density density Before After
Code index %
gm/ml gm/ml adding adding
glidants glidants
PE1 12.6 0.415 0.498 26.8 23.3
PE2 8.96 0.342 0.3757 27.07 20.85
PE3 12 0.398 0.452 28.9 24.11
PE4 6.06 0.308 0.32 22.56 22.30
PE5 3.03 0.298 0.308 21.80 19.98
PE6 6.06 0.293 0.312 22.33 22.06
PE7 7.06 0.299 0.318 26.5 23.19
PE8 12.1 0.297 0.338 26.21 22.05
PE9 8.96 0.342 0.375 27.12 20.85

Table: 5.3. Evaluation of Physical Characteristics of controlled release matrix tablets of Perindopril Erbumine (n=3).
Drug
Hardness content Disintegration
Formula Weight Thickness Diameter Friability
( kg/cm2 ( mg ± SD Time
code (mg ±SD) (mm ± SD) ( mg ± SD) %
±SD) (sec)
PE 1 100.4±1.24 4.93±0.23 3.009±0.002 6.008±0.000 3.806±0.001 0.8 9.667±0.115
PE 2 100.9±1.61 4.13±0.30 3.009±0.002 6.010±0.002 3.85±0.003 0.4 12.133±0.208
PE 3 100.4±1.56 3.73±0.11 3.008±0 6.009±0.002 3.84±0.001 0.16 14.267±0.152
PE 4 100.3±1.28 3.93±0.230 3.009±0.002 6.010±0.002 3.93±0.001 0.4 15.200±0.450
PE 5 100.8±1.16 4.13±0.115 3.008±0 6.009±0.002 3.91±0.002 0.6 17.567±0.115
PE 6 100.0±1.42 4.4±0.2 3.010±0.002 6.008±0.000 3.9±0.0005 0.6 21.500±0.500
PE 7 100.8±1.00 4.0±0.2 3.009±0.002 6.009±0.002 3.92±0.001 0.9 20.933±0.404
PE 8 100.8±1.28 3.53±0.115 3.009±0.002 6.010±0.002 3.94±0.001 1.8 23.000±0.500
PE 9 100.3±1.04 3.26±0.115 3.009±0.002 6.010±0.002 3.93±0.002 1.1 26.833±0.288

Table: 5.4. Swelling studies of controlled release matrix tablets of Perindopril Erbumine.
Swelling Index%
Time (h) 0.25 0.50 0.75 1 2 3 4 5 6 7 8
PE 1 31.26 39.07 43.67 48.33 52.91 54.46 55.89 61.39 64.10 66.61 70.86
PE 2 37.45 42.54 46.68 51.46 54.75 55.59 57.72 63.41 66.73 68.83 72.41
PE 3 41.15 44.81 48.53 52.33 56.61 57.38 59.62 64.59 68.81 71.98 74.97
PE 4 18.72 22.76 27.62 30.93 34.93 36.49 38.56 42.51 46.75 51.54 56.48
PE 5 27.83 33.58 36.48 39.59 42.92 44.42 50.57 53.36 56.22 56.58 59.47
PE 6 35.41 40.94 44.38 48.43 51.12 53.12 55.45 59.05 61.98 62.85 64.21
PE 7 30.58 32.50 37.92 43.45 45.38 47.41 50.13 55.42 58.17 60.68 61.88
PE 8 38.52 43.09 46.98 47.41 55.62 60.74 62.68 64.53 - - -
PE 9 39.47 45.62 48.21 51.28 59.45 63.56 65.31 66.54 - - -

Table: 5.5. In vitro release of Perindopril Erbumine from controlled
matrix tablets containing 20%w/w Xanthan gum , (PE1) (n=3).
Cumulative amount % Cumulative

S.No Time ( h )
(mg) Drug Release ± SD
1 0 0
0.000
2 0.16 0 0.000
3 0.5 0 0.000
4 0.75 0 0.000
5 1 0.004 0.105
6 2 0.039 1.037
7 3 0.115 3.038
8 4 0.220 5.780
9 5 0.340 8.959
10 6 0.478 12.578
11 7 0.631 16.607
12 8 0.795 20.911
13 9 0.968 25.462
14 10 1.148 30.204
15 11 1.344 35.357
16 12 1.542 40.566
Y=0.125X - 0.147

50
45
40
% Cumulative release
35
30
25
20
15
10
5
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (h)
Fig.5.1. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 20%w/w Xanthan gum (PE 1) .

matrix tablets containing 25%w/w Xanthan gum (PE 2) (n=3).

S.No Time ( h )
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.004 0.109
5 1 0.016 0.407
6 2 0.076 1.980
7 3 0.171 4.449
8 4 0.283 7.378
9 5 0.413 10.742
10 6 0.552 14.377
11 7 0.705 18.365
12 8 0.869 22.624
13 9 1.043 27.154
14 10 1.232 32.091
15 11 1.430 37.245
16 12 1.633 42.535
Y=0.133 X - 0.136

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time(h)
Fig.5.2. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 25%w/w Xanthan gum (PE 2).

matrix tablets containing 30%w/w Xanthan gum (PE 3) (n=3).

S .No Time ( h )
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.006 0.163
5 1 0.026 0.678
6 2 0.081 2.116
7 3 0.177 4.612
8 4 0.293 7.623
9 5 0.426 11.095
10 6 0.577 15.028
11 7 0.749 19.504
12 8 0.932 24.278
13 9 1.126 29.324
14 10 1.324 34.478
15 11 1.526 39.741
16 12 1.732 45.112
Y= 0.142X - 0.146

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time(h)
Fig.5.3. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 30%w/w Xanthan gum (PE 3) (n=3).

matrix tablets containing 20%w/w Eudragit RL 100 (PE 4) (n=3).

S .No Time ( h )
(mg) Drug Release
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.003 0.080
5 1 0.022 0.557
6 2 0.075 1.908
7 3 0.170 4.320
8 4 0.297 7.554
9 5 0.446 11.344
10 6 0.614 15.612
11 7 0.789 20.065
12 8 0.968 24.624
13 9 1.153 29.342
14 10 1.343 34.166
15 11 1.543 39.255
16 12 1.745 44.397
Y = 0.145 - 0.986

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (h)
Fig.5.4. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 20%w/w Eudragit RL 100 (PE 4) (n=3).


S .No Time ( h )
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.007 0.186
5 1 0.029 0.746
6 2 0.090 2.291
7 3 0.184 4.715
8 4 0.313 7.992
9 5 0.461 11.802
10 6 0.626 16.011
11 7 0.799 20.434
12 8 0.980 25.069
13 9 1.168 29.865
14 10 1.359 34.767
15 11 1.560 39.908
16 12 1.767 45.183
Y = 0.146 X - 0.987

50
45
40
35
30
25
20
15
10
0
0 2 4 6 8 10 12
Time (h)


SI .No Time ( h )
1 0 0 0
2 0.16 0 0
3 0.5 0.000 0.000
4 0.75 0.005 0.128
5 1 0.014 0.369
6 2 0.073 1.864
7 3 0.171 4.375
8 4 0.289 7.420
9 5 0.426 10.919
10 6 0.580 14.872
11 7 0.751 19.252
12 8 0.935 23.980
13 9 1.129 28.948
14 10 1.331 34.129
15 11 1.536 39.391
16 12 1.747 44.786
Y = 0.143 X - 0.151

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time(h)

matrix tablets containing 20%w/w Almond gum (PE 7) (n=3).

SI .No Time ( h )
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.003 0.080
5 1 0.013 0.319
6 2 0.073 1.860
7 3 0.175 4.464
8 4 0.311 7.945
9 5 0.472 12.038
10 6 0.654 16.688
11 7 0.841 21.445
12 8 1.032 26.334
13 9 1.227 31.303
14 10 1.425 36.352
15 11 1.630 41.587
16 12 1.839 46.902
Y = 0.153 X - 0.158

50
45
40
35
30
25
20
15
10
5
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Tim e(h)
Fig.5.7. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 20%w/w Almond gum (PE 7) (n=3).


SI .No Time ( h )
(mg) Drug Release
1 0 0 0
2 0.16 0 0
3 0.5 0 0
4 0.75 0.019 0.476
5 1 0.046 1.163
6 2 0.103 2.617
7 3 0.200 5.076
8 4 0.340 8.619
9 5 0.499 12.664
10 6 0.680 17.264
11 7 0.868 22.023
12 8 1.061 26.941
13 9 1.258 31.937
14 10 1.458 37.014
15 11 1.664 42.222
16 12 1.875 47.589
Y = 0.156 X - 0.158

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time(h)
Fig.5.9. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 25%w/w Almond gum (PE 8) (n=3).


SI .No Time ( h )
1 0
0.000 0.000
2 0.16
0.000 0.000
3 0.5 0.000 0.000
4 0.75 0.021 0.530
5 1 0.050 1.272
6 2 0.110 2.810
7 3 0.211 5.381
8 4 0.339 8.614
9 5 0.490 12.458
10 6 0.657 16.725
11 7 0.844 21.469
12 8 1.043 26.532
13 9 1.248 31.754
14 10 1.456 37.055
15 11 1.669 42.462
16 12 1.888 48.028
Y = 0.155 X - 0.146

50
45
40
35
30
25
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time(h)
Fig: 5.10. In vitro release of Perindopril Erbumine from controlled matrix tablets containing 30%w/w Almond gum (PE 9) (n=3).

Table 5.14: Drug content after 90 days of stability studies of controlled release
matrix tablets of Perindopril Erbumine (PE1, PE2, PE3) at
400C/75% RH (n=3).
S.No Time PE1 PE2 PE3

(days)
D.C (mg) D.C (mg) D.C (mg)
1 0 3.806 3.852 3.846
2 1 3.784 3.83 3.842
3 3 3.766 3.81 3.814
4 5 3.748 3.784 3.796
5 7 3.736 3.756 3.76
6 15 3.714 3.728 3.738
7 30 3.684 3.702 3.706
8 45 3.667 3.694 3.692
9 60 3.641 3.687 3.685
10 90 3.806 3.852 3.846
*Theoretical content = 4 mg

400C/75% RH (n=3).
S.No Time PE4 PE5 PE6

(days)
1 0 3.938 3.917 3.908
2 1 3.876 3.842 3.89
3 3 3.852 3.8 3.814
4 5 3.796 3.778 3.746
5 7 3.749 3.752 3.732
6 15 3.678 3.73 3.711
7 30 3.644 3.714 3.687
8 45 3.632 3.691 3.674
9 60 3.624 3.679 3.663
10 90 3.938 3.917 3.908

400C/75% RH (n=3).
PE7 PE8 PE9

Time
S.No
(days)
1 0 3.921 3.942 3.935
2 1 3.916 3.868 3.87
3 3 3.894 3.846 3.842
4 5 3.868 3.822 3.804
5 7 3.794 3.764 3.77
6 15 3.752 3.76 3.734
7 30 3.743 3.654 3.69
8 45 3.736 3.648 3.681
9 60 3.722 3.631 3.668
10 90 3.921 3.942 3.935

Table: 5.17. In vitro release after 90 days of stability studies of controlled release matrix tablets of Perindopril Erbumine
(PE1, PE2, PE3) at 400C/75% RH (n=3)
PE 1 PE 1 90 day PE 2 PE 2 90 day PE 3 PE 3 90 day
s.no time % cum amt % cum amt % cum amt % cum amt % cum amt % cum amt
1 0 0 0 0 0 0 0
2 0.16 0 0 0 0 0 0
3 0.5 0 0 0 0 0 0
4 0.75 0 0.006 0.004 0 0.006 0.003
5 1 0.004 0.025 0.016 0.006 0.026 0.013
6 2 0.039 0.063 0.076 0.041 0.081 0.072
7 3 0.115 0.119 0.171 0.116 0.177 0.169
8 4 0.220 0.194 0.283 0.216 0.293 0.281
9 5 0.340 0.294 0.413 0.338 0.426 0.409
10 6 0.478 0.422 0.552 0.475 0.577 0.547
11 7 0.631 0.556 0.705 0.628 0.749 0.700
12 8 0.795 0.703 0.869 0.797 0.932 0.859
13 9 0.968 0.875 1.043 0.972 1.126 1.028
14 10 1.148 1.050 1.232 1.153 1.324 1.213
15 11 1.344 1.234 1.430 1.347 1.526 1.406
16 12 1.542 1.425 1.633 1.544 1.732 1.609
Deptartment of Pharmaceutics, V.L.C.P, Raichur. 115

(PE4, PE5, PE6) at 400C/75% RH (n=3).
1 0 0 0 0 0 0 0
2 0.16 0 0 0 0 0 0
3 0.5 0 0 0 0 0 0
4 0.75 0 0 0 0 0 0
5 1 0.003 0 0.007 0 0.005 0
6 2 0.022 0.009 0.029 0.006 0.014 0.025
7 3 0.075 0.038 0.090 0.028 0.073 0.069
8 4 0.170 0.094 0.184 0.078 0.171 0.138
9 5 0.297 0.197 0.313 0.169 0.289 0.247
10 6 0.446 0.338 0.461 0.306 0.426 0.378
11 7 0.614 0.491 0.626 0.459 0.580 0.522
12 8 0.789 0.650 0.799 0.634 0.751 0.675
13 9 0.968 0.819 0.980 0.819 0.935 0.838
14 10 1.153 0.994 1.168 1.009 1.129 1.013
15 11 1.343 1.178 1.359 1.206 1.331 1.203
16 12 1.543 1.372 1.560 1.406 1.536 1.403

(PE7, PE8, PE9) at 400C/75% RH (n=3).
1 0 0 0 0 0 0 0
2 0.16 0 0 0 0 0 0
3 0.5 0 0 0 0 0 0
4 0.75 0 0 0 0 0 0
5 1 0.003 0 0.007 0 0.005 0
6 2 0.022 0.009 0.029 0.006 0.014 0.025
7 3 0.075 0.038 0.090 0.028 0.073 0.069
8 4 0.170 0.094 0.184 0.078 0.171 0.138
9 5 0.297 0.197 0.313 0.169 0.289 0.247
10 6 0.446 0.338 0.461 0.306 0.426 0.378
11 7 0.614 0.491 0.626 0.459 0.580 0.522
12 8 0.789 0.650 0.799 0.634 0.751 0.675
13 9 0.968 0.819 0.980 0.819 0.935 0.838
14 10 1.153 0.994 1.168 1.009 1.129 1.013
15 11 1.343 1.178 1.359 1.206 1.331 1.203
16 12 1.543 1.372 1.560 1.406 1.536 1.403

6. DISCUSSION
Drug like Perindopril Erbumine has been selected as model drug because the
drug shows promising pharmacokinetics and physico-chemical properties required for
control release dosages. Perindopril Erbumine is a dipeptide monoacid monoester
with a perhydro indole group and no sulphydryl radical; chemical name, tert-
butylammonium (2S, 3aS, 7aS)-1-(N-[(S)-1-ethoxycarbonyl butyl]-L-alanyl)
perhydroindole-2-carboxylate and used for the treatment of patients with
hypertension and symptomatic heart failure. Perindopril Erbumine has molecular
weight of 368.49 gm/mol, oral bioavailability <90%, protein binding is 10-20% and
elimination half life is 1.2 hrs. Thus, it was considered as a potential drug for
controlled drug delivery.
Perindopril erbumine was characterized for physico-chemical properties. The
UV absorption maximum was found at 215.5 nm which was nearer to the literature
value 215-217 nm and the method developed during the course of this work was
validated for linearity, accuracy and precision. The method so developed was found
to be linear, accurate, reproducible and precise. The melting point of Perindopril
erbumine was found to be 126.5 C (n=3) which corroborates with previously
reported literature value 126-128 C.
From the study it was ascertained that the Perindopril erbumine sample
received as gift sample was fairly pure and the validated analytical method shows
that the analytical method developed follows Beer‟s law. The study of Partition
coefficient of the drug indicates that Perindopril erbumine is hydrophilic. The
solubility of Perindopril erbumine was found to decrease with increase in pH.

In this present work, we developed controlled matrix tablets containing
Perindopril erbumine using microcrystalline cellulose as a direct compressible
vehicle. Xanthan gum, Eudragit RL100 and Almond gum polymers were used as
Matrix carriers at thee levels (20 % w/w, 25 % w/w, and 30 % w/w).
The pre-compressional characteristics were investigated for all the
formulations. Compressional characteristics of the controlled matrix tablets were also
investigated. In vitro release studies were conducted in a USP XXIV dissolution
apparatus using pH 6.8 as dissolution media at 370 C and 60 rpm using 900 mL of
dissolution fluid. In vitro studies were conducted to understand whether drug is being
released from the matrix slab. The study was conducted to know the actual release
profile of the drug for a period of 12 h. During the study 1 mL were samples were
withdrawn periodically and sink conditions were maintained. Further stability studies
according ICH guidelines, for accelerated stability of pharmaceuticals, were
conducted at 400 C/ 75% RH for a period of 90 days and the data of stability study is
given in tables 5.24 to 5.35.
Perindopril erbumine tablets were prepared by dry granulation compression
using different ratios of polymers like Xanthan gum, eudragit RL 100, almond gum
using microcrystalline cellulose as a hydrophilic matrix carrier. All the ingredients
were weighed, passed though #120 and blended to fineness in a clean and dry mortar
and pestle for 10mins. After sufficient mixing of drug as well as other ingredients talc
(lubricant) and magnesium stearate (anti-adherent) was added at 2:1 ratio and further
mixed for additional 3-5mins and then compressed into in to 100 mg tablets on a pilot
press machine (PP1D, Chamunda Pharma, India) using 6 mm diameter, flat faced
punches at a pressure of approximately 5-6 kgs /cm2. Totally 9 formulations

(PE1-PE9) were developed and studied. Also, the powder bed prior to compression
was characterized for rheological properties.
Study of powder rheology indicated a Carr‟s compressibility index of less
than 15 % and therefore it was ascertained that, the powder bed is compressible. The
study of repose angle showed less than 300. This indicated the powder beds of all the
formulations are freely flowable and easily compressible and further improvement
was seen when glidants/ lubricants were added. It was understood that the powder is
less bulky as the bulk density and tapped density of powder bed was found to be less
than 1 (table 5.2).
The thickness, diameter and weight of the tablets were found to be uniform
and consistent as indicated by their low SD values (table 5.3). The hardness of the
compressed tablets determined using hardness tester (Pfizer, India) indicates that the
tablets are of adequate strength. The percent friability of the tablets was very low and
therefore it was understood that the tablets are of sufficient strength to withstand the
stress of transportation. Drug content of all tablet formulations was found to be
uniform. The study on swelling behaviour revealed that, amount of matrix carriers in
the formulation influences the swelling rather than the amount of diluent. Also, all the
formulations containing matrix carriers swell considerably for a significant period,
without losing the shape or integrity of the tablet. Swelling was observed to be
increasing with increase in matrix polymer content in the formulation.
The in vitro dissolution study was conducted using USP XXIV dissolution
testing apparatus in pH 6.8 at 50 rpm and temperature was maintained at 37 0.5 C.
The dissolution was carried out for 12 h and samples of 1 mL were withdrawn

periodically and analyzed spectrophotometrically at 215.5 nm. Average of triplicates
readings was considered and the data have been tabulated and shown in tables 5.5 to
5.13. In vitro release data obtained was statistically analyzed by ANOVA and a value
of p < 0.05 was considered to be significant. The raw data was also subjected to
regression analyses by least squares method.
Matrix tablets containing gelatin were studied for in vitro release. PE1
containing 20 % w/w xanthun gum, released 40.56 % of drug at end of 12 h. And,
Formulation PE2, containing 25% w/w xanthun gum released 42.53 %. Similarly PE3
containing 30 % w/w xanthun gum released 45.11% of the drug at end of 12 h. As the
content of xanthun gum in the tablet is increased, the rate of release is retarded as
indicated by their slope values. The linearity of the curve ( r= 0.984) indicates that the
drug release could be following zero order kinetics with a rate of 0.125 , 0.133, and
0.142 , respectively.
PE4 containing 20 % w/w eudragit RL100 released 44.39% of drug at end of
12 h. And, Formulation PE5, containing 25 % w/w eudragit RL100 released 45.18 %.
Similarly PE6 containing 30 % w/w eudragit RL100 released 44.78 % of the drug at
end of 12 h. As the content of eudragit RL100 in the tablet is increased, the rate of
release is retarded as indicated by their slope values. The linearity of the curve
(r=0.987) indicates that the drug release could be following zero order kinetics with a
rate of 0.145, 0.146, and 0.143, respectively.
PE7 containing 20 % w/w almond gum released 46.90 % of drug at end of
12 h. And, Formulation PE8, containing 25 % w/w almond gum 47.58 %. Similarly
PE 9 containing 30 % w/w xanthan gum 48.02 % of the drug at end of 12 h. As the

content of almond gum in the tablet is increased, the amount of drug released is
retarded the rate of release is retarded as indicated by their slope. The linearity of the
curve (r= 0.987) indicates that the drug release could be following zero order kinetics
with a rate of 0.153 , 0.156, and 0.155, respectively.
Stability studies were conducted according to ICH protocol at 40 °C /75% RH
for a period of 90 days. The data of stability study shown in table 5.14-5.19 indicates
that there was no decrease in the drug content over a period of 90 days. At the end of
90 days the tablets were subjected to dissolution studies, the data is presented in table
5.19, and the profiles so obtained were compared with the profiles of in vitro release
obtained without stress (400 C/ 75% RH). It was found that the dissolution profiles
were comparable and there was no significant difference observed between the means
of dissolution profile conducted without stress and with stress at p<0.05.

7. CONCLUSIONS
In the present work, an attempt was made to develop Controlled matrix tablets
of Perindopril Erbumine as an improved and better patient compliant dosage form.
From the study conducted, the following conclusions are drawn.
Controlled formulations of Perindopril Erbumine in the form of controlled
matrix tablets were developed to a satisfactory level, in terms of drug release, content
uniformity, swelling index, friability, hardness and weight variation.
 The analytical method developed during the course of the work resulted in a
λ max of 215.5 nm which corroborates with the literature value of 215-216 nm.36
 The method was found to be linear, precise and accurate.
 Melting point of Perindopril erbumine was found to be 129.5 °C which
corroborates with the literature value of 126-128 °C. 37
 The solubility of drug was found to be 355 μg/mL in distilled water.
 Partition coefficient of the pure drug was determined in n-Octanol: Water
(50:50), and it was found to be 0.464 (n=3), corroborating with the reported
literature value of 0.489. Indicating its lipophilic nature.
 Bulk density of powder bed for formulation was in the range of 0.293 gm/mL -
0.415 gm/mL, which was found to be less than 1 mg/mL for all formulations.
Similarly, the tapped density of powder bed for formulations was in the range of
0.498 mg/mL - 0.312 mg/mL which was less than 1 mg/mL for all formulations.

 The compressibility index was 3.03% - 12.6% for Controlled matrix tablets
which was found to be less than 15 % indicating that the powder bed is
compressed into a compact mass of tablet.
 Angle of repose (°θ) for the formulations before adding glidants was 21.8°-
28.9°. Angle of repose (°θ) for the formulations after adding glidants was
19.98°- 24.11°. A considerable decrease in angle of repose upon addition of
glidants (Talc: Magnesium Stearate = 2:1) signifies improved flow ability.
 The weight of Controlled matrix tablets containing Perindopril erbumine was
found to be fairly uniform ranging between, 100.3 ± 1.04 to 100.9 ± 1.61 mg for
a 100 mg tablet (n=10).
 The thickness of the tablets of all the formulation was in the range of 3.008 ±
0.002 mm to 3.010 ± 0.002 (n=3).
 The hardness was found to be fairly consistent and uniform, ranging between
3.26 ± 0.115 Kg/cm2 to 4.93 ± 0.23 Kg/cm2 (n=3).
 The drug content of all the formulations having dose, of 4 mg were found to be
fairly uniform, reproducible and consistent, ranging between 3.806± 0.001 mg
to 3.94 ± 0.001mg per tablet of 100 mg.
 The friability of all the formulations were determined in a friabilator operated
for 4 min at 25 rpm, and the percent friability was found to be ranging 0.4 % to
0.9%.

 The Controlled matrix tablets showed a disintegration time ranging from 15 ± 1
to 70 ± 0 seconds, owing to the variation in amount and type of
superdisintegrant incorporated.
 Percent swelling index was to be increasing with time and with increase in
hydrophilic polymer content. Controlled matrix tablets containing Xanthan gum
showed better swelling index and mechanical properties followed by Controlled
matrix tablets containing almond gum and eudragit RL 100.
 The cumulative percentage release of drug from PE1, PE2 and PE3 were found
to be 40.56% (r = 0.978), 42.53% (r = 0.984) and 45.112 % (r = 0.984) within
12 h of study respectively.
to be 44.39% (r = 0.986), 45.18% (r = 0.987) and 44.78 % (r = 0.983) within
12 h of study respectively.
to be 46.90 % (r = 0.986), 47.58% (r= 0.987) and 48.02% (r = 0.986) within 12
h of study respectively.
 Stability studies conducted as per ICH guidelines at 40 °C / 75 % RH indicated
that there is no decrease in drug content or no significant difference between the
means of profiles without stress and with stress at p<0.05 observed for a period
of 3 months . Thus, the manufactured fast dissolving tablets were found to be
stable with respect to physicochemical and release characteristics.

The investigations so far and the results obtained there of, for various
formulations fulfilled the objectives of the current investigation however, further
studies could be carried out to know the effect of varying compressional parameters
on actual production and also actual in vivo benefit to a patient.

8. SUMMARY
Controlled release tablets are dosage forms which remain in the
gastro- intestinal tract for a long period, improve the bioavailability of those
drugs whose therapeutic window is in the stomach or proximal part of small
intestine. Such controlled release dosages are therapeutically highly beneficial
in the treatment of hypertension.
The present investigation was planned to formulate controlled release
tablets to improve perindopril erbumine bioavailability. The starch as binder and
talc and magnesium stearate (2:1) as glidants were optimized. Also the effect of
various matrix carrier excipients like Microcrystalline cellulose, Xanthan gum,
Almond gum, Eudragit RL 100 was studied. Chapter 1 gives an over view of the
controlled release dosage forms and hypertension. Current literature cites various
approaches and different drugs that have been successfully formulated and
evaluated, has been described in chapter 3. Throughout the work, standard
techniques and methods, as outlined in various text books, research articles and
other sources were reviewed and used in this investigation. The investigation
carried out on various formulations resulted in totally all formulation obeying
fickian diffusion or zero order release kinetics. Chapter 5 and 6, describes the
results obtained from various experiments conducted and discusses the results
and mechanism of the release. The study on rheological characteristics of
powder/granule bed indicated that, all the granules were freely flowing and
compressible. Studies on compression characteristics indicated that the tablet
remain intact over the period of more than 9 h. drug content was found to be more

than 93 % and was fairly uniform and consistent.
In vitro results indicated that, Microcrystalline cellulose, a l m o n d g u m ,
xanthun gum and eudragit RL 100 tablets containing starch as binder follow fickian
diffusion or zero order release kinetics. The increasing the amount of glidants does
not significantly alter the drug release kinetics, it improve the flow ability of the
granule bed. Stability studies at 40ºC and 75 % RH for a p e r iod of 90 days. The
drug content found at the end of everyday shows that there is little decrease in
drug content which is statistically not significant (p<0.05).
Conclusions drawn from the results are mentioned in chapter-7. The present
study conclusively proved that Perindopril erbumine matrix tablets could be
successfully developed using various polymers. The prepared tablets gave promising
results with respect to swelling strength and in vitro release from the dosage form.
Vancouver style was followed to quote the references in the study and is listed in the
chapter of Bibliography (chapter 9).

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DEVELOPMENT AND EVALUATION OF CONTROLLED

RELEASE MATRIX TABLETS CONTAINING PERINDOPRIL IN

Under the Guidance of

‘TO GAYATHRI LAKSHMI.B WHO HAVE BEEN AN

IMMENSE SUPPORT AND BELIEVING IN ME’

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “Development and evaluation

of controlled release matrix tablets containing perindopril in the treatment of

guidance of Dr. Somashekar Shyale, Professor, Department of Pharmaceutics, V.L.

College of Pharmacy, Raichur.

Place: Raichur (N.Srikanth Reddy)

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “Development and evaluation

of controlled release matrix tablets containing perindopril in the treatment of

hypertension” is a bonafide research work done by Mr. N.Srikanth Reddy in partial

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

Pharmaceutics under my guidance at V.L. College of Pharmacy, Raichur.

Date: Dr. Somashekar Shyale

ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION

This is to certify that the dissertation entitled “Development and evaluation

of controlled release matrix tablets containing perindopril in the treatment of

hypertension” is a bonafide research work done by Mr. N.Srikanth Reddy under

the guidance of Dr. Somashekar Shyale at V.L. College of Pharmacy, Raichur.

Dr. Y. Anand Kumar Dr. S.M Shanta Kumar

Declaration by the Candidate

or electronic format for academic /research purpose.

Place: Raichur (N.Srikanth Reddy)

© Rajiv Gandhi University of Health Science, Bengaluru, Karnataka.

the continued blessings showered on me to successfully complete my dissertation.

I deeply express my gratitude whole heartedly to my mother Smt. N. Aruna,

It gives me immense pleasure to acknowledge, the help rendered to me by a

every front of my life.

Department of Pharmaceutics V.L. College of Pharmacy, under the supervision of

sincere gratitude for his continuous encouragement, valuable suggestions, dynamic

the period of this work.

Gowda, Department of Pharmaceutics, for their concern, co-operation and

encouragement throughout the duration of the course.

I thank respected Dr. K.M.K. Swamy, Dr. Srinivasalu, Shri. Zaheeruddin

Pramod Kumar Dept. of Pharmacognosy, for their encouragement and moral

I also acknowledge with heartfelt thanks the contributions of M/s Lupin

I express my special thanks and regards to my roommates Mr. T.Rajesh, Mr.

I hereby acknowledge the cooperation and help rendered by my departmental

Shashikala and Miss. Areefa .

the student days, especially Miss. Gayathri Lakshmi Bahumanyam,

Mr.P.V.BalaSubramanyam, Mr. Riaz basha, Mrs. Sujatha Reddy , Mr. Krishna

not forgotten me in spite of the long distance between us.

Miss Roopa for their co-operation and help.

I thank my juniors especially Miss Gayathri Lakshmi Bahumanyam Mr.

Miss and for their cooperation and help.

completion of this dissertation work.

At last but not least I heartly thankful to my school Priyadarshini English

motivate me to this position.

Background and Objectives:

Perindopril Erbumine (PE) is an Ace inhibitor. It is effective in the treatment

< 60 %. Perindopril erbumine shows promising pharmacokinetics and Physico-

selected as model drugs for this investigation.

The objectives of the present research work is to formulate and evaluate

controlled matrix tablets containing Perindopril Erbumine (PE) as a drug using

bioavailability of the drug.

An UV Spectrophotometric method was developed to quantitate Perindopril

guidelines at 40°C/ 75 % RH for a period of 90 days.

which corroborates with the literature value 1260C−1280C. Solubility of Perindopril

Perindopril Erbumine was found to be 0.464.