FORMULATION AND EVALUATION OF GRANULES AND ...gnu.inflibnet.ac.in/bitstream/123456789/891/1/MT-584-Khartri... · Use of Metoprolol Succinate and Olmesartan ... 7 FORMULATION AND OPTIMIZATION

FORMULATION AND EVALUATION OF GRANULES AND

TABLET IN CAPSULE DOSAGE FORM OF

ANTIHYPERTENSIVE DRUGS COMBINATION

A Dissertation

Submitted as a Partial Fulfillment for Degree of

Master of PharmacyMaster of PharmacyMaster of PharmacyMaster of Pharmacy

In The Faculty of Pharmacy

(PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY)

To

GANPAT UNIVERSITY, GANPAT VIDYANAGAR

May, 2013

Guided By: Submitted By: Dr. Girish N. Patel Mr. Kaushal S. Khatri M. Pharm., Ph. D. B. Pharm.

SHREE S.K.PATEL COLLEGE OF PHARMACEUTICAL EDUCATION &

RESEARCH, GANPAT UNIVERSITY, GANPAT VIDYANAGAR-384012.

DIST. - MEHSANA (GUJARAT), INDIA.

CERTIFICATE

I hereby certify that Mr. Kaushal Shaileshbhai Khatri has

completed his Dissertation work for Master of pharmacy in

Pharmaceutics and Pharmaceutical Technology on the topic

“Formulation and Evaluation of Granules and Tablet in Capsule

Dosage Form of Antihypertensive Drugs Combination”. I further

certify that work was carried out under my supervision and guidance at

Department of Pharmaceutics and Pharmaceutical Technology, Shree S.

K. Patel College of Pharmaceutical Education and Research, Ganpat

University during academic year 2012-13. This work is up to my

satisfaction.

Research Guide: Head of Department: ______________ ______________ Dr. G. N. Patel Dr. R. P. Patel M. Pharm., Ph.D. M. Pharm., Ph.D. Assistant Professor, Associate Professor, Dept. of Pharmaceutics & Dept. of Pharmaceutics & Pharmaceutical Technology Pharmaceutical Technology

Forwarded Through:

______________ Dr. R. K. Patel M. Pharm., Ph.D. I/C Principal, Shree S. K. Patel College of Pharmaceutical Education & Research DATE: PLACE: Ganpat University, Ganpat Vidyanagar.

DECLARATIONDECLARATIONDECLARATIONDECLARATION

I, Kaushal S. Khatri, hereby declare that the Dissertation work

entitled ““““Formulation and Evaluation of Granules and Tablet in Formulation and Evaluation of Granules and Tablet in Formulation and Evaluation of Granules and Tablet in Formulation and Evaluation of Granules and Tablet in

Capsule Dosage Form of Antihypertensive Drugs CombinationCapsule Dosage Form of Antihypertensive Drugs CombinationCapsule Dosage Form of Antihypertensive Drugs CombinationCapsule Dosage Form of Antihypertensive Drugs Combination””””

which is submitted to the Ganpat University, in partial

fulfillment for the award for Degree of Master of Pharmacy in

Pharmaceutics and Pharmaceutical Technology Department of

Shree S. K. Patel College of Pharmaceutical Education &

Research, is my own project work carried out under the

supervision and guidance of Dr. G. N. Patel, Assistant Professor,

Dept. of Pharmaceutics and Pharmaceutical Technology Shree S.

K. Patel College of Pharmaceutical Education and Research,

Ganpat University, Ganpat Vidyanagar.

The work presented in this thesis has not been submitted for the

award of any degree in this or any other University. The work

was carried out by me during academic year 2012-2013.

Kaushal S. Khatri

B. Pharm.

Date:

Place: Ganpat University, Ganpat Vidyanagar.

ACKNOWLEDGEMENTACKNOWLEDGEMENTACKNOWLEDGEMENTACKNOWLEDGEMENT

� This research work is a synergistic product of many persons. It is not a

chronology of events, but a collection of ideas at work. The completion of

this dissertation is not only fulfillment of my dreams but also the dreams of

my Parents, who have taken lots of pain for me in completion of my higher

studies. This thesis had its own set of challenges, therefore this is the time to

say sincere thanks to all those who have, in some way or the other helped me

to sail through.

� I offer flowers of gratitude to the almighty GOD who has been the source of

strength in my life.

� This is great opportunity on my part to express my gratitude and sincere

respectto one and all. I take this opportunity and it gives me immense

pleasure to express my deep sense of gratitude to my guide Dr. Girish N.

Patel, Assistant Professor of the Department of Pharmaceutics, Shree S.K.

Patel College of pharmaceutical education and research, for his lively

discussion, constructive critism, unending enthusiasm and immense guidance,

help and heartly support at all stages of this work. I also thank to other

faculty members for their co-operation.

� My sincere thank to Dr. R. K. Patel, I/C Principal of Shree S. K. Patel

college of Pharmaceutical Education and Research for providing me

infrastructure, laboratory and library facility. I am extremely thankful to Dr.

Rakesh P. Patel, Head of Department of Pharmaceutics and Pharmaceutical

Technology for his support and encouragement.

� I am also thankful to other non-teaching staff Mr. Manishbhai, for their

kind co-operation.

� I cannot forget the sweet memories of the time that I have spent with my

colleagues; I extend my thanks to all my colleagues.

� I would like to express my love and gratitude to my beloved Mother Smt.

Nitaben and my Father Mr. Shaileshbhai from depth of my heart for giving

me more than what I deserved. Their blessings always inspire me to work

hard and to overcome all the difficulties throughout my life. It gives me an

immense pleasure to dedicate my research work at their feet without whose

blessings and vision, I would not have been able to achieve this task.

� I am very much thankful to my brother Chirag for his immense love, care, and

emotional support and confidence that he infused in me.

� Last but not the least, I express my gratitude and apologize to everyone

whose contribution, I could not mention in this page.

Kaushal S. KhatriKaushal S. KhatriKaushal S. KhatriKaushal S. Khatri

Dedicated

To Beloved God Ganesha,

My Parents, Friends And

Teachers

Index

M.Pharm Thesis S.K.P.C.P.E.R.

INDEX

Sr.No.

Title PageNo.

1 AIM & OBJECTIVE 1-4

1.1 Rational Behind Project Work 2

1.2 Following criteria were aimed to achieve 2

1.3 References 3

2 INTRODUCTION 5-32

2.1 Introduction to Disease 5

2.1.1 Causes of Hypertension 5

2.1.2 Therapy for Hypertension 6

2.1.3Use of Metoprolol Succinate and OlmesartanMedoxomil in Treatment of Hypertension

6

2.2 Introduction to Formulation 7

2.2.1 Granules and Tablets-in-a capsule technology 7

2.2.1Formulation of Granule and tablet-in-capsulesystems

8

2.3 Introduction to Extended release drug delivery system 9

2.3.1Suitable Drug Candidate for Extended ReleaseDrug Delivery System

10

2.3.2 Merits of Extended Release Drug Delivery System 11

2.3.3 Demerits Extended Release Drug Delivery System 11

2.3.4Factors Affecting the Extended Release DrugDelivery System

11

2.4 Introduction to Immediate Release dosage form 14

2.4.1 Advantages of immediate release formulation 15

2.4.2 Disadvantages of immediate release formulation 15

2.4.3 Mechanism of Superdisintegrants 15

2.4.4 Method of addition of disintegrants 17

2.5 Introduction to Drugs 17

2.5.1 Metoprolol Succinate 17

2.5.2 Olmesartan Medoxomil 20

2.6Introduction to Polymers 23

2.6.1 Hypromellose 23

2.6.2 Sodium starch glycollate 25

Index


2.6.3 Croscarmellose Sodium 26

2.6.4 Crospovidone 27

2.7 References 29

3 LITERATURE REVIEW 33-45

3.1 Literature Review of Formulation 33

3.2 Literature Review of Metoprolol Succinate 37

3.3 Literature Review of Olmesartan Medoxomil 41

3.4 Reference 43

4 EXPERIMENTAL SET UP 46-47

4.1 Instruments used in present work 46

4.2 Materials used in the present work 47

5 PREFORMULATION STUDY 48-58

5.1 Bulk Density 48

5.2 Carr’s Index 48

5.3 Hausner’s Ratio 49

5.4 Angle of repose 49

5.5 Drug and Polymer interaction study 50

5.6 Result & Discussion 50

5.6.1 Density, Flow property and Angle of Repose 50

5.6.2 Drug and Excipients Compatibility Study 51

5.7 Conclusion 55

5.8 References 56

6 FORMULATION AND DEVELOPMENT OF IMMEDIATE

RELEASE GRANULES OF OLMESARTAN MEDOXOMIL57-72

6.1 Preparation of standard curve of Olmesartan Medoxomil 57

6.2 Selection and justification of Excipients 58

6.3Preliminary trials for the Immediate release granules ofOlmesartan Medoxomil using SSG

59

6.3.1 Evaluation of Preliminary Trials 60

6.3.2 Result and Discussion 61

6.4Optimization of Immediate release granules of Olmesartanmedoxomil

64

6.4.1 Evaluation 65


Index


6.5Optimization of Immediate release granules of Olmesartanmedoxomil using Cross povidone

67

6.5.1 Evaluation 68


6.6 Conclusion 71

6.7 References 71

7 FORMULATION AND OPTIMIZATION OF EXTENDED

RELEASE TABLET OF METOPROLOL SUCCINATE72-98

7.1 Preparation of standard curve of Metoprolol Succinate 72

7.2 Selection and justification of Excipients 73

7.3Preliminary trial of Metoprolol Succinate ERT withHPMC K100M

74

7.3.1 Evaluation Parameters 75


7.4Formulation of ERT of Metoprolol Succinate with HPMCK4M and HPMC K100M

78

7.4.1Evaluation of Pre compressional parameters oftrial via wet granulation

79

7.4.2Evaluation of Post compressional parameters oftrial via wet granulation

80

7.5Optimization of formulation by using 32 full factorialdesigns

82

7.5.1 Evaluation of Pre compressional parameters ofERT using 32 Full Factorial Design

84

7.5.2 Evaluation of Post compressional parameters ofERT using 32 Full Factorial Design

84

7.5.3 Response R1: Drug release at 1st hour 89

7.5.4 Response R2: Drug release at 8th hour 90



7.5.7 Response R5: T50% 91

7.5.8 Response R6: T80% 91

7.5.9 Comparison of Experimental and Predicted valueof Optimized formula

95

7.7 Result and Discussion 96

7.8 Conclusion 97

7.9 References 98

Index


8. FORMULATION AND DEVELOPMENT OF GRANULESAND TABLET IN CAPSULE DOSAGE FORM

99-112

8.1Analytical Method for the Estimation of MetoprololSuccinate and Olmesartan Medoxomil in CombineDosage form by HPLC

99

8.1.1 Apparatus 99

8.1.2 Materials and Reagents 99

8.1.3 Preparation of solutions & Reagents 99

8.1.4 Chromatographic Condition 100

8.1.5 Determination of analytical wavelength 100

8.1.6 Calibration Curve 101

8.2Formulation of granules and tablet in capsule dosage formof METO and OLME

103

8.3 Evaluation of Granules and Tablet in Capsule dosage form 103

8.4 Result and Discussion 106

8.5 Conclusion 111

8.6 References 112

9. SUMMARY 113-114

List of Tables 115-116

List of Figures 117-119

List of Abbreviations 120-121

Chapter 1: Aim & Objective

M.Pharm Thesis S.K.P.C.P.E.R. Page 1

1. AIM AND OBJECTIVE:

It is well known that solid oral dosage forms, particularly tablets, are the most

acceptable form of delivering medication. However, some new variations are

beginning to emerge such as granules and tablet in capsule technology (Huang J. et al,

1999), which offer formulation flexibility. These biphasic delivery systems are

designed to release a drug at two different rates or in two different periods of time:

they are either quick/slow or slow/quick (Carla M. et al, 2006). A quick/slow release

system provides an initial burst of drug release followed by a constant rate (ideally) of

release over a defined period of time and in slow/quick release system provides

release vice versa. Generally, conventional controlled dosage forms delay the release

of therapeutic systemic levels and do not provide a rapid onset of action (Lauretta M.

et al, 1999). While immediate release granules give fast release to provide rapid onset

of action, but fails to provide longer duration of action. A relatively constant plasma

level of a drug is often preferred to maintain the drug concentration within the

therapeutic window (Makoto I. et al, 2006). However, it is difficult to achieve,

especially for once-daily dosage forms, partly because the environment for drug

diffusion and/or absorption varies along the gastrointestinal (GI) tract (Leblanc JC et

al, 2010). Here Metoprolol Succinate tablet was formulated as an extended release

tablet and Olmesartan medoxomil was formulated as an immediate release granules.

Olmesartan medoxomil provides immediate onset of action while Metoprolol

succinate provides extended release up to 24 hour drug release.

Metoprolol Succinate is a beta1-selective (cardioselective) adrenergic

antagonist class sympatholytic drug. It is use in hypertension, cardiac failure and

angina pectoris (S.A, et al, 2010). When dose is missing it may causes nocturnal

attack. Metoprolol well absorbed orally but absolute oral bioavaibility average about

50% because of hepatic first pass metabolism. Its biological half life is 3-6 hours

(Mujoriya R. et al, 2010). Hence, in this work; an attempt is made to formulate

extended release tablets of Metoprolol Succinate to increase patient compliance by

reducing dosing frequency and to achieve even plasma concentration profile over 24

hrs. The drug is freely soluble in water and hence judicious selection of release

retarding excipients is necessary to achieve a constant in vivo input rate of the drug

(Vijaya R. et al, 2009). The most commonly used method of modulating the drug

release is to include it in a matrix system. Hydrophilic polymer matrix systems are



widely used in oral controlled drug delivery because of their flexibility to obtain a

desirable drug release profile, cost-effectiveness, and broad regulatory acceptance

(Gohel M. et al, 2009) Hence the aim of present investigation was to develop

extended release formulation of Metoprolol Succinate using HPMC K4M & K100M

and evaluated by invitro study.

Olmesartan Medoxomil, specific angiotensin II type 1 antagonist. It is use in

hypertension, cardiac failure. Olmesartan well absorbed orally but absolute oral

bioavaibility average about 26% because of hepatic first pass metabolism. Its

biological half life is 14-16 hours. Hence in this work, attempt is made to formulate

Olmesartan medoxomil immediate release granules and to achieve loading dose.

Various types of disintegrant like sodium starch glycolate, cross povidone, cross

carmellose sodium were used to obtain good release pattern in quick time. Hence the

aim of present investigation was to develop immediate release formulation of

Olmesartan medoxomil using various disintegrant and evaluated by invitro study

(Galge D. et al, 2012).

1.1 Rational Behind Project Work:

The rationale behind use of this drug combination is that in treatment of

hypertension in patients whose blood pressure is not adequately controlled by

monotherapy, oral administration of drugs has been found to be more effective

than the use of either drug alone.

The current investigation aims at development of dosage form tablets having

extended release patterns of Drug Metoprolol Succinate, and Granules having

rapid release pattern of Drug Olmesartan Medoxomil.

So rapid release pattern of the drug decrease high blood pressure initially and

sustain release pattern of drug maintain blood pressure. And the tablet and

granules are filled into capsule of appropriate size.

1.2 Following criteria were aimed to achieve

To formulate Extended release tablet of Metoprolol Succinate

To prepare Immediate release Granules of Olmesartan Medoxomil

To optimize formulation



1.3 References:

Ansel W., Dosage form design, General considerations pharmaceuticals ingredients,

product information and CGMP, in pharmaceutical dosage forms and Drug delivery

systems, VIth Edition, New Delhi: BI. Waverly Pvt Ltd. page No. 569.

Bahera A. Nayak A. Mohanthy B. Barik B, Development and optimization of

Losartan potassium tablet, Int J of Applied Pharmaceutics, 2012,Vol 2 Issue 2,pg

no:15-19

Galge D, Raut R, Adimoolam S, Masurkar S. Formulation and evaluation of

Irbesartan immediate release tablet, Int research j of pharmacy, 2012, 3(4), ISSN 2230

– 8407, pg no:410-415.

Gohel M, Parikh R, Nagori S, Jena D. Fabrication of Modified Release Tablet

Formulation of Metoprolol Succinate using Hydroxypropyl Methylcellulose and

Xanthan Gum. AAPS Pharm Tech sci. 2009; 10(1), pg no: 62-68.

Huang J, Kao H, Wu XY., The pH-dependent biphasic release of Azidothymidine

from layered composite of PVA disks and P (MMA/MAA) spheres, Toronto, Ontario,

CanadaM5S2S2, 1999.

Jamsheer A, Adimoolam S, Shantesh M, Jivan K, Vantoor B., Formulation and

evaluation of venalfexine immediate release tablet, Int research j of pharmacy, 2012,

3 (4), ISSN 2230 – 8407,pg no: 324-329.

K. Reeta Vijaya Rani, S. Eugine Leo Prakash, R. Lathaeswari S. Rajeswari,

formulation and evaluation of ER Metoprolol Succinate tablet, Int J of PharmTech

Research, July-Sept 2009:Vol.1, No.3, pg no: 634-638,

Lauretta M., Evelyn Ochoa M., Maria Luisa Torrea, and Ubaldo Conte., Formulation

of biphasic release tablets containing slightly soluble drugs. Eur J Pharma Biopharma

1999, pg no: 48: 37-42.

Leblanc JC, Yoon H, Kombadjian A, Verger P. Nutritional intakes of vegetarian

populations in France. Eur J Clin Nutr 2000, pg no: 54:443-9.

Lopes C. Loboa J. Joao F. and Paulo C., Compressed mini-tablets as a biphasic

delivery system. Int J Pharmaceutics 323:2006, pg no: 93-100.



Makoto I., Kenichi A., Minoru H., Masao K. A novel approach to sustained

pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules. Int J

Pharma 2008; 359, pg no: 46–52.

Moawia M. Al-Tabakha. HPMC Capsules: Current Status and Future Prospects. J

Pharm Sci 2010; 13(3), pg no: 428 - 442.

Mujoriya R. Venkateshvarlu D. Singh V. Gupta A. Bisen A, Formulation

Development and Evaluation of Metoprolol Succinate Er and Amlodipine Besilate

Bilayer Tablet, Research J. Pharm. and Tech. Oct.-Dec. 2010: 3(4).

Chapter 2: Introduction


2. INTRODUCTION:

2.1 Introduction to Disease:

Hypertension:

Hypertension, also referred to as high blood pressure, is a condition in which the

arteries have persistently elevated blood pressure. Every time the human heart beats, it

pumps blood to the whole body through the arteries. Blood pressure is the force of

blood pushing up against the blood vessel walls. The higher the pressure the harder

the heart has to pump. Hypertension can lead to damaged organs, as well as several

illnesses, such as renal failure (kidney failure), aneurysm, heart failure, stroke, or

heart attack.

Hypertension may be classified as essential or secondary. Essential hypertension is

the term for high blood pressure with unknown cause. It accounts for about 95% of

cases. Secondary hypertension is the term for high blood pressure with a known direct

cause, such as kidney disease, tumours, or birth control pills. Some 70 million adults

in the United States are affected by hypertension. The condition also affects about two

million teens and children.

2.1.1 Causes of Hypertension:

Though the exact causes of hypertension are usually unknown, there are several

factors that have been highly associated with the condition. These include:

Smoking

Obesity or being overweight

Diabetes

Sedentary lifestyle

Lack of physical activity

High levels of salt intake (sodium sensitivity)

High levels of alcohol consumption

Stress

Aging

Medicines such as birth control pills

Genetics and a family history of hypertension - Chronic kidney disease

Adrenal and thyroid problems or tumour.



2.1.2 Therapy for Hypertension:

The main goal of treatment for hypertension is to lower blood pressure to less than

140/90 - or even lower in some groups such as people with diabetes, and people with

chronic kidney diseases. Treating hypertension is important for reducing the risk of

stroke, heart attack, and heart failure. High blood pressure may be treated medically,

by changing lifestyle factors, or a combination of the two. Important lifestyle changes

include losing weight, quitting smoking, eating a healthful diet, reducing sodium

intake, exercising regularly, and limiting alcohol consumption. Medical options to

treat hypertension include several classes of drugs. ACE inhibitors, ARB drugs, beta-

blockers, diuretics, calcium channel blockers, alpha-blockers, and peripheral

vasodilators are the primary drugs used in treatment. These medications may be used

alone or in combination, and some are only used in combination. In addition, some of

these drugs are preferred to others depending on the characteristics of the patient

(diabetic, pregnant, etc.). If blood pressure is successfully lowered, it is wise to have

frequent checkups and to take preventive measures to avoid a relapse of hypertension.

2.1.3 Use of Metoprolol Succinate and Olmesartan Medoxomil in Treatment of

Hypertension:

Metoprolol Succinate is a beta1-selective (cardioselective) adrenoceptor blocking

agent. The mechanism of the antihypertensive effects of beta-blocking agents has not

been elucidated. However, several possible mechanisms have been proposed:

(1) Competitive antagonism of catecholamine’s at peripheral (especially cardiac)

adrenergic neuron sites, leading to decreased cardiac output;

(2) A central effect leading to reduced sympathetic outflow to the periphery;

(3) Suppression of renin activity.

Olmesartan is used to reduce high blood pressure. It is an angiotensin-II receptor

antagonist, sometimes known as an antihypertensive. It is used to treat high blood

pressure (hypertension). Olmesartan lowers blood pressure by relaxing the blood

vessels. Benefits of being on this drug can include a reduction in blood pressure

which is associated with a reduction in the risk of stroke, heart attack, heart failure or

kidney failure.



2.2 Introduction to Formulation:

2.2.1 Granules and Tablets-in-a capsule technology:

Biphasic delivery systems are designed to release a drug at two different rates or in

two different periods of time: they are either quick/slow or slow/quick. A quick/slow

release system provides an initial burst of drug release followed by a constant rate

(ideally) of release over a defined period of time and in slow/quick release system

provides release vice versa (Moawia M et al, 2010).

Figure 2.1: Granules and Tablets-in-a capsule Dosage form

Biphasic release system is used primarily when maximum relief needs to be achieved

quickly, and it is followed by a sustained release phase to avoid repeated

administration. Suitable candidate drugs for this type of administration include non-

steroidal anti-inflammatory drugs (NSAIDs) antihypertensive, antihistaminic, and

anti-allergic agents. Generally, conventional controlled dosage forms delay the release

of therapeutic systemic levels and do not provide a rapid onset of action. While

immediate release granules give fast release to provide rapid onset of action, but fails

to provide longer duration of action. A relatively constant plasma level of a drug is

often preferred to maintain the drug concentration within the therapeutic window

(Moawia M et al, 2010). However, it is difficult to achieve, especially for once-daily

dosage forms, partly because the environment for drug diffusion and/or absorption

varies along the gastrointestinal (GI) tract. On the basis of these considerations, we

have proposed a new oral delivery device, in the form of a double component tablet

and granules, in which the one portion is formulated to obtain a prompt release of the

drug, with the aim of reaching a high serum concentration in a short period of time.

The second portion is a sustain release matrix, which is designed to maintain an

effective plasma level for a prolonged period of time (Makoto I. et al, 2008).



This concept can be used to produce a biphasic delivery system combining a fast

release together with the slow release period of the drug, provided that the excipients

powder that fills The void spaces between the tablets incorporate a part of the total

drug dose. This system can produce a rapid rise in the plasmatic concentrations for

some drugs (such as analgesic, anti-inflammatory, anti hypertensive and

antihistaminic agents) that are requested to promptly exercise the therapeutic effect,

followed by an extended release phase in order to avoid repeated administrations.

2.2.2 Formulation of Granule and tablet-in-capsule systems:

The formulation process of mini-tablet-in-capsule systems can be divided into three

steps:

The formulation/production of tablets

Filling of these tablets into hard gelatin or HPMC capsules.

Filling of granules and tablets-in-capsule systems.

A capsule is a solid dosage form in which the active ingredients and diluents are

contained in a two-piece hard shell, usually made of gelatin. The success achieved by

the hard gelatin capsules, popularly known as HGC, is well known and is reflected by

the fact that hard gelatin capsules shells have been used in the pharmaceutical field for

more than 100 years and continue to grow in acceptance as the preferred oral dosage

form. Hard gelatin capsules do have some drawbacks, so that the in the present work

HPMC capsules are preferred. The principal drawback of hard gelatin capsules is that

the capsule shells have 13 to 16% water content and therefore may not be suitable for

use with readily hydrolysable drugs. Some drugs react with amine group of gelatin,

causing formation of cross-link between gelatin molecules and reducing the solubility

of the capsule shell. Furthermore gelatin products are avoided by many as a result of

religious, cultural or vegetarian restrictions. In addition, recent safety report suggests

theoretical risks of transmitting spongiform encephalopathy via gelatin capsules (Bin

Li et al, 2004)

To overcome these problems, pharmaceutical scientists has been working for decades

to develop capsules made of starch, cellulose derivatives and polyvinyl alcohol

copolymer. In 1998, shionogi qualicep successfully manufactured HPMC capsules,

QUALI-V with the properties suitable for pharmaceutical products and dietary

supplements.



Figure 2.2: Size of the capsule to fill weight

HPMC capsules are available in a wide range of sizes- 00, 0, 1, 2, 3, 4. It comes in

crystal clear or colored as per the needs including a range of natural colors to

complement the brand HPMC40-42 capsules can be manufactured by the same

dipping and forming method that is employed for the manufacture of classic hard

gelatin capsules.

2.3 Introduction to Extended release drug delivery system:

It includes any drug delivery system that achieves slow release of drug over an

extended period of time (Jantzen GM et al, 1996).

Figure 2.3: Characteristic representation of plasma concentration of a

Conventional immediate release (IR), Sustained release and Zero order

Controlled release (ZOCR)

Oral route is the most oldest and convenient route for the administration of

therapeutic agents because of low cost of therapy and ease of administration leads to

higher level of patient compliance. Approximately 50% of the drug delivery systems

available in the market are oral drug delivery systems and historically too, oral drug

administration has been the predominant route for drug delivery. It does not pose the

Toxic level

ideal dosing

Minimumeffective level



sterility problem and minimal risk of damage at the site of administration. During the

past three decades, numerous oral delivery systems have been developed to act as

drug reservoirs from which the active substance can be released over a defined period

of time at a predetermined and controlled rate.

The oral controlled release formulation have been developed for those drug that are

easily absorbed from the gastrointestinal tract (GIT) and have a short half-life are

eliminated quickly from the blood circulation. As these will release the drug slowly

into the GIT and maintain a constant drug concentration in the plasma for a longer

period of time (Lachman L. Et al, 1987).The sustained release, sustained action,

prolonged action, controlled release, extended action, timed release, depot and

respiratory dosage forms are terms used to identify drug delivery system that are

designed to achieve a prolonged therapeutic effect by continuously releasing

medication over an extended period of time after administration of a single dose

Extended release formulation is an important program for new drug research and

development to meet several unmet clinical needs. There are several reasons for

attractiveness of these dosage forms viz. provides increase bioavailability of drug

product, reduction in the frequency of administration to prolong duration of effective

blood levels, Reduces the fluctuation of peak trough concentration and side effects

and possibly improves the specific distribution of the drug. Extended release drug

delivery system achieves a slow release of the drug over an extended period of time or

the drug is absorbed over a longer period of time. Extended release dosage form

initially releases an adequate amount of drug to bring about the necessary blood

concentration (loading dose, DL) for the desired therapeutic response and therefore,

further amount of drug is released at a controlled rate (maintenance dose, DM) to

maintain the said blood levels for some desirable period of time (Sastry SV et

al,2001).

2.3.1 Suitable Drug Candidate for Extended Release Drug Delivery System:

The drugs that have to be formulated as an ERDDS should meet following

parameters.

It should be orally effective and stable in GIT medium.

Drugs that have short half-life, ideally a drug with half life in the range of 2 – 4

hrs makes a good candidate for formulation into ER dosage forms eg.

Captopril, Salbutamol Sulphate.



The dose of the drug should be less than 0.5g as the oral route is suitable for

drugs given in dose as high as 1.0g eg. Metronidazole.

Therapeutic range of the drug must be high. A drug for ERDDS should have

therapeutic range wide enough such that variations in the release do not result

in concentration beyond the minimum toxic levels (Vyas S et al, 2000).

2.3.2 Merits of Extended Release Drug Delivery System:

The extended release formulations may maintain therapeutic concentrations

over prolonged periods.

The use of extended release formulations avoids the high blood concentration.

Reduce the toxicity by slowing drug absorption.

Minimize the local and systemic side effects.

Improvement in treatment efficacy.

Minimize drug accumulation with chronic dosing.

Improvement of the ability to provide special effects.

Enhancement of activity duration for short half life drugs.

2.3.3 Demerits Extended Release Drug Delivery System:

Despite of several merits, extended release dosage forms are not devoid of

certain demerits explained following:

In case of acute toxicity, prompt termination of therapy is not possible.

Less flexibility in adjusting doses and dosage regimens.

Risk of dose dumping upon fast release of contained drug.

High cost of preparation.

The release rates are affected by various factors such as, food and the rate

transit through the gut.

The larger size of extended release products may cause difficulties in ingestion

or transit through gut (Srivastav M et al, 2011).

2.3.4 Factors Affecting the Extended Release Drug Delivery System:

Physiochemical Properties:

Aqueous Solubility:

Certain drug substance having low solubility is reported to be 0.1 mg/ml. As the drug

must be in solution form before absorption, drug having low aqueous solubility

usually suffers oral bioavailability problem due to limited GI transit time of

undissolved drug and limited solubility at absorption site. So these types of drug are



undesirable to be formulated as extended release drug delivery system. Drug having

extreme aqueous solubility are undesirable for extended release because, it is too

difficult to control release of drug from the dosage form.

Partition Co-efficient:

As biological membrane is lipophilic in nature through which the drug has to pass, so

partition co-efficient of drug influence the bioavailability of drug very much. Drug

having lower partition co-efficient values less than the optimum activity are

undesirable for oral ER drug delivery system, as it will have very less lipid solubility

and the drug will be localized at the first aqueous phase it come in contact. Drug

having higher partition co-efficient value greater than the optimum activity are

undesirable for oral ER drug delivery system because more lipid soluble drug will not

partition out of the lipid membrane once it gets in the membrane (Pogula M et al,

2001).

Protein Binding:

The Pharmacological response of drug depends on unbound drug concentration rather

than total concentration and all drugs bound to some extent to plasma and/or tissue

proteins. Proteins binding of drug play a significant role in its therapeutic effect

regardless the type of dosage form as extensive binding to plasma, increase biological

half life and thus, such type of drug will release upto extended period of time then

there is no need to develop extended release drug delivery for this type of drug.

Drug Stability:

As most of ER Drug delivery system is designing to release drug over the length of

the GIT, hence drug should be stable in GI environment. So drug, which is unstable,

can’t be formulated as oral ER drug delivery system, because of bioavailability

problem.

Mechanism and Site of Absorption:

Drug absorption by carrier mediated transport and those absorbed through a window

are poor candidate for oral ER drug delivery system. Drugs absorbed by passive

diffusion, pore transport and through over the entire length of GIT are suitable

candidates for oral ER drug delivery system.

Dose Size:

If a product has dose size >0.5g it is a poor candidate for ER drug delivery system,

because increase in bulk of the drug, thus increases the volume of the product. Thus



dose of drug should small to make a good drug candidate for extended release drug

delivery system.

Biological Properties:

Absorption:

The absorption behaviour of a drug can affect its suitability as an extended release

product. The aim of formulating an extended release product is to place a control on

the delivery system. It is essential that the rate of release is much slower than the rate

of absorption. If we assume the transit time of most drugs and devices in the

absorptive areas of GI tract is about 8-12 hours, the maximum half-life for absorption

should be approximately 3-4 hours. Otherwise the device will pass out of absorptive

regions before drug release is complete. Therefore the compounds with lower

absorption rate constants are poor candidates for extended release systems. Some

possible reasons for a low extent of absorption are poor water solubility, small

partition co-efficient, acid hydrolysis, and metabolism or its site of absorption.

Distribution:

The distribution of drugs in tissues can be important factor in the overall drug

elimination kinetics. Since it not only lowers the concentration of circulating drug but

it also can be rate limiting in its equilibrium with blood and extra vascular tissue,

consequently apparent volume of distribution assumes different values depending on

time course of drug disposition. Drugs with high apparent volume of distribution,

which influence the rate of elimination of the drug, are poor candidate for oral ER

drug delivery system e.g. Chloroquine. For design of extended release products, one

must have information on disposition of the drug.

Metabolism:

Drug, which extensively metabolized is not suitable for ER drug delivery system. A

drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site

of absorption or first-pass effect is poor candidate for ER delivery, since it could be

difficult to maintain constant blood level e.g. levodopa, nitroglycerine. Drugs that are

metabolised before absorption, either in lumen or the tissues of the intestine, can show

decreased bioavailability from the extended releasing systems. Most intestinal walls

are saturated with enzymes. As drug is released at a slow rate to these regions, lesser

drug is available in the enzyme system. Hence the systems should be devised so that

the drug remains in that environment to allow more complete conversion of the drug

to its metabolite.



Half-life of Drug:

A drug having biological half-life between 2 to 8 hours is best suited for oral ER drug

delivery system. As if biological half-life < 2hrs the system will require unacceptably

large rate and large dose and biological half-life > 8hrs formulation of such drug into

ER drug delivery system is unnecessary (Pogula M et al, 2010).

2.4 Introduction to Immediate Release dosage form:

Tablets are solid dosage form, each containing a unit dose of one or more

medicament. Pharmaceutical tablets are solid, flat or biconvex discs, unit dosage

form, prepared by compressing a drug or a mixture of drugs, with or without diluents.

Many a times in the disease condition like depression, anxiety, suicidal tendency,

severe heart disease etc the drug need to be presented immediately at the site of action

to exhibit it therapeutic activity. Thus in this condition drug is presented in immediate

release dosage forms. The criteria for immediate release formulation are 85% of drug

should be released in 15 min in case of very rapidly dissolving drug and 30 min in

case of rapidly dissolving drug.

Disintegrating agents are substances routinely included in tablet formulations and in

some hard shell capsule formulations to promote moisture penetration and dispersion

of the matrix of the dosage form in dissolution fluids. Superdisintegrants improve

disintegrant efficiency resulting in decreased use levels when compared to traditional

disintegrants.

Traditionally, starch has been the disintegrant of choice in tablet formulation, and it is

still widely used. For instance, starch generally has to be present at levels greater than

5% to adversely affect compatibility, especially in direct compression. Drug release

from a solid dosage form can be enhanced by addition of suitable disintegrants.

Superdisintegrants are generally used at a low level in solid dosage form, typically 1-

10% by weight relative to total weight of the dosage unit (Seager H et al, 1998).

Ideal candidates for immediate dosage form

Disintegrates and dissolves within a few minutes.

Has sufficient strength to withstand the rigors of the manufacturing process and

Post-manufacturing handling.

Allow high drug loading.

Insensitive to environmental conditions such as humidity and temperature.



2.4.1 Advantages of immediate release formulation:

Rapid drug therapy intervention.

Achieve increased bioavailability through pregastric absorption of drugs from

mouth, pharynx, and esophagus as saliva passes down.

Convenience of administration and accurate dosing as compared to liquids.

Rapid dissolution of drug and absorption of drug which may produce rapid

onset of action.

Ability to provide advantage of liquid medication in the form of solid

preparation.

Improve patient compliance by reducing dose.

Allow high drug loading.

2.4.2 Disadvantages of immediate release formulation:

Sometime lead to unwanted side effect due to dose dumping.

Special packing is required for protection from moisture

2.4.3 Mechanism of Superdisintegrants:

There are four major mechanisms for tablets disintegration as follow:

Swelling:

Perhaps the most widely accepted general mechanism of action for tablet

disintegration is swelling. Tablets with high porosity show poor disintegration due to

lack of adequate swelling force. On the other hand, sufficient swelling force is exerted

in the tablet with low porosity. It is worthwhile to note that if the packing fraction is

very high, fluid is unable to penetrate in the tablet and disintegration is again slows

down.

Porosity and capillary action (Wicking):

Disintegration by capillary action is always the first step. When we put the tablet into

suitable aqueous medium, the medium penetrates into the tablet and replaces the air

adsorbed on the particles, which weakens the intermolecular bond and breaks the

tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the

drug /excipients and on tableting conditions. For these types of disintegrants

maintenance of porous structure and low interfacial tension towards aqueous fluid is

necessary which helps in disintegration by creating a hydrophilic network around the

drug particles.



Due to disintegrating particle/particle repulsive forces:

Another mechanism of disintegration attempts to explain the swelling of tablet made

with `nonswellable' disintegrants. Guyot-Hermann has proposed a particle repulsion

theory based on the observation that nonswelling particle also cause disintegration of

tablets. The electric repulsive forces between particles are the mechanism of

disintegration and water is required for it. Researchers found that repulsion is

secondary to wicking.

Due to deformation:

During tablet compression, disintegrated particles get deformed and these deformed

particles get into their normal structure when they come in contact with aqueous

media or water. Occasionally, the swelling capacity of starch was improved when

granules were extensively deformed during compression. This increase in size of the

deformed particles produces a breakup of the tablet. This may be a mechanism of

starch and has only recently begun to be studied.

Table 2.1: Classification of "Superdisintegrants"

Structure Type

(NF Name)Description Trade Name

Modified starches

(Sodium starch

glycolate

NF)

Sodium carboxy methyl starch

carboxymethyl groups induced

hydrophilicity and cross-linking

reduces solubility.

Explotab

Primojel

Modified cellulose

(Croscarmallose NF)

Sodium carboxy methyl cellulosewhich

has been cross-linked to render the

material insoluble.

Ac-Di-Sol

Nymcel

Solutab

Cross-linked

polyvinylpyrrolidone

(Crospovidone. NF)

Cross-linked polyvinylpyrrolidone,

high molecularweight and cross-linking

render the material insoluble in water.

Crospovidone

Kollidon

Polyplasdone



2.4.4 Method of addition of disintegrants:

There are two methods incorporating disintegrating agents into the tablet:

(a) Internal Addition (Intragranular)

(b) External Addition (Extragranular)

(c) Partly Internal and External

In external addition method, the disintegrant is added to the sized granulation with

mixing prior to compression. In Internal addition method, the disintegrant is mixed

with other powders before wetting the powder mixtures with the granulating fluid.

Thus the disintegrant is incorporated within the granules. When these methods are

used, part of disintegrant can be added internally and part externally. This provides

immediate disruption of the tablet into previously compressed granules while the

disintegrating agent within the granules produces further erosion of the granules to the

original powder particles. The two step method usually produces better and more

complete disintegration than the usual method of adding the disintegrant to the

granulation surface only.

2.5 Introduction to Drugs:

2.5.1 Metoprolol Succinate:

Figure 2.4: Chemical structure of Metoprolol Succinate

Generic name: Metoprolol Succinate

Chemical name: (+) -1- (isopropyl amino) - [p- (2-methoxy-ethyl)]-2-propanol

succinate

CAS number: 54163-88-1

Empirical formula: (CI5H15NO3)2 C4E1606

Molecular weight: 652.8 g/mol

Description: A White to almost white crystalline powder, practically odorless.



Related Substances:

Unknown Impurities: 0.08%w/w (Not more than 0.3%)

Total Impurities: 0.21% (Not more than 1.0%)

Assay on Anhydrous bases: 100.83% (98% - 102%w/w)

Loss of Drying: 0.12% W/W at 600Cfor 4 hours under vacuum (Not more than 0.2%)

Heavy Metals: Not more than 0.001% w/w

Melting Point: 140 - 145°C

Solubility: It is freely soluble in water; soluble in methanol; sparingly soluble in

ethanol; slightly soluble in dichloromethane; and 2-propanol; practically insoluble in

ethyl- acetate, acetone, diethyl ether and heptanes.

Storage: It should be stored in a cool place, protected from light (The Internet Drug

Index, 2010).

Category: Beta 1 selective blocker

Mechanism of action: It blocks beta receptor; primarily affecting cardiovascular

system (decrease heart rate, decrease contractility, decrease BP), and lungs (promotes

bronchospasm) (Nicholson SJ et al, 1990).

Pharmacokinetics

Metoprolol is almost completely absorbed after oral administration, but bioavailability

is relatively low (about 40%) because of first pass metabolism. Plasma concentrations

of the drug vary widely (up to seventeen fold), perhaps because of genetically

determined differences in the rate of metabolism. Metoprolol is extensively

metabolized in the liver, with CYP2D6 the major enzyme involved, and only 10% of

the administered drug is recovered unchanged in the urine. The half life is 3 to 4 hrs

but can increase up to 7 to 8 hrs in CYP2D6 poor metabolizers (Drug Information

online, 2010).

Indications

Essential hypertension.

Tachycardia.

Coronary heart disease (prevention of angina attacks). Secondary prevention

after a myocardial infarction.

Treatment of heart failure.

Migraine prophylaxis.

Adjunct in treatment of hyperthyroidism.



Long QT syndrome, especially for patients with asthma, as Metoprolol 131

selectivity tends to interfere less with asthma drugs which are often 02-

adrenergic receptor-agonist drugs.

Due to its selectivity in blocking the beta1 receptors in the heart, Metoprolol is

also prescribed for off-label use in performance anxiety, social anxiety

disorder, and other anxiety disorders.

Contraindication

Metoprolol is contraindicated in severe bradycardia, second or third degree heart

block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrom.

Dosage and Administration

Hypertension: The usual initial dose is 2 to 100mg daily in a single dose for adults.

For pediatric hypertensive patients > 6years of age, the recommended starting dose is

1.0 mg/kg once daily (www.drugbank.com).

Angina pectoris: The usual initial dosage is 100mg daily, given in a single dose. Heart

failure: The recommended starting dose is 25mg once a daily.

Adverse Effects

Transient effects include dizziness, drowsiness, fatigue, diarrhea, unusual dreams,

ataxia, trouble sleeping, depression, and vision problems. It may also reduce blood

flow to the hands and feet, causing them to feel numb and cold; smoking may worsen

this effect.

Serious side effects which are advised to be reported immediately include, but are not

limited to, symptoms of bradycardia (a very slow heartbeat (less than 50 bpm)),

persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of

the fingers and toes, numbness/tingling/swelling of the hands or feet, sexual

dysfunction, erectile dysfunction (impotence), hair loss, mental/mood changes,

depression, trouble breathing, cough, dyslipidemia, and increased thirst. Other highly

unlikely symptoms include easy bruising or bleeding, persistent sore throat or fever,

yellowing skin or eyes, stomach pain, dark urine, and persistent nausea. Symptoms of

an allergic reaction include: rash, itching, swelling, and severe dizziness.

(http://en.wikipedia.org/wiki/Metoprolol_succinate).

Precautions

Metoprolol may worsen the symptoms of heart failure in some patients. Check with

your doctor right away if you are having chest pain or discomfort; dilated neck veins;



extreme fatigue; irregular breathing; an irregular heartbeat; shortness of breath;

swelling of the face, fingers, feet, or lower legs; weight gain; or wheezing.

This medicine may cause changes in your blood sugar levels. Also, this medicine may

cover up signs of low blood sugar, such as a rapid pulse rate. Check with your doctor

if you have these problems or if you notice a change in the results of your blood or

urine sugar tests. This medicine may cause some people to become less alert than they

are normally. If this side effect occurs, do not drive, use machines, or do anything else

that could be dangerous if you are not alert while taking Metoprolol.

Overdose

Excessive doses of Metoprolol can cause severe hypotension, bradycardia, metabolic

acidosis, seizures and cardio respiratory arrest. Blood or plasma concentrations may

be measured to confirm a diagnosis of poisoning in hospitalized patients or to assist in

a medico legal death investigation. Plasma levels are usually less than 200mg/L

during therapeutic administration, but can range from 1-20 mg/L in overdose victims

(Baxter K. Stockley, 2006).

2.5.2 Olmesartan Medoxomil:

Figure 2.5: Chemical structure of Olmesartan Medoxomil

Olmesartan is an antihypertensive agent which belongs to the class of medicines

called angiotensin II receptor antagonists. It acts rapidly to lower high blood pressure.

It is marketed worldwide by Daiichi Sankyo, Ltd. and in the United States by Daiichi

Sankyo, Inc. and Forest Laboratories.

Generic name: Olmesartan Medoxomil

Chemical Name: 4-(2-hydroxypropan-2-yl)-2-propyl-1-({4-[2-(1H-1, 2, 3, 4-tetrazol-

5-yl) phenyl] phenyl} methyl)-1H-imidazole-5-carboxylic acid

CAS Number: 144689-63-4

Empirical Formula: C24H26N6O3

Molecular weight: 446.5016 g/ml



Description: A White to off white powder, practically odorless.

Related Substances:

Unknown Impurities: 0.10%w/w (Not more than 0.5%)

Total Impurities: 0.50% (Not more than 1.0%)

Assay on Anhydrous bases: 99.5% (98% - 102%w/w)

Loss of Drying: 0.28% W/W at 600Cfor 4 hours under vacuum (Not more than 0.2%)

Heavy Metals: Not more than 10ppm

Melting Point: 180- 1850C

Solubility: water solubility- 1.05e-02 g/l, sparingly soluble in strong acid, soluble in

strong base (pH 3 to 9)

Storage: Store between 20°C-25°C. Protect from Moisture and Heat.

Category: Angiotensin II Type 1 Receptor Blockers (The Internet Drug Index, 2010).

Mechanism of action:

Olmesartan is a prodrug that works by blocking the binding of angiotensin II to the

AT1 receptors in vascular muscle; it is therefore independent of angiotensin II

synthesis pathways, unlike ACE inhibitors. By blocking the binding rather than the

synthesis of angiotensin II, Olmesartan inhibits the negative regulatory feedback on

renin secretion. As a result of this blockage, Olmesartan reduces vasoconstriction and

the secretion of aldosterone. This lowers blood pressure by producing vasodilatation,

and decreasing peripheral resistance (Nicholson SJ et al, 1990).

Pharmacokinetics:

Orally administered Olmesartan medoxomil was rapidly absorbed from the

gastrointestinal tract and converted during absorption to Olmesartan, the

pharmacologically active metabolite that was subsequently excreted without further

metabolism. The medoxomil moiety was released as diacetyl that was rapidly cleared

by further metabolism and excretion. Peak plasma concentrations of Olmesartan

occurred 1-3 h after administration, after which concentrations decreased quickly. The

elimination half-life was 10-15 h. Olmesartan medoxomil was not measurable in

plasma and excreta. The volume of distribution was low, consistent with limited extra

vascular tissue distribution.

Indications

Olmesartan is indicated for the treatment of hypertension. It may be used alone or in

combination with other antihypertensive agents.[1] The U.S. Food and Drug

Administration (FDA) have determined that the benefits of Benicar continue to



outweigh its potential risks when used for the treatment of patients with high blood

pressure according to the drug label.

Contraindications

Contraindications for treatment with Olmesartan include biliary obstruction (BNF).

Another major contraindication is pregnancy; reports in the scientific literature reveal

fetal malformations for pregnant women taking sartan-derived drugs.

Cautions

Angiotensin-II receptor antagonists should be used with caution in renal artery

stenosis. Monitoring of plasma-potassium concentration is advised, particularly in the

elderly and in patients with renal impairment; lower initial doses may be appropriate

in these patients. Angiotensin-II receptor antagonists should be used with caution in

aortic or mitral valve stenosis and in hypertrophic cardiomyopathy. Those with

primary aldosteronism, and Afro-Caribbean patients (particularly those with left

ventricular hypertrophy), may not benefit from an angiotensin-II receptor antagonist.

Dosage and administration

The usual recommended starting dose of Olmesartan is 20 mg once daily. The dose

may be increased to 40 mg after two weeks of therapy, if further reduction in blood

pressure is desirable. Doses above 40 mg do not appear to have greater effect, and

twice-daily dosing offers no advantage over the same total dose given once daily. No

adjustment of dosage is typically necessary for advanced age, renal impairment, or

hepatic dysfunction. For patients with possible depletion of intravascular volume

(e.g., patients treated with diuretics), Olmesartan should be initiated with caution;

consideration should be given to use of a lower starting dose in such cases. If blood

pressure is not controlled by Benicar alone, a diuretic may be added. Benicar may be

administered with other antihypertensive agents. Benicar may be administered with or

without food (Baxter K. Stockley, 2006).

Overdose:

The most likely manifestations of over dosage would be hypotension and tachycardia;

bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If

symptomatic hypotension should occur, supportive treatment should be initiated. The

dialyzability of Olmesartan is unknown.

No lethality was observed in acute toxicity studies in mice and rats given single oral

doses up to 2000 mg/kg Olmesartan medoxomil. The minimum lethal oral dose of

Olmesartan medoxomil in dogs was greater than 1500 mg/kg.



Interactions

Olmesartan may interact with non-prescription products that contain stimulants,

including diet pills and cold medicines, and potassium supplements, including salt

substitutes (Drug Information online, 2010).

2.6 Introduction to Polymers:

2.6.1 Hypromellose:

Nonproprietary Names

BP: Hypromellose

JP: Hydroxypropylmethylcellulose

PhEur: Hypromellosum

USP: Hypromellose

Synonyms

Benecel MHPC;E464;hydroxypropylmethylcellulose; HPMC; Methocel;

methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose;

Tylopur.

Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O- methylated and O-(2-

hydroxypropylated) cellulose. Molecular weight is approximately 10 000–1 500 000.

Structural Formula

Figure 2.6: Chemical structure of Hypromellose

Where R is H, CH3, or CH3CH (OH) CH2

Functional Category

Coating agent film-former; rate-controlling polymer for sustained release; stabilizing

agent; suspending agent; tablet binder; viscosity-increasing agent.



Description

Hypromellose is an odourless and tasteless, white or creamy- white fibrous or

granular powder.

Stability and Storage Conditions

Solutions are stable at pH 3–11. Increasing temperature reduces the viscosity of

solutions. Hypromellose undergoes a reversible sol–gel transformation upon heating

and cooling, respectively. The gel point is 50–900C, depending upon the grade and

concentration of material. Hypromellose powder should be stored in a well-closed

container, in a cool, dry place.

Table 2.2: Typical viscosity values for 2% (w/v) aqueous solutions of Methocel

Typical viscosity values for 2% (w/v) aqueous solutions of Methocel (Dow Chemical

Co.). Viscosities measured at 20°C (Lewis RJ, 2004).

Applications in Pharmaceutical Formulation or Technology

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical

formulations. In oral products, hypromellose is primarily used as a tablet binder, in

Methocel product USP 28 designation Nominal viscosity(mPa.s)

Methocel K100 PremiumLVEP

2208 100

Methocel K4M Premium 2208 4000

Methocel K15M Premium 2208 15 000

Methocel K100M Premium 2208 100 000

Methocel E4M Premium 2910 4000

Methocel F50 Premium 2906 50

Methocel E10M Premium CR 2906 10 000

Methocel E3 Premium LV 2906 3





Metolose 60SH 2910 50, 4000, 10 000



film-coating and as a matrix for use in extended-release tablet formulations.

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

dry-granulation processes. Hypromellose is also used as an emulsifier, suspending

agent, and stabilizing agent in topical gels and ointments. As a protective colloid, it

can prevent droplets and particle from coalescing or agglomerating, thus inhibiting the

formation of sediments. Hypromellose is also used as a suspending and thickening

agent in topical formulations. Compared with methylcellulose, hypromellose produces

aqueous solutions of greater clarity, with fewer undispersed fibers present, and is

therefore preferred in formulations for ophthalmic use. In addition, hypromellose is

used in the manufacture of capsules, as an adhesive in plastic bandages, and as a

wetting agent for hard contact lenses. It is also widely used in cosmetics and food

product (Rowe RC et al, 2009).

2.6.2 Sodium starch glycollate


BP: Sodium starch glycollate

PhEur: Carboxymethylamylum natricum

USPNF: Sodium starch glycolate

Synonyms

Carboxymethyl starch, sodium salt; Explosol; Explotab; Glycolys; Primojel; starch

carboxymethyl ether, sodium salt; Tablo; Vivastar P.


Sodium carboxymethyl starch [9063-38-1]


The USPNF 23 states that sodium starch glycolate is the sodium salt of a

carboxymethyl ether of starch, containing 2.8–4.2% sodium. The molecular weight is

typically 5 *105–1*106gm/mol.

Structural Formula

Figure 2.7: Chemical structure of sodium starch glycolate



Functional Category

Tablet and capsule disintegrant.

Description

Sodium starch glycolate is a white to off-white, odorless, tasteless, free-flowing

powder. The PhEur 2005 states that it consists of oval or spherical granules, 30–100

mm in diameter, with some less-spherical granules ranging from 10–35 mm in

diameter.


Tablets prepared with sodium starch glycolate have good storage properties. Sodium

starch glycolate is stable and should be stored in a well-closed container in order to

protect it from wide variations of humidity and temperature, which may cause caking.

The physical properties of sodium starch glycolate remain unchanged for up to 3–5

years if it is stored at moderate temperatures and humidity (Rowe RC et al, 2009).


Sodium starch glycolate is widely used in oral pharmaceuticals as a disintegrant in

capsule and tablet formulations. It is commonly used in tablets prepared by either

direct- compression or wet-granulation processes. The usual concentration employed

in a formulation is between 2% and 8%, with the optimum concentration about 4%,

although in many cases 2% is sufficient. Disintegration occurs by rapid uptake of

water followed by rapid and enormous swelling. Although the effectiveness of many

disintegrants is affected by the presence of hydrophobic excipients such as lubricants,

the disintegrant efficiency of sodium starch glycolate is unimpaired. Increasing the

tablet compression pressure also appears to have no effect on disintegration time.

2.6.3 Croscarmellose Sodium


BP: Croscarmellose sodium

PhEur: Carmellosum natricum conexum

USPNF: Croscarmellose sodium

Synonyms

Ac-Di-Sol; Crosslinked carboxymethylcellulose sodium; Explocel; modified

cellulose gum; Nymcel ZSX; Pharmacel XL; Primellose; Solutab; Vivasol.


Cellulose, carboxymethyl ether, sodium salt, Crosslinked [74811-65-7]




Croscarmellose sodium is a Crosslinked polymer of carboxymethylcellulose sodium.

Typical molecular weight is 90 000–700 000.

Structural Formula

Figure 2.8: Chemical structure of croscarmellose sodium

Functional Category

Tablet and capsule disintegrant.

Description

Croscarmellose sodium occurs as an odorless, white or grayish- white powder.


Croscarmellose sodium is a stable though hygroscopic material. Croscarmellose

sodium should be stored in a well-closed container in a cool, dry place.


Croscarmellose sodium is used in oral pharmaceutical formulations as a disintegrant

for capsules, tablets, and granules. In tablet formulations, croscarmellose sodium may

be used in both direct-compression and wet-granulation processes. When used in wet

granulations, the croscarmellose sodium should be added in both the wet and dry

stages of the process (intra- and extra granularly) so that the wicking and swelling

ability of the disintegrant is best utilized. Croscarmellose sodium at concentrations up

to 5% w/w may be used as a tablet disintegrant (Rowe RC et al, 2009).

2.6.4 Crospovidone


BP: Crospovidone

PhEur: Crospovidonum

USPNF: Crospovidone

Synonyms

Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M Polyplasdone XL;

polyvinylpolypyrroli- done; PVPP; 1-vinyl-2-pyrrolidinone homopolymer.




1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]


(C6H9NO) n >1000000

The USPNF 23 describes crospovidone as a water-insoluble synthetic cross linked

homopolymer of N-vinyl-2-pyrrolidinone. An exact determination of the molecular

weight has not been established because of the insolubility of the material.

Structural Formula

Figure 2.9: Chemical structure of Crospovidone

Functional Category

Tablet disintegrant.

Description

Crospovidone is a white to creamy-white, finely divided, free- flowing, practically

tasteless, odorless or nearly odorless, hygroscopic powder.


Since crospovidone is hygroscopic, it should be stored in an airtight container in a

cool, dry place.


Crospovidone is a water-insoluble tablet disintegrant and dissolution agent used at

2–5% concentration in tablets prepared by direct-compression or wet- and dry-

granulation methods. It rapidly exhibits high capillary activity and pronounced

hydration capacity, with little tendency to form gels. Studies suggest that the particle

size of crospovidone strongly influences disintegration of analgesic tablets. Larger

particles provide a faster disintegration than smaller particles. Crospovidone can also

be used as a solubility enhancer (Rowe RC et al, 2009).



2.7 References:

Aher K , Bhavar G , Joshi H , Chaudhari S , Recent advances in compression-

coated tablets as a controlled drug delivery system, Saudi pharmaceutical j, 2011,

01.pg no: 322-331.

Baxter K. Stockley’s Drug interactions, A source book of interaction, their

mechanisms, clinical importance and management, Pharmaceutical Press, 7th edi.

2006, pg no: 623.

Bhad M, Shajahan A, Jaiswal S, Chandewar A, Jain J, Sakarkar D. MUPS Tablets – A

Brief Review, Int J of PharmTech Research, 2010; 2 (1), pg no: 847-855.

Bin Li, JiaBi Zhu, ChunLi Zheng, Wen Gong, A novel system for three-pulse drug

release based on “tablets in capsule” device, 2007; pg no: 1-6.

Bonferoni M, Caramella C, Sangalli M. Rheological behaviour of hydrophilic

polymers and drug release from erodible matrices, Controlled Release, 1992; 18, pg

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Chapter 3: Literature Review


3. LITERATURE REVIEW

3.1 Literature Review of Formulation

Katakamet V. et al (2012) developed and evaluated Gas Formation-based Multiple-

Unit Gastro-Retentive Floating Delivery System of Dipyridamole. They prepared

mini tablets to be filled into a capsule that was designed to float on the gastric

contents based on gas formation technique. The drug-containing core mini-tablets

were prepared by wet granulation method followed by a coating of the core units with

seal coating, an effervescent layer and a gas-entrapping polymeric membrane. The

effect of the preparative parameters like amount of the effervescent agent layered onto

the seal coated units, type and coating level of the gas-entrapping polymeric

membrane, floating ability and drug release properties of the multiple-unit FDDS

were evaluated.

Rao R. et al (2012) developed and evaluated matrix tablet filled capsule system for

chronotherapeutic drug delivery of Terbutaline sulphate. The drug loaded core tablets

were produced by wet granulation procedure using alcoholic solution of PVP K-30 as

a binder. Different composition of IRT prepared with varying amount of sodium

starch glycolate (as a superdisintegrant), and SRT was prepared with different ratios

of ethyl cellulose to HPMC and number (5 of tablets in a HPMC capsule) were used

to obtain different drug release rates. They concluded that, tablets-filled-capsule

systems containing Terbutaline sulphate shows both sustained release as well as

immediate release may improve the bioavailability and efficacy.

Khatavkar U. et al (2012) evaluated Controlled release reservoir mini tablets

approach for controlling the drug release of Galantamine Hydrobromide. They

investigate the reservoir mini tablets approach to control the release of Galantamine

Hydrobromide in comparison to desired release profile to the Innovator formulation

Razadyne(®) ER capsules as disclosed in US Patent 7,160,559 which was granted to

Janseen Pharmaceutica NV. They observed that core formulation plays an important

role in controlling the drug release as well as maintaining pH independent drug

release profile.

Patel H. et al (2011) developed and evaluated biphasic drug delivery system of

diclofenac sodium as a compressed mini tablet. The outer layer that fills the void

spaces between the mini-tablets was formulated to release the drug in a very short



time (fast release), while the mini-tablets provided a prolonged release. Fast releasing

component comprising of superdisintegrant croscarmellose sodium, while mini-tablet

was formulated using different concentration of HPMC K100M and Ethyl cellulose to

obtain different drug release rates. The In-Vitro performance of these systems showed

the desired biphasic behaviour. The drug contained in the fast releasing phase

(powder enrobing the mini-tablets) dissolved within the first 15 min, whereas the drug

contained in the mini-tablets was released at different rates, depending upon

composition of mini tablets.

Rao R. et al (2011) developed and evaluated tablet filled capsule system for

chronotherapeutic delivery of montelukast sodium. The system comprises of different

doses of immediate release tablets (IRT) and sustained release tablets (SRT)

contained in a HPMC capsule. The drug-loaded core tablets were produced by wet

granulation procedure using alcoholic solution of PVP K-30 as a binder. Different

composition of IRT prepared with varying amount of sodium starch glycolate (as a

disintegrant), and SRT was prepared with different ratios of ethyl cellulose to HPMC

and number (5 of tablets in a HPMC capsule) were used to obtain different drug

release rates. They concluded that tablets containing HPMC and EC were particularly

suitable approaching to sustain or prolong release over 10-12 hrs time periods. From

this, study it can be concluded that, tablets-filled-capsule systems containing

montelukast sodium shows both sustained release as well as immediate release may

improve the bioavailability and efficacy.

Ostwalet P. al (2011) developed and evaluated tablet in capsule for Atenolol and

Nifedipine. Nifedipine was planned to design as the sustained release part and

Atenolol as the immediate release part. After preformulation studies it was decided to

prepare Atenolol part by free flowing powder and Nifedipine by wet granulation

method. For sustained release portion HPMC k100 polymer was used in

extragranularly. In the formulation of immediate release sodium starch glycolate and

was used as super disintegrant. The free flowing powder of Atenolol was evaluated

for weight variation study.

Patil D. al (2011) researched on Modulation of Combined Release Behaviours from

A Novel Pellets and Mini Tablet in Capsule System of Propranolol HCL. A

multifunctional and multiple unit system, combined release formulation i.e. “pellets

and tablet in capsule” which contains pellets as well as mini-tablet in a hard gelatin



capsule. They conclueded that Propranolol hydrochloride Sustained-release pellets

40mg (SRPs) formulation was successfully developed using fluid bed layering and

coating techniques (FBP). Flunarizine dihydrochloride immediate release mini-

Tablets 10mg (IRMTs) formulations were developed by wet granulation method.

After two month stability study of Propranolol hydrochloride pellets and Flunarizine

dihydrochloride tablet have shown related impurities respectively 0.18 % and 1.9%

which complied the limit of impurities (NMT 3.0%) required in final formulation.

Mirelabodea et al (2010) researched on identification of critical variable of

formulation of Metoprolol Tartrate mini tablet. They studied the influence of the

formulation factors on the characteristics of the granules obtained through a fluid bed

method, and mini-tablets subsequently prepared. Powder flow and tooling lubrication

have a very important influence for mini-tablets formulation.

Rennan P. et al (2009) developed a modified-release dosage form for oral

administration containing plural enteric-coated mini-tablets, comprising a

therapeutically effective amount of a factor Xa inhibitor within a matrix of polymers.

The mini-tablets were suitably encapsulated in a gelatin capsule.

Makoto I. et al (2008) developed a novel pseudoephedrine hydrochloride sustained-

release dosage form which comprises of immediate-release mini-tablets (IRMT) and

sustained-release Mini-tablets contained in a HPMC capsule. The IRMT was coated

with HPMC a water soluble polymer and the SRMT was coated with a mixture of

HPMC and water insoluble polymer ethyl cellulose. The release profile for SRMT

was varied by varying the thickness of the coat.

Huo V. et al (2008) investigated the enteric performance of lansoprazole mini-

tablets using methacrylic acid co-polymers (Acryl-EZE-aqueous acrylic enteric

system and eudragit L30 D-55) in a perforated pan. It was concluded that the

enteric-coated mini-tablets exhibited low acid uptake in pH 1.2 Hcl and pH 4.5

acetate buffers, and consistent drug release in USP phosphate buffer pH 6.8.

Hue V. et al (2008) investigated the enteric-coating efficiency of mini-tablets

using a perforated-pan or a fluid-bed coating machine and found for both types of

equipment, good enteric coating efficiency was obtained and the results were

comparable and the main benefit of using the perforated pan was a shorter process

time.



Shivakumar H. et al (2007) developed and evaluated pH sensitive mini-tablets for

chronotherapeutic delivery of theophylline using different coat weights of Eudragit-S-

100 applied to the drug loaded core mini-tablets. The studies showed that a coat

weight of 10% weight gain was sufficient to impart an excellent gastro resistant

property to the tablets for effective release of the drug at higher pH values.

Carla M et al (2006) has reported biphasic delivery system as compressed mini-

tablets of ibuprofen which has the ability to release the drug at a zero-order rate

using ethyl cellulose and HPMC as prolonged release components and

microcrystalline cellulose and sodium croscarmellose as fast release component.

Based on the release kinetic parameters calculated, it can be concluded that mini-

tablets containing HPMC were particularly suitable approaching to zero-order release

over 8 hrs time period.



3.2 Literature Review of Metoprolol Succinate

Agrawal S. et al (2012) developed delayed-onset extended-release tablets of

Metoprolol Tartrate using hydrophilic-swellable polymers HPMC K4M and HPMC

K100M. They suggested that an optimal lag period in both acidic and basic

environments, due to the initial swelling of polymers, followed by complete drug

release in a controlled manner could be obtained owing mainly to diffusion through

the swollen polymer and in part to the slow erosion of the core.

Shah A. et al (2010) developed sustain release tablet of Metoprolol succinate by wet

granulation method. They demonstrated that by using the polymers HPMC K -100 the

release can be so well controlled that it almost coincides the theoretical release pattern

for the drug by proper adjustment of polymer ratio. They suggested that the mono

layer tablet designed possesses all the qualities of a sustained release formulation.

Mujoriya R. et al (2010) developed Metoprolol Succinate Er and Amlodipine

Besilate Bilayer Tablet by using different polymer (HPMC, Methocel, Carbapol) with

different diluents (MCC, Cellulose Phosphate, Starch, Croscarmellose Sodium) and

then evaluated. They suggested that stable bilayer tablet of Metoprolol succinate ER

and Amlodipine Besilate can be prepared by using HPMC K 15 M and carbomer as a

polymer. They concluded that a stable bilayer tablet of Metoprolol succinate ER and

Amlodipine besilate can be prepared by using HPMC K 15 M and carbomer as a

polymer. It was found that the in vitro drug release of Metoprolol succinate ER was

best explained by first order (r2 =0. 9994), as the plots showed the highest linearity,

followed by Higuchi’s equation (r2 = 0.9974) and zero-order (r2 = 0.9471).

Vijaya R. et al (2009) developed extended release tablet of Metoprolol succinate by

using wet granulation technique and coated with hydroxy propyl methyl cellulose

(KM 100) and hydroxyl methyl cellulose for extended release. They suggested that

the dose release properties of matrix device may be dependent upon the solubility of

the drug in the polymer matrix, the solubility in the sink solution within the particles

pore network. Hydroxy methyl cellulose is the dominant hydrophilic vehicle used for

the preparation of oral controlled drug delivery. While preparing ER tablets with

HPMC, a change in the manufacturing variable yields a significant change in

dissolution profile for the same formulation.



Gohel M. et al (2009) investigated modified release tablets of Metoprolol Succinate

using HPMC and xanthan gum as a matrixing agent. A 32 full factorial design was

employed for the optimization of formulation. The in vitro drug dissolution study was

carried out in pH 6.8 phosphate buffer employing paddle rotated at 50 rpm. The

similarity factor (f2) was calculated for selection of best batch considering mean in

vitro dissolution data of Seloken® XL as a reference profile. It is concluded that the

desired drug release pattern can be obtained by using a proper combination of HPMC

(high gelling ability) and xanthan gum (quick gelling tendency). The economy of

xanthan gum and faster hydration rate favors its use in modified release tablets. The

matrix integrity during dissolution testing was maintained by using hydroxypropyl

methylcellulose.

Vijaya R. et al (2009) made to reduce the frequency of dose administration, to

prevent nocturnal heart attack and to improve the patient compliance by developing

extended release (ER) matrix tablet of Metoprolol succinate. ER matrix tablets of

Metoprolol succinate were developed by using wet granulation technique and coated

with hydroxy propyl methyl cellulose (KM 100) and hydroxyl methyl cellulose for

extended release. Compressed tablets were evaluated for weight variation, hardness,

friability and in vitro dissolution using paddle (USP type II) method. All formulation

showed compliance with pharmacopoeial standards.

Muschert et al (2009) studied drug release mechanisms from aqueous ethylcellulose-

coated pellets containing different types of drugs and starter cores. Theophylline,

Paracetamol, Metoprolol Succinate, Diltiazem HCl and Metoprolol Tartrate were used

as model drugs exhibiting significantly different solubilities (e.g. 14, 19, 284, 662 and

800 mg/mL at 37 degrees C in 0.1N HCl). The pellet core consisted of a drug matrix,

drug-layered sugar bead or drug-layered microcrystalline cellulose (MCC) bead,

generating different osmotic driving forces upon contact with aqueous media.

Importantly, the addition of small amounts of poly(vinyl alcohol)-poly(ethylene

glycol) graft copolymer (PVA-PEG graft copolymer) to the ethyl cellulose coatings

allowed for controlled drug release within 8-12h, irrespective of the type of drug and

composition of the pellet core. Drug release was found to be controlled by diffusion

through the intact polymeric membranes, irrespective of the drug solubility and type

of core formulation. The ethyl cellulose coating was dominant for the control of drug

release, minimizing potential effects of the type of pellet core and nature of the



surrounding bulk fluid, e.g. osmolality. Thus, this type of controlled drug delivery

system can be used for very different drugs and is robust.

Nagaraju R. et al (2009) prepared core-in-cup matrix tablets of Metoprolol succinate

by wet granulation technique. The optimized formulation followed zero-order kinetics

of drug release. Study of drug release kinetics was performed by application of

dissolution data to various kinetic equations like zero-order; first order, Higuchi and

Korsmeyer-Peppas, from R2 value (0.9975) it was concluded that the drug release

followed zero order kinetics with both erosion and diffusion as the release

mechanisms.

Deshmukh V. et al (2009) designed and evaluated oral sustained drug delivery

system for Metoprolol succinate using natural hydrophilic gums such as karaya gum

and xanthan gum as a release modifier. Matrix tablets were prepared by wet

granulation method and were evaluated for weight variation, content uniformity,

friability, hardness, thickness, swelling index, in vitro dissolution, and stereo

photography. The kinetic treatment showed that the optimized formulation follow

zero order kinetic with release exponent (n) 0.7656 and having good stability as per

ICH guidelines. No chemical interaction between drug and gums was seen as

confirmed by IR studies. The matrix formulation F8 showed sustained release of

Metoprolol succinate by the diffusion mechanism.

Hainer J. et al (2009) researched on lowering elevated blood pressure (BP) with drug

therapy reduces the risk for catastrophic fatal and nonfatal cardiovascular events such

as stroke and myocardial infarction. Given the heterogeneity of hypertension as a

disease, the marked variability in an individual patient’s BP response, and low

response rates with monotherapy, expert groups such as the Joint National Committee

(JNC) emphasize the value of combination antihypertensive regimens, noting that

combinations, usually of different classes, have additive antihypertensive effects.

Metoprolol succinate extended-release tablet is a beta-1 (cardio-selective)

adrenoceptor-blocking agent formulated to provide controlled and predictable release

of Metoprolol. Hydrochlorothiazide (HCT) is a well-established diuretic and

antihypertensive agent, which promotes natruresis by acting on the distal renal tubule.

The pharmacokinetics, efficacy, and safety/tolerability of the antihypertensive

combination tablet, Metoprolol extended release hydrochlorothiazide, essentially

reflect the well-described independent characteristics of each of the component



agents. Not only is the combination product more effective than monotherapy with the

individual components but the combination product allows a low-dose multidrug

regimen as an alternative to high-dose monotherapy, thereby, minimizing the

likelihood of dose-related side-effects.



3.3 Literature Review of Olmesartan Medoxomil:

Yadav A. et al (2012) Enhanced solubility and dissolution rate of Olmesartan

medoxomil using crystallo-co-agglomeration technique. The effect of different

polymers such as poly-vinyl pyrollidone (PVPK30), and hydroxypropyl- β-

cyclodextrin (HPβCD) on solubility, dissolution rate and flowability of olmesartan

medoxomil was studied by crystallo-co-agglomeration technique. The agglomerates

were characterized by X-ray powder diffractometry (XRPD), Scanning electronic

microscopy (SEM) and Fourier transformation infrared spectroscopy (FTIR). They

found that found that saturation solubility, micromeritic properties and dissolution

characteristics of agglomerates were significantly improved than that of pure

olmesartan medoxomil.

Gat V. (2012) invented invention provides a solid oral dosage form comprising

Olmesartan medoxomil and polyethylene glycol having a molecular weight of about

1,000 - 10,000. In this patent he developed the immediate release tablet of Olmesartan

medoxomil using wet granulation method. He used diluent, e.g. lactose monohydrate

and microcrystalline cellulose and optionally the disintegrant, e.g. low substituted

hydroxypropyl cellulose, binder PVP and/or hydroxypropyl cellulose and a stabilizer

e.g. PEG 6000, lubricant magnesium stearate and optionally the disintegrant, e.g.

croscarmellose sodium and dissolution was done by dissolving a tablet in an USP-

Apparatus II in 900 ml 0.05M phosphate buffer pH 6.8 or 0.1 N HCI at 37°C and

stirring speed of 50 rpm. The dissolution tests were carried out using USP-Apparatus.

Patel M. et al (2010) developed and evaluated Lipid Based Formulation of

Olmesartan Medoxomil. 4 different types of lipid based formulation are available.

They formed type 1 and type 4 lipid based formulation. Type I systems are mixtures

of lipophilic materials which have little or no solubility in water. Typically they are

blends of food glycerides derived from vegetable oils, which are safe for oral

ingestion, rapidly digested, and absorbed completely from the intestine. Type IV

systems are essentially pure surfactants or mixtures of surfactants and co-solvents. It

is generally accepted that formulation of poorly water soluble drugs in pure co-

solvents is likely to result in precipitation of the drug. The only advantage that could

be gained is the possibility that the drug precipitates as a suspension of very fine

crystalline or amorphous particles.



Chrysant S. et al (2010) researched Efficacy and tolerability of Amlodipine plus

Olmesartan medoxomil in patients with difficult-to-treat hypertension. Report a

prespecified secondary analysis of the efficacy of Amlodipine (10mgday), Olmesartan

medoxomil (40mgday), a combination of the two and placebo in these subgroups.

Patients were randomized to treatment for 8 weeks. They found that The

antihypertensive effect of the combination of Amlodipine Olmesartan medoxomil was

generally greater than the constituent Amlodipine or Olmesartan medoxomil

monotherapy, regardless of subgroup. They suggest that the combination of

Amlodipine Olmesartan medoxomil provides a safe and effective option for the

treatment of hypertension in challenging patient populations.

Kereiakes D. et al (2010) researched Long-Term Efficacy and Safety of Triple-

Combination Therapy with Olmesartan Medoxomil and Amlodipine Besylate and

Hydrochlorothiazide for Hypertension. They done 40- week open-label extension of

the 12-week double-blind Triple Therapy with Olmesartan Medoxomil, Amlodipine

and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY) evaluated the

efficacy and safety of triple combination treatments with Olmesartan medoxomil,

Amlodipine besylate, and hydrochlorothiazide (OM ⁄ AML ⁄ HCTZ) in 2112

participants with moderate to severe hypertension. At the end of the study, 44.5% to

79.8% of participants reached BP goal and the mean BP decreased from 168.6 ⁄ 100.7

mm Hg (baseline BP at randomization) to 125.0 to 136.8 mm Hg⁄ 77.8 to 82.5 mm

Hg, depending on treatment. Long term treatment with OM⁄AML⁄HCTZ was well

tolerated and effective with no new safety concerns.



3.4 References:

Agrawal S. Sarika M, Agrawal M, Formulation and evaluation of delayed-onset

extended-release tablets of Metoprolol Tartrate using hydrophilic-swellable polymers,

Acta Pharm. 62 (2012), pg no:105–114.

Carla Lopes M, Jose Manual Souza Lobo, Jaao Pinto F, Paulo, Costa, Compressed

mini-tablet as a biphasic drug delivery system, Int. J. Pharm. 2006; 323: 93-100.

Chrysant S, Lee J, Melino M, Karki S and Heyrman R, Efficacy and tolerability of

amlodipine plus olmesartan medoxomil in patients with difficult-to-treat

hypertension, J of Human Hypertension (2010) 24, pg no:730–738.

Deshmukh VN, Singh SP, Sakarkar DM, Formulation and Evaluation of Sustained

Release Metoprolol Succinate Tablet using Hydrophilic gums as Release modifiers.

International Journal of PharmTech Research, 2009; 1(2): pg no: 159-163.

Gohel M. Parikh R, Nagori S, Jena D. Fabrication of Modified Release Tablet

Formulation of Metoprolol Succinate using Hydroxypropyl Methylcellulose and

Xanthan Gum. AAPS PharmTechsci. 2009; 10(1): pg no: 62-68.

Hainer JW, Jennifer S. Metoprolol succinate extended release/hydrochlorothiazide

combination tablets, Vascular Health and Risk Management, 2007:3(3)

Hue Voung, Palmer D. Levina M. Rajabi R, Investingation of enteric coating of

Mini-tablets using a perforated pan or a fluid-bed machine, Poster reprint

Controlled Release Society, Annual Meeting 2008 July.

Hue Vuong, Marina Revina, and Rajab R, Siabhoomi, Evaluation of the enteric

performance of Lansoprazole Mini-tablets coated in a perforated pan, Poster reprint

Amer. Ass. Pharm. Scientists, (AAPS), 2008 Nov.

K. Reeta Vijaya Rani, S. Eugine Leo Prakash, R. Lathaeswari S.

Rajeswari,formulation and evaluation of ER Metoprolol succinate tablet, International

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Katakam V, Reddy S. Somagoni J. Panakanti P. Preparation and Evaluation of a Gas

Formation-based Multiple-Unit Gastro-Retentive Floating Delivery System of

Dipyridamole ,International Journal of Pharmaceutical Sciences and Nanotechnology,

April – June 2012,Volume 5 • Issue 1.pg no: 220-231.



Kereiakes D, Steven G. Chrysant M, Joseph L, Thomas L, Suzanne O, Michael M,

Lee J, Long-Term Efficacy and Safety of Triple-Combination Therapy With

Olmesartan Medoxomil and Amlodipine Besylate and Hydrochlorothiazide for

Hypertension, J of Clinical Hypertension, March 2012,Vol 14, pg no:149-157.

Khatavkar U. Shimpi Patel S. Deo K. Controlled release reservoir mini tablets

approach for controlling the drug release of Galantamine

Hydrobromide.Pharmaceutical Development and Technology, 07/2012; 17(4): pg no:

437-42.

Mako I. Keichi A. Hashezime M. A novel approach to Sustained Pseudoephedrine

release- Differentially coated nini-tablets in HPMC capsules. Int. J. Pharm. 2008; 359:

pg no:46-52

Mirelabodea A. Tomuta I, identification of critical variable of formulation of

Metoprolol Tartrate mini tablet, Farmacia, 2010, Vol. 58, 6

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mechanisms from ethylcellulose: PVA-PEG graft copolymer-coated pellets. Eur J

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Nagaraju R. Meera DS. Kaza R. Arvind V, Venkateswarlu V. Core-in-cup tablet

design of metoprolol succinate and its evaluation for controlled release, Curr Drug

Discov Technol. 2009; 6(4): pg no: 299-305.

Ostwal P. Salunkhe P, Jain M, Patel S. development and evaluation of tablet filled

capsule system ofr nifedipine and atenolol, Int J of Pharmacy and Biological Sciences,

Volume 1, Issue 4 ,2011, pg no: 468-473.

Patel H. Patel N., formulation and evaluation of biphasic drug delivery system of

diclofemac sodium as compressed mini tablet, International Journal of Pharma

Research and Development, 2011, vol 3, issue 1.

Patel M, Patel N, Bhandari A. Formulation and Assessment of Lipid Based

Formulation of Olmesartan Medoxomil, Int J of Drug Development & Research,2011,

Vol. 3 | Issue 3 | ISSN 0975-9344, pg no:320-327.

Patent number: EP 2521540A2, Solid oral dosage form containing Olmesartan

medoxomil, publication 2012.



Patil D. Sajeeth C. Sirwani R and Santhi K. Modulation of Combined Release

Behaviours from A Novel Pellets and Mini Tablet in Capsule System, International

Journal of Research in Pharmaceutical and Biomedical Sciences, Apr – Jun 2011,

Vol. 2 (2), pg no: 649-660.

R.Z. Mujoriya, Venkateshvarlu, D.C. Singh, V.A. Gupta, A Bisen, and A.B. Bondre,

Formulation Development and Evaluation of Metoprolol Succinate Er and

Amlodipine Besilate Bilayer Tablet, Research J. Pharm. and Tech. Oct.-Dec. 2010,

3(4): pg no: 234-251.

Rao R., Mohd A. Mansoori W, Shrishail M. development and evaluation of tablet

filled capsule system for chronotherapeutic delivery of montelukast sodium, Int J Of

Pharmacy&Technology,March-2011, Vol. 3, Issue No.1 , pg no: 1702-1721.

Rao R., Panchal H. Mohd A. Reddy M. developement and evaluation of matrix tablet

filled capsule system for chronotherapeutic drug delivery of Terbutaline sulphate,

World j of pharmaceutical research, 2012, Volume 1, Issue 3, pg no: 757-775.

Rennan P. Omar A. Yong Hu, Kimberly A. Robert F. Leposki K. Patel R. Shukla R.

Patent application title: Pharmaceutical composition comprising a plularity of mini-

tablets comprising a factor XA inhibitor, Research triangle park, NC US. Patent

Application Number: 20090285881.

Shivkumar HN, Sarosija Suresh, Desai BG. Design and evaluation of pH sensitive

mini-tablets for chronotherapeutics delivery of theophylline. Ind. J. Pharm. Sci.2007;

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Smrrat A, Brhambahtt V, Karthikeyan M, Manidipa S. Ravisankar S, Formulation and

evaluation of metoproolol succinate tablet, Int J of Pharmaceutical & Biological

Archives 2010; 1(5): pg no: 416 – 420

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Metoprolaol Succinate Tablets, International Journal of PharmTech Research. 2009;

1(3): pg no: 634-638.

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technique, Der Pharmacia Sinica, 2012, 3(2): pg no:160-169.

Chapter 4: Experimental Setup


4. EXPERIMENTAL SETUP:

4.1 Materials and Instruments used in the Present Investigation

Table 4.1: Materials used in the present investigation

Sr.No.

Materials Manufacturer/Supplier

1. Metoprolol Succinate Acme Pharma, Gujarat, India

2. Olmesartan Medoxomil Zydus cadila Healthcare,Ahmadabad, India

3. HPMC K 4M & 100M Signet chemicals, India.

5. PVP K30 & K 90 Acme Pharma, Gujarat, India

6. Microcrystalline Cellulose

pH101 & pH 102

Signet Chemicals, India.

7. Iso Propyl Alcohol Central drug House(P) Ltd, NewDelhi

8. Sodium starch glycolate Acme Pharma, Gujarat, India

9. Cross carmellose sodium S.D.Fine Chemical Ltd, Mumbai,India

10. Cross povidone S.D.Fine Chemical Ltd, Mumbai,India

11. Lactose Acme Pharma, Gujarat, India

12. PEG 6000 S.D.Fine Chemical Ltd, Mumbai,India

13. Magnesium Stearate Acme Pharma, Gujarat, India

14. Talc Acme Pharma, Gujarat, India

Chapter 4: Experimental Setup


Table 4.2: Equipments / Machine used in the present investigation

Sr.No.

Equipments/ Machine Manufacturer/Supplier

1. Electronic Analytical BalanceBT 220H -Shimadzu DigitalBalance, Japan

2.Bulk Density measurement apparatus( ETD-1020)

Electro lab, India.

3. Tablet compression machineRimek, minipress 10 stationrotary machine, Karnavathiengineering Ltd, Gujarat.

4. Hardness tester Pfizer hardness tester, Servewellequipments Pvt. Ltd., Bangalore.

5. Friability Test Apparatus 020334 -Veego Digital

6. Thickness tester Screw Gauze.

7. Tablet Dissolution Test Apparatus 220307-Electrolab USP (XXIII)

8. UV SpectrophotometerUV-1800 Double beamSpectrophotometer,Shimadzu (Kyoto, Japan.).

9. HPLC (LC- 2010 CHT) Shimadzu, India.

10. FT-IR Spectrometer Perkin Elmer Instruments, USA.

11. DSCDSC60 Shimadzu Corporation,Japan.

Chapter 5: Preformulation Study


5. PREFORMULATION STUDY:

Preformulation can be defined as investigation of physical and chemical properties of

drug substance alone and when combined with excipients.

Preformulation studies are the first step in the rational development of dosage form of

a drug substance. The objectives of preformulation studies are to develop a portfolio

of information about the drug substance, so that this information is useful to develop

formulation.

Followings parameters were studied in the preformulation study.

5.1 Bulk Density (BD)

a) Loose Bulk Density (LBD): Weigh accurately 25 g of drug (M), which was

previously passed through 20 # sieve and transferred in 100 ml graduated cylinder.

Carefully level the powder without compacting, and read the unsettled apparent

volume (V0). Calculate the apparent bulk density in gm/ml by the following formula.

…………….. (1)

b) Tapped bulk density (TBD): Weigh accurately 25 g of drug, which was

previously passed through 20 # sieve and transfer in 100 ml graduated cylinder. Then

mechanically tap the cylinder containing the sample by raising the cylinder and

allowing it to drop under its own weight using mechanically tapped density tester that

provides a fixed drop of 14± 2 mm at a nominal rate of 300 drops per minute. Tap the

cylinder for 250 times initially and measure the tapped volume (V1) to the nearest

graduated units, repeat the tapping an additional 750 times and measure the tapped

volume (V2) to the nearest graduated units. Calculate the tapped bulk density in

gm/ml by the following formula:

…………….. (2)

5.2 Carr’s Index

The Compressibility Index of the powder blend was determined by Carr’s

compressibility index. It is a simple test to evaluate the BD and TD of a powder and

the rate at which it packed down. The formula for Carr’s Index is as below:

………….. (3)

Loose Bulk density = Weight of powder / Bulk volume

Tapped Bulk Density = Weight of powder / Tapped volume

Carr’s Index (%) = [(TD-BD) x100]/TD



5.3 Hausner’s Ratio

The Hausner’s ratio is a number that is correlated to the flowability of a powder or

granular material.

……………. (4)

Table 5.1: Effect of Carr’s Index and Hausner’s Ratio on flow property

Carr’s Index (%) Flow Character Hausner’s Ratio

< 10 Excellent 1.00–1.11

11–15 Good 1.12–1.18

16–20 Fair 1.19–1.25

21–25 Passable 1.26–1.34

26–31 Poor 1.35–1.45

32–37 Very poor 1.46–1.59

>38 Very, very poor >1.60

5.4 Angle of repose

The angle of repose of API powder was determined by the funnel method. The

accurately weight powder blend were taken in the funnel. The height of the funnel

was adjusted in such a way the tip of the funnel just touched the apex of the powder

blend. The powder blend was allowed to flow through the funnel freely on to the

surface. The diameter of the powder cone was measured and angle of repose was

calculated using the following equation.

…………. (5)

Where, h and r are the height and radius of the powder cone respectively.

Table 5.2: Effect of Angle of repose (ф) on Flow property

Angle of Repose (Ф) Type of Flow

< 20 Excellent

20-30 Good

30-34 Passable

>35 Very poor

Hausner’s Ratio = TD / BD

= tan-1 h/r



5.5 Drug and Excipients Compatibility study:

a) FTIR studies:

IR spectra for pure drug Olmesartan medoxomil, Metoprolol Succinate and best

formulations were recorded in a Fourier transform infrared (FTIR) spectrophotometer

(Shimadzu Corporation 8600, Japan) with KBr pellets.

b) DSC studies:

DSC studies were carried out for pure drug Olmesartan medoxomil, Metoprolol

Succinate and best formulations. DSC scan of about 5mg accurately weighed sample

and optimized formulations were performed by using an automatic thermal

analyzer system (DSC60 Shimadzu Corporation, Japan). Sealed and perforated

aluminum pans were used in the experiments for all the samples. Temperature

calibrations were performed using indium as standard. An empty pan sealed in the

same way as for the sample was used as a reference. The entire samples were run at a

scanning rate of 10° C/min from 50-300° C.

5.6 Result & Discussion:

5.6.1 Density, Flow property and Angle of Repose:

Result of Physical parameters of the Metoprolol and Olmesartan shown in Table 5.3

and 5.4 respectively.

Table 5.3: Result of Preformulation study of Metoprolol Succinate

Bulk Density (g/ml) Flow propertiesAngle of repose

Loose bulk Tapped bulk Carr’s index (%) Hausner’s Ratio

0.364

± 0.23

0.607

± 0.31

40.03 ± 0.67

(very poor)

1.66 ± 0.19

(very poor)32.34 ± 1.47

Table 5.4: Result of Preformulation study of Olmesartan Medoxomil

Bulk Density (g/ml) Flow propertiesAngle of repose

Loose bulk Tapped bulk Carr’s index (%) Hausner’s Ratio

0.317

± 0.36

0.429

± 0.29

26.10 ± 1.39

(poor)

1.35 ± 0.12

(very poor)37.84 ± 1.18



The result of preformulation study for the Metoprolol Succinate as described

in Table 5.3 indicated that the Carr’s index for the Metoprolol Succinate was 40.03

and Hausner’s ratio was 1.66 which indicates poor compressibility property and flow

property.

The result of preformulation study for the Olmesartan medoxomil as described

in Table 5.4 indicated that the Carr’s index for the drug Olmesartan medoxomil was

26.10 and Hausner’s ratio was 1.35 which indicates poor compressibility property and

poor flow property.

5.6.2 Drug and Excipients Compatibility Study:

a) FTIR spectra:

FTIR Spectra of the Metoprolol and Olmesartan has shown in the figure 5.1


Metoprolol has got carboxylic groups which have exhibited a broad peak

around 2991 cm-1 and a C-H bend near 1425 cm-1. It exhibited C-H Stretching at

around 1072 cm-1. And numbers of aromatic C-H peaks are also observed between

2900cm-1 to 3000cm-1. These are the characteristic absorption peak of Metoprolol

Succinate.

Olmesartan has got carboxylic acid peak which is in the form of a salt has

exhibited a strong peak near 1700 cm-1 and an aromatic C-H Stretch at around 3000-

3100 cm-1. It exhibited ring C=C stretch at 1720 cm-1. These are the characteristic

absorption peak of Olmesartan Medoxomil.

Figure 5.1: FTIR of Metoprolol Succinate



Figure 5.2: FTIR of Olmesartan Medoxomil

Figure 5.3: FTIR of Metoprolol Succinate + Olmesartan Medoxomil

Table 5.5: FTIR Spectrum bands of Metoprolol Succinate

AssignmentWavelength(cm-1)

Theoretical Peaks Practical Peaks

Carboxylic Acid 3300-2500 2991

C-H Bend 1470-1450 1425

Ether, C-H Stretch 1300-1000 1072

Aromatic ring 3100-3000 3105



Table 5.6: FTIR Spectrum bands of Olmesartan Medoxomil

b) DSC Thermogram:

DSC thermogram of Metoprolol and Olmesartan has shown in the figure 5.4


The Metoprolol Succinate which is in the pure form, when subjected for

DSC studies gives very sharp peak at 143.8º C indicating the sample is in the pure

form and exhibited a sharp melting range. The Olmesartan medoxomil which is in

the pure form, when subjected for DSC studies gives very sharp peak at 185.03º C

indicating the sample is in the pure form and exhibited a sharp melting range.

In combination of Metoprolol and Olmesartan, the DSC results showed Major

unwanted difference between endothermic or exothermic peaks were obtained, which

would have shown the presence of any incompatible reaction. Hence, it can’t be

utilized successfully in combination for further formulation preparation step. So,

preparing Granules and Tablet in Capsule dosage form, Bilayer Tablet and coating

pellet etc…are the solution to overcome from this problem.

AssignmentWavelength(cm-1)

Theoretical Peaks Practical Peaks

Aliphatic C–H stretch 3200-3300 2974

Aromatic C–H stretch 3200-3300 3039

Broad, O-H stretch 3200-3300 3271

C=O of carboxylic group 1705-1725 1720

ring C=C stretch 1500-1600 1504

C–N stretch 1400-1500 1483

ring C-O-C stretch 900-1200 1053



100.00 200.00 300.00Temp [C]

-40.00

-30.00

-20.00

-10.00

0.00

mWDSC

143.76 x100C

Figure 5.4: DSC of Metoprolol Succinate

100.00 200.00 300.00Temp [C]

-10.00

0.00

10.00

mWDSC

185.03x100C

Figure 5.5: DSC of Olmesartan medoxomil



Figure 5.6: DSC of Metoprolol Succinate + Olmesartan Medoxomil

5.7 Conclusion:

Preformulation was carried out to study the micromeritic properties and drug

excipients compatibility. The micromeritic properties revealed that both API shown

very poor flow and compressibility property. So, we have to increase the flow

property of both the drugs. FTIR and DSC study was showed that there was no

interaction between both the drugs.




5.7 Conclusion:









5.7 Conclusion:








5.8 References:

Aulton ME. The Science of dosage form design. 2nd edition. Churchill living stone;

2002: 414-418.

Baertschi, SW. Pharmaceutical stress testing, predicting drug degradation, Taylor and

Francis group, 2005, 344-350.

Cooper J, Gun C. Powder Flow and Compaction. Inc Carter SJ, Eds. New Delhi.

Tutorial Pharmacy. hidix CBS Publishers and Distributors; 1986: p. 211-233.

Gohel M, Nagori S, Jena D. Fabrication of Modified Release Tablet Formulation of

Metoprolol Succinate using Hydroxypropyl Methylcellulose and Xanthan Gum.

AAPS Pharm Tech sci. 2009; 10(1):62-68.

ICH Guideline Q1A (R2), Guidance for industry, stability testing of new drug

substance and products (Available on: http:// http://www.ich.org).

ICH topic 8 Pharmaceutical guidelines, Note for Guidance on Pharmaceutical

Developments, (EMEA/CHMP167068/2004).

Kibbe A. Handbook of pharmaceutical excipients; 3rd Ed. Washington London:

American Pharmaceutical Association and Pharmaceutical Press; 2000, 102-106.

Lachman L, Lieberman HA, Kanig JL. The theory and practice of Industrial

pharmacy. Bombay. Varghese Publishing House; 1987: p. 171-293.

Martin A. Micromeretics, In: Martin A, ed. Physical Pharmacy. Baltimores, MD:

Lippincott Williams and Wilkins; 2001, 423-454.

Shah VP, Tsong Yi, Sathe P, Williams RL.Dissolution Profile Comparison

Using Similarity Factor, f2, Office of Pharmaceutical Science, Center for Drug

Evaluation and Research. Food and Drug Administration, Rockville, MD Available

on http://www.dissolutiontech.com/DTresour/899Art/DissProfile.html

The Indian Pharmacopoeia; Ministry of Health and Family Welfare, Government of

India, Controller of Publications, New Delhi; 1996; 4th Edition; Volume II.

The United State Pharmacopoeia. The official compendia of standards. Asian edition.

2005;USP 28 NF 23: 1280



Chapter 6: Formulation and Optimization of Immediate ReleaseGranules of Olmesartan Medoxomil


6. FORMULATION AND OPTIMIZATION OF IMMEDIATE RELEASE

GRANULES OF OLMESARTAN MEDOXOMIL

6.1 Preparation of standard curve of Olmesartan medoxomil

Determination of λmax:

This is performed by using UV spectrophotometer by using 0.1 N HCL as medium.

Maximum absorbance was found at 255 nm as shown in the figure 6.1

Primary Stock Solution

50 mg of pure Olmesartan medoxomil drug was dissolved in 50 ml of 0.1 N HCL in a

50 ml of standard volumetric flask (1000 µg/ml).

Secondary Stock Solution

From the primary stock solution 5 ml was taken and diluted to 50 ml of 0.1 N HCL

(100µg/ml). From the above solution serial dilutions are made to get solutions having

concentration range from 4µg/ml to 14µg/ml. The absorbance was measured at 248 nm

using ultraviolet spectrophotometer. Beers law is obeyed to range of 4-14µg/ml.

Figure 6.1: UV spectra of Olmesartan medoxomil





































6.2 Selection and justification of Excipients

Diluents: In view of the low or medium dose of drug it is essential to add bulking

agents or diluents to increase the weight of the tablet. Mannitol was selected as diluent

and gives better flowability.

Binder: The main application area for Povidone K 25, K 30, and K 90 is as a binder in

tablets and granulates. The binding effect is achieved both in wet and dry granulation

and in direct tablet compression. While Povidone K 25 and K 30 are very similar, the

binding effect of Povidone K 90 is considerably greater; this means that only about half

the concentration of Povidone K 90 needs to be used. Wet granulation with Povidone K

25, K 30, or K 90 results generally in hard granules with excellent flow properties.

Povidone can be used with all current granulation techniques.

Disintegrant: Sodium starch glycolate is widely used in oral pharmaceuticals as a

disintegrant in capsule and tablet formulations. It is recommended to use in tablets

prepared by either direct-compression or wet-granulation processes. The recommended

concentration in a formulation is 2-8%, with the optimum concentration about 4%

although in many cases 2% is sufficient. Disintegration occurs by rapid uptake of water

followed by rapid and enormous swelling.

Lubricants: Magnesium stearate was widely used as lubricating agent (Kibbe AH et al,

2010).

y = 0.043x - 0.022R² = 0.997

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 5 10 15

Absorbance

concentration(mcg/ml)

Calibration curve of Olmesartanmedoxomil in 0.1N Hcl at 255 nm

Concentration

(µg/ml)Absorbance

0 0

4 0.150±0.002

6 0.243±0.003

8 0.326±0.004

10 0.409±0.005

12 0.485±0.004

14 0.595±0.003

Table 6.1: Absorbance valuesof OLME in 0.1 N Hcl

Figure 6.2: Calibration curve of OLME in

0.1 N Hcl



Table 6.2: Ingredients and their function

Sr. No. Ingredients Function

1. Olmesartan medoxomil API

3. Mannitol Diluent

4. Sodium starch glycolate Disintegrant

5. Cross carmellose sodium Disintegrant

6. Cross povidone Disintegrant

7. PEG 4000 Stabilizer

8. PVP K 90 Binder

9. Micro crystalline cellulose Wicking action

10. Magnesium stearate Lubricant

6.3 Preliminary trials for the Immediate release granules of Olmesartan

Medoxomil using SSG:

Table 6.3: Formulation for Preliminary trials using SSG

Preliminary trials of immediate release granules of Olmesartan medoxomil using

Sodium starch glycolate was prepared by wet granulation method. Olmesartan

Medoxomil, mannitol, and MCC pH 102 were passed through the 40 # sieve and

thoroughly mixed. PEG 4000 containing PVP K-90 was used as a binder solution. This

solution was added in above mixture and granulated and dried in hot air oven at 60 0 C

for 15 min. Dried granules were passed through 20 # sieve and the fines were separated

Ingredients A1 A2 A3 A4 A5 A6 A7 A8

Olmesartan medoxomil 20 20 20 20 20 20 20 20

PEG 4000 4 4 4 4 4 4 4 4

Mannitol 57.58 57.0 56.5 56.0 55.5 55.0 54.5 54.0

MCC pH02 11.7 11.7 11.7 11.7 11.7 11.7 11.7 11.7

PVP k 90 2.64 2.64 2.64 2.64 2.64 2.64 2.64 2.64

SSG 1 1.5 2 2.5 3 3.5 4 4.5

Mg stearate 3 3 3 3 3 3 3 3

Total (mg) 100 100 100 100 100 100 100 100



using 40 # sieve to obtain 20-40 # granules. SSG was passed through 40 # sieve and

mixed with dried granules. These granules were lubricated with magnesium stearate.

Angle of repose, Hausner’s ratio, true and bulk density and disintegration test were

performed for the granules.

6.3.1 Evaluation of Preliminary Trials:

Preliminary trial batches of immediate release granules were evaluated for Angle of

repose, Bulk density, Taped density, Hausner’s ratio, Carr’s index, In-vitro dissolution.

Method to calculate the above parameters described in section 5.

Friability

The friability of twenty tablets was measured by Roche friabilator for 4min at 25rpm

for 100 revolutions. Accurately weigh twenty tablets placed into Roche friabilator for

100 revolutions than deduct the tablets and weigh (Lachman L et al, 1987).

100%0

0

W

WWFriability

Disintegration

The disintegration test is carried out using the disintegration tester which consists of a

basket rack holding 6 plastic tubes, open at the top and bottom, the bottom of the tube is

covered by a 10-mesh screen. The basket is immersed in a bath of suitable liquid held at

37oC, preferably in a 1L beaker.

Dissolution

In vitro drug release studies details:

The in-vitro dissolution study was conducted in triplicate using USP Type-II

dissolution apparatus. The study was carried out in 900 ml of (pH 1.2) for 2Hr. The

bath temperature was maintained at 37 ± 0.5°C. The basket was rotated at 50 rpm. At

different time intervals as described above, 10 ml sample was withdrawn and at each

time of withdrawal, 10 ml of fresh corresponding medium was replaced into the

dissolution flask. The samples were filtered through membrane filter (0.45) and proper

dilutions were made. The absorbance was measured at 255 nm against blank. The

amount of drug was calculated using standard graph and the Using absorbance,

percentage and cumulative percentage release were calculated (Vyas S et al, 2000)

Apparatus used : USP type II dissolution test apparatus

Dissolution medium : 0.1 N HCL



Dissolution medium volume : 900 ml

Temperature : 37 ± 0.5º C

Speed of basket paddle : 50 rpm

Sampling intervals : 15, 30, 45, 60, 90, 120min

Sample withdraw : 5 ml

Absorbance measured : 255 nm

6.3.2 Result and Discussion:

Evaluation of Powder Blend of IRG of Olmesartan medoxomil:

The powder blends of preliminary trial batches of Olmesartan medoxomil taken with

disintegrant Sodium starch glycolate were evaluated for LBD, TBD, compressibility

index, angle of repose and housner’s Ratio (Table 6.4).

Table 6.4: Result of Evaluation of Powder Blend of preliminary trials

Angle of repose (θ):

Values of angle of repose ≤30º generally indicate the free flowing material and angle of

≥40º suggest a poor flowing material. The angle of repose is indicative of the flow

ability of the material.

The angle of repose of A1 to A8 batches was found around 22.490 to 25.140. i.e.

granules were of good flow properties. This was further supported by lower Carr’s

index values.

Bulk density:

Bulk density may influence compressibility, tablet porosity, dissolution and other

properties and depends on the particle size, shape and tendency of particles to adhere

Powder

blend

Loose Bulk

Density

(g/ml)

Tapped Bulk

Density

(g/ml)

Carr’s Index

(%)

Angle of

Repose (0)

Hausner’s

Ratio

A1 0.462±0.0034 0.524±0.0045 11.83±0.03 24.69±0.1 1.13±0.02

A2 0.438±0.0045 0.517±0.0023 15.28±0.02 23.31±0.2 1.18±0.04

A3 0.431±0.0038 0.504±0.0010 14.48±0.02 24.31±0.4 1.17±0.05

A4 0.459±0.0010 0.534±0.0036 14.04±0.12 25.14±0.4 1.16±0.04

A5 0.468±0.0042 0.547±0.0012 15.28±0.23 23.52±0.6 1.18±0.05

A6 0.450±0.0032 0.520±0.0078 13.46±0.04 22.49±0.7 1.15±0.12

A7 0.445±0.0067 0.521±0.0065 15.16±0.06 23.67±0.8 1.17±0.04

A8 0.459±0.0045 0.530±0.0048 13.39±0.05 22.58±0.3 1.15±0.07



together. Loose bulk density (LBD) and tapped bulk density (TBD) for the blend was

performed.

For A1 to A8 batches granules, the LBD and TBD were found around 0.431 to 0.468

and 0.504 to 0.547 gm/cc respectively. This indicates good packing capacity of the

granules.

Hausner’s ratio:

Hausner’s ratio is simple method to evaluate stability of powder column and to estimate

flow properties. Hausner’s ratio of A1 to A8 batches granules was found around 1.13 to

1.18. The granules of whole the batches had shown lower Hausner’s ratio values

(<1.25) which indicates better flow properties.

Carr’s consolidation index:

Degree of compression is characteristic of compression capability of the granules. The

results of Carr’s consolidation index or compressibility index (%) for A1 to A8 batches

granules was found around 11.83% to 15.28%. The granules of batches had shown

excellent compressibility index values up to 15 % result in good to excellent flow

properties.

Disintegration time:

The disintegration time was found around 5.6, 5.1, 4.6, 4.7, 3.8, 3.2, 4.0 and 4.1min for

batch A1 to A8 respectively.

In-Vitro Release study

The results of %Cumulative Drug Release (%CDR) and in-vitro comparative

dissolution profile of trial batches A1 to A8 shown in the Table 6.5 and Figure 6.3

respectively.

As described in Table 6.3 it can be seen that all batches of Olmesartan medoxomil

shown above 90% drug release within 2 hour. In batch A1 to A6 the drug release at 60

min (1 hour) was 72.93 to 82.09%. While in batches A7 and A8 the drug release at 60

min (1hour) was 80.39 and 73.65% respectively. In batches A1 to A8 the concentration

of Sodium starch glycolate (SSG), a disintegrant was 1 to 4.5 % respectively.

It can be concluded that the drug release for Olmesartan medoxomil granules was

increase in 1 to 3.5 % concentration after that it was decrease. So 3.5% concentration of

Sodium starch glycolate was taken as optimum concentration to formulate the

immediate release granules of Olmesartan medoxomil.



Table 6.5: Result of In-vitro Release of Preliminary trials

Time(min) A1 A2 A3 A4 A5 A6 A7 A8

0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

59.31±

0.4

8.69±

0.2

5.13±

0.4

5.13±

0.3

6.49±

0.4

5.55±

0.4

14.55±

0.4

5.86±

0.7

1538.62±

0.5

29.08±

0.4

40.45±

0.4

42.55±

0.1

43.92±

0.2

42.45±

0.3

45.58±

0.6

32.19±

0.6

3055.37±

0.4

49.08±

0.5

61.94±

0.7

61.44±

0.9

66.38±

0.3

66.88±

0.8

66.28±

0.7

54.32±

0.4

4566.86±

0.6

62.60±

0.7

75.39±

0.7

72.37±

0.6

75.80±

0.6

79.44±

0.9

75.38±

0.2

66.95±

0.5

6072.93±

0.3

69.14±

0.5

81.76±

0.4

79.23±

0.3

81.86±

0.2

82.09±

0.6

80.39±

0.5

73.65±

0.5

7577.07±

0.4

74.39±

0.4

84.95±

0.1

82.08±

0.4

85.47±

0.4

85.91±

0.7

84.92±

0.6

77.48±

0/7

9082.92±

0.3

78.23±

0.7

87.85±

0.4

84.63±

0.5

87.54±

0.3

87.56±

0.5

87.61±

0.4

80.72±

0.4

12086.10±

0.6

81.47±

0.3

88.99±

0.5

86.89±

0.7

89.30±

0.7

89.54±

0.4

89.27±

0.4

82.63±

0.5

Figure 6.3: Comparative dissolution profile of Preliminary trails

0.00

10.00

20.00

30.00

40.00

50.00

60.00

70.00

80.00

90.00

100.00

0 50 100 150

%C

cum

ulat

ive

drug

rel

ease

Time(min)

Comparitive Dissolution Profile

A1

A2

A3

A4

A5

A6

A7

A8



6.4 Optimization of immediate release granules of Olmesartan medoxomil by

using Super Disintegrants:

Table 6.6: formulation of batches F1 to F3

Ingredients F1 F2 F3

Olmesartan Medoxomil 20 20 20

PEG 4000 4 4 4

Mannitol 55.08 55.08 55.08

MCC pH 102 11.77 11.77 11.77

PVP K 90 2.644 2.644 2.644

CCS 3.5 - -

SSG - 3.5 -

CP - 3.5

Mg Stearate 3 3 3

Total(mg) 100 100 100

Procedure for the formulation of immediate release granules using Sodium starch

glycolate, cross carmellose sodium and cross povidone was same as described in

section 6.3.1

6.4.1 Evaluation:

Evaluation of immediate release granules of Olmesartan medoxomil containing Sodium

starch glycolate, cross carmellose sodium and cross povidone was carried out same as

described in section 6.3.

6.4.2 Result and discussion:

Evaluation of Powder Blend of Batches F1 to F3

The powder blends of preliminary trial batches of Olmesartan medoxomil taken with

disintegrant Sodium starch glycolate, cross carmellose sodium and cross povidone were

evaluated for LBD, TBD, compressibility index, angle of repose and housner’s Ratio

(Table 6.7).




ability of the material.



The angle of repose of F1 to F3 batches was found around 23.280 to 25.270. i.e.

granules were of good flow properties. This was further supported by lower Carr’s

index values.

Table 6.7: Result of Evaluation of Powder Blend of Trial Batches F1 to F3

Bulk density:




performed.

For F1 to F3 batches granules, the LBD and TBD were found around 0.428 to 0.443

and 0.495 to 0.519 gm/cc respectively. This indicates good packing capacity of the

granules.

Hausner’s ratio:


flow properties. Hausner’s ratio of F1 to F3 batches granules was found around 1.15 to

1.17. The granules of whole the batches had shown lower Hausner’s ratio values

(<1.25) which indicates better flow properties.



results of Carr’s consolidation index or compressibility index (%) for F1 to F3 batches

granules was found around 13.53% to 14.64%. The granules of batches had shown

excellent compressibility index values up to 15 % result in good to excellent flow

properties.


The disintegration time was found around 4.1, 3.2 and 2.45 min for batches F1 to F3

respectively.

Powder

blendLoose Bulk

Density(g/ml)

Tapped Bulk

Density(g/ml)

Carr’s

Index

(%)

Angle of

Repose(0)

Hausner’s

Ratio

F1 0.431±0.0034 0.504±0.0023 14.48±0.2 24.31±0.5 1.17±0.01

F2 0.443±0.0023 0.519±0.0038 14.64±0.4 23.28±0.7 1.17±0.03

F3 0.428±0.0018 0.495±0.0023 13.53±0.1 25.27±0.2 1.15±0.07



In-Vitro Drug Release study

The results of %Cumulative Drug Release (%CDR) and in-vitro comparative

dissolution profile of trial batches F1 to F3 shown in the table 6.8 and Figure 6.4

respectively.

Table 6.8: Result of In-vitro Drug Release of Batches F1 to F3

Time(min)% Cumulative Drug Release

F1(3.5%CCS)

F2(3.5%SSG)

F3(3.5%CP)

0 0.00 0.00 0.005 5.44±0.4 5.55±0.4 5.97±0.1

15 30.51±0.6 42.45±0.1 45.07±0.530 62.88±0.1 66.88±0.6 76.33±0.645 76.23±0.5 79.44±0.7 90.99±0.1

60 81.15±0.2 82.09±0.3 94.18±0.590 90.4±0.3 90.49±0.6 100.0±0.8

120 95.35±0.4 96.48±0.8 -

Figure 6.4: Comparative dissolution profile of F1 to F3

From the table 6.8, it could be seen that all batches of Olmesartan medoxomil shown

above 90% drug release within 2 hour. In batch F1 containing the Crosscarmellose

sodium the cumulative drug release at 5 min was 5.44% after that 15 min it was

30.51%. At 1 hour the drug release found was 81.15% and lead up to 95.35% at 2 hour.

In batch F2 containing the Sodium starch glycolate the cumulative drug release at 5 min

was 5.55 which were nearby batch F1, Cross carmellose sodium. At 1 hour the drug

release found was 82.09 which were also nearby the batch F1. In batch F3 containing

0102030405060708090

100

0 50 100 150

% C

umiu

lati

ve d

rug

rele

ase

Time(min)

Comparitive disolution profile

F1 (3.5%CCS)

F2 (3.5%SSG)

F3 (3.5%CP)



Cross povidone the cumulative drug release at 5 min was 5.97% and after 1 hour the

drug release was 90.99% which was much higher than batch F1 and F2 and at 90 min

the drug release found was 100%.


higher in Cross povidone than Sodium starch glycolate and Cross carmellose sodium

using same concentration.

6.5 Optimization of immediate release granules of Olmesartan medoxomil using

Cross povidone:

Table 6.9: formulation of batches using cross povidone

Procedure for the formulation of immediate release granules using cross povidone was

same as described in section 6.3.1

6.5.1 Evaluation:

Evaluation of immediate release granules of Olmesartan medoxomil containing Sodium

starch glycolate, cross carmellose sodium and cross povidone was carried out same as

described in section 6.3.

6.5.2 Result and discussion:

Evaluation of Powder Blend of Batches F3 to F5




ability of the material.The angle of repose of F3 to F5 batches was found around 24.310

to 25.270. i.e. granules were of good flow properties. This was further supported by

lower Carr’s index values.

Ingredients F3 F4 F5

Olmesartan Medoxomil 20 20 20

PEG 4000 4 4 4

Mannitol 55.08 56.08 54.08

MCC pH 102 11.77 11.77 11.77

PVP K 90 2.644 2.644 2.644

CP 3.5 2.5 4.5

Mg stearate 3 3 3

Total (mg) 100 100 100



Table 6.10: Result of Evaluation of Powder Blend of batches containing CP

Bulk density:




performed.

For F3 to F5 batches granules, the LBD and TBD were found around 0.428±0.0018 to

0.459±0.0010 and 0.495±0.0023 to 0.534±0.0036 gm/cc respectively. This indicates

good packing capacity of the granules.

Hausner’s ratio:


flow properties. Hausner’s ratio of F3 to F5 batches granules was found around

1.15±0.07 to 1.17±0.04. The granules of whole the batches had shown lower Hausner’s

ratio values (<1.25) which indicates better flow properties.



results of Carr’s consolidation index or compressibility index (%) for F3 to F5 batches

granules was found around 13.53±0.01% to 14.48±0.02%. The granules of batches had

shown excellent compressibility index values up to 15 % result in good to excellent

flow properties.


The disintegration time was found around 2.45, 3.0 and 3.2min for batches F3 to F5

respectively.

In-Vitro Drug Release study

The results of % Cumulative Drug Release (%CDR) and in-vitro comparative

dissolution profile of trial batches F3 to F5 shown in the table 6.11 and Figure 6.5

respectively.

Powder

blend

Loose Bulk

Density(g/ml)

Tapped Bulk

Density(g/ml)

Carr’s

Index (%)

Angle of

Repose(0)

Hausner’s

Ratio

F3 0.428±0.0018 0.495±0.0023 13.53±0.01 25.27±0.2 1.15±0.07

F4 0.431±0.0038 0.504±0.0010 14.48±0.02 24.31±0.6 1.17±0.05

F5 0.459±0.0010 0.534±0.0036 14.04±0.02 25.14±0.4 1.16±0.04



Table 6.11: Result of In-vitro Release of batches using cross povidone

As indicated in Table 6.11, in batch F3 containing 3.5% cross povidone the cumulative

drug release at 45min was 90.99%. In batch F4 containing 2.5% cross povidone the

cumulative drug release at 45min was 83.08%, while in batch F5 containing 4.5% cross

povidone it was 81.05%. So cumulative drug release at 45 min was higher in batch F3

containing 3.5% cross povidone than the batch F4 and F5 containing 2.5% and 4.5%

cross povidone respectively.

Figure 6.5: Comparative dissolution profile of batches using cross povidone


higher in Cross povidone with 3.5% than 2.5% and 4.5% concentration of cross

povidone. So batch F3 was taken as Optimize batch.

0102030405060708090

100

0 20 40 60 80 100

% c

umul

ativ

e dr

ug r

elea

se

Time(min)


F3 (3.5%CP)

F4 (2.5%CP)

F5 (4.5%CP)

Time(min)%Release

F3(3.5%CP)

F4(2.5%CP)

F5(4.5%CP)

0 0.00 0.00 0.005 5.97±0.5 6.17±0.2 4.60±0.4

15 45.07±0.2 28.01±0.4 24.33±0.230 76.33±0.4 59.40±0.5 60.91±0.545 90.99±0.4 83.08±0.1 81.05±0.360 94.18±0.3 90.59±0.3 88.43±0.590 100.02±0.6 98.69±0.3 98.18±0.5



FTIR Spectra:

Figure 6.6: FTIR of Olmesartan Medoxomil granules formulation

The Immediate release granules of Olmesartan medoxomil contain Olmesartan and

cross povidone. The cross povidone contains C=O group in a molecule which is

indicated by peak at 3100 cm-1 which is the expected place wherein C=O groups can

observe. Similarly, to above instead of aromatic C-H number of aliphatic C-H are

observed near 2900 cm-1. In IR granules of Olmesartan medoxomil when the drug is

formulated along with the polymer cross povidone the IR of this of this batch did not

exhibit any extra peaks only peaks which are present in the drug and the cross povidone

were repeated indicating that during the process of formulation no chemical reaction

has taken place. Only hydrogen bonding between the drug molecule and Cross

povidone has taken place. This was a reversible bonding, hence cross povidone can

carry the drug to the local of its action and can be released for the purpose to which it

was administered.

DSC Thermogram:

In IR granules batch, the drug Olmesartan medoxomil was taken with cross povidone.

In this case during the DSC measurement the formulation has started the melting

process at around 170ºC and completed at 180ºC. This more than 7ºC range suggests



that this formulation was also not a reaction product but it was a mixture of drug and

polymers cross povidone. This was the reason why the batch IR granules had given

wide range of melting process.

Figure 6.7: DSC of Olmesartan medoxomil Granules Formulation

6.6 Conclusion:

In the present work, an attempt has been made to develop immediate release Granules

of Olmesartan medoxomil.

Amongst the various disintegrants used in the study, granules that were formulated

using Cross povidone exhibited quicker disintegration and dissolution of granules than

compared to those other disintegrants in different concentration. Formulation F3 was

the optimized formulation having maximum disintegration time as well as other

parameters was in acceptable range.

6.7 References:

Lee TW, Robinson JR. In Remington: The science and practice of pharmacy; Gennaro,

Ed. Baltimore. Lippincott Williams and Wilkins; 2000 ;( 2), pg no: 903-929.











6.6 Conclusion:








6.7 References:













6.6 Conclusion:








6.7 References:







Chapter 7: Formulation and Optimization of Extended Release Tablet ofMetoprolol Succinate


7. FORMULATION AND OPTIMIZATION OF EXTENDED RELEASE

TABLET OF METOPROLOL SUCCINATE

7.1 Preparation of standard curve of Metoprolol Succinate





50 mg of pure Metoprolol Succinate drug was dissolved in 50 ml of 0.1 N HCL and

Phosphate buffer pH 6.8 in a 50 ml of standard volumetric flask (1000 µg/ml).



and Phosphate buffer pH 6.8 (100µg/ml). From the above solution serial dilutions are

made to get solutions having concentration range from 5µg/ml to 25µg/ml. The

absorbance was measured at 222 nm using ultraviolet spectrophotometer. Beers law is

obeyed to range of 5-25µg/ml.

Con.

(µg/ml)

Absorbance

in 0.1 N

HCL

Absorbance

in pH 6.8

5 0.223±0.042 0.24±0.024

10 0.390±0.045 0.412±0.037

15 0.573±0.035 0.641±0.045

20 0.724±0.056 0.833±0.067

25 0.910±0.031 1.039±0.021

Table 7.1: Abs. values of Metoprolol in0.1 N HCL & pH 6.8

Figure 7.1: UV spectra of MetoprololSuccinate



Figure 7.2 Calibration curve of METO in 0.1 N HCL

Figure 7.3 Calibration curve of METO in phosphate buffer pH 6.8

7.2 Selection and justification of Excipients (Yie WC, 2005)

Diluents: In view of the low or medium dose of drug it is essential to add bulking

agents or diluents to increase the weight of the tablet. Microcrystalline Cellulose

(Avicel) was selected as diluent and gives better flowability.

Matrix-forming Polymers: HPMC K 100M and HPMC K 4M which are most

widely used matrix-forming polymer because of its excellent compatibility,

multifunctional property and cost effective. HPMC is available in different grades

depending upon its viscosity eg. HPMC K4M, HPMC K15M and HPMC K100M. For

ER preparation, high viscosity grades of polymers useful to extend the drug. So,

y = 0.034x + 0.052R² = 0.999

00.10.20.30.40.50.60.70.80.9

1

0 5 10 15 20 25 30

Abs

orba

nce

concentration(ug/ml)

Calibration curve of Metoprolol succinate in0.1 N Hcl at 222nm wavelength

y = 0.040x + 0.027R² = 0.998

0

0.2

0.4

0.6

0.8

1

1.2

0 10 20 30

Abs

orba

nce

Concentration(ug/ml)

Calibration curve of Metoprolol succinate inPhosphate Buffer [pH 6.8] at 222nm

wavelength



HPMC K 100M and HPMC K 4M was selected as matrix forming agent. PVP K 30

was used as a binder in formulation.

Table 7.2: Ingredients and their function

Sr. No. Ingredients Function

1. Metoprolol Succinate API

3. Microcrystalline Cellulose (Avicel) Diluent

4. HPMC K 4M Matrix-forming Polymer (10-80%)

5. HPMC K 100M Matrix-forming Polymer (10-80%)

6. PVP K 30 Binder

7. Isopropyl alcohol (IPA) Binder

8. Mg Stearate Lubricant

9. Talc Glidant (0.25-4%)

7.3 Preliminary trial of Metoprolol Succinate ERT with HPMC K 100M

Metoprolol Succinate SR Tablets were prepared by direct compression technique.

Drug and MCC pH 101 were passed through 40# sieve. HPMC K 100M was passed

through 40 # sieve. Mg Stearate and talc were passed through 60# sieve. Metoprolol

Succinate, MCC pH 101 & HPMC K 100M were mixed for 10min. Add Mg Stearate

into above mixture and nixed it for 3min add talc for 2 min. The prepared blend was

compressed (13/32 diameter, standard biconcave punches) using tablet compression

machine (Cadmach, Ahmadabad, India).

Table 7.3: Formulation trials using HPMC K100M

Ingredients PT1 PT2 PT3

Metoprolol Succinate 25 25 25

MCC pH101 1.86 11.86 21.86

HPMC K 100M 31.5 41.5 51.5

Magnesium Stearate 1 1 1

Talc 0.64 0.64 0.64

Total (mg) 60.0 80.0 100.0



7.3.1 Evaluation Parameters (Xiaoling Li, 2005):

7.3.1.1 Precompression parameters:

Loose Bulk density (LBD), Tapped bulk density (TBD), compressibility index, angle

of repose and Hausner’s ratios were calculated for RFC (Ready for compression)

material as described in chapter 5.

7.3.2.2 Post compression parameters:

Weight variation test:

20 tablets are selected randomly from the lot and weighted individually to check for

weight variation. Weight variation specification as per I.P. is shown in tablet no.

Table 7.4: Weight Variation Specification as per IP

Average weight of Tablets % Deviation

80 mg or less ± 10

More than 80 mg but less than 250 mg ± 7.5

250 mg or more ± 5

Hardness

The hardness of five tablets was determined using the Pfizer hardness tester and the

average values were calculated.

Thickness and Diameter

The Thickness and Diameter of the tables was determined by using Digital vernier

calipers. Five tablets were used, and average values were calculated.

Friability

The friability of twenty tablets was measured by Roche friabilator for 4min at 25rpm

for 100 revolutions. Accurately weigh twenty tablets placed into Roche friabilator for

100 revolutions than dedust the tablets and weigh.

100%0

0

W

WWFriability

In – vitro drug release:

Drug release studies of coated tablets were carried out using a USP type II dissolution

rate test apparatus (Apparatus 2, 50 rpm, 37 °C) for 2 hr in 0.1 M HCL (900 ml) as

the average gastric emptying time is about 2 hr. Then the dissolution medium was

replaced with pH 6.8 phosphate buffer (900 ml) for tested for drug release up to



complete drug release. At the end of the time period 10 ml of the samples were taken

and analyzed for Metoprolol Succinate content. A 10 ml volume of fresh and filtered

dissolution medium was added to make the volume after each sample withdrawal.

Sample was analyzed using UV Spectrophotometer at 222 nm (Lauretta M, 1999).

Assay

For tablet assay determination, Comparison between standard and sample in

employed using UV spectrophotometric method.

Preparation of Standard:

10mg of accurately weighed pure drug is transferred to 100ml volumetric flask.

Add 100ml methanol (100μg/ml). From this pipette out 1ml of standard solution

and Transfer it in to 10ml volumetric flask. Dilute this solution with methanol up

to the mark (10μg/ml). Take absorbance of this solution at 255nm.

Preparation of Sample:

Five tablets were selected randomly from each formulation and powdered in a

glass mortar and the powder equivalent to 50 mg of drug was placed into 50 ml

volumetric flask containing 20 ml of pH 6.8 phosphate buffer. The contents of the

flask were filtered through a filter and the residue was washed with another 20 ml

of pH 6.8 phosphate buffer and the volume was made up to the mark. The sample

was suitably diluted and analyzed by UV-visible spectrophotometer at 255nm.

7.3.2 Result and Discussion:

7.3.2.1 Evaluation of Pre compressional parameters of trials using HPMC

K100M

The powder blends of preliminary trial batches of Metoprolol Succinate taken with

polymer HPMC K100M were evaluated for LBD, TBD, compressibility index, angle

of repose and Hausner’s Ratio (Table 7.5).

Table 7.5: Result of Precompression parameters of trials using HPMC K100M

Powder

blend

Loose Bulk

Density

(g/ml)

Tapped Bulk

Density

(g/ml)

Carr’s

Index

(%)

Angle of

Repose

(0)

Hausner’s

Ratio

PT 1 0.462±0.004 0.524±0.002 11.83±0.2 24.69±0.4 1.13±0.04

PT 2 0.431±0.005 0.504±0.001 14.48±0.6 24.31±0.4 1.17±0.01

PT 3 0.468±0.003 0.547±0.005 15.28±0.1 23.52±0.6 1.18±0.03



The results of angle of repose and compressibility index ranged from 23.52 to 24.69

and 11.83 to 15.28 respectively. The results of Hausner’s ratio and blend uniformity

ranged from1.13 to 1.18 and 98.23 to 99.21 respectively. The results of angle of

repose (<30) indicate good flow properties of the powder based on table 5.3. This was

further supported by lower compressibility index values. Generally, compressibility

index values up to 15% results in good to excellent flow properties.

7.3.2.2 Evaluation of Post compressional parameters of trails using HPMC

K100M

The formulations were evaluated for different parameter like hardness, friability,

assay, weight variation (table 7.6).

Table 7.6: Result of Post compression parameters of trials using HPMC K100M

Trial

batches

Hardness

(kP)

Thickness

(mm)

Friability

(%)

Weight

variation(mg)

Assay

(%)PT 1 11.3±0.5 2.82±0.01 0.62±0.034 60.00+0.80 94.86

PT 2 12±0.1 3.05±0.05 0.48±0.045 80.00+0.920 91.92

PT 3 11±0.4 3.48±0.02 0.49±0.051 100.00+0.370 95.00

Hardness of the prepared tablets was found in range of 11-12 kP. All the tablet

formulations showed acceptable pharmacotechnical properties and complied with the

in-house specifications for weight variation, drug content, hardness, and friability

except assay as shown in Table 7.6.

In-Vitro Drug Release study:

The results of % Cumulative Drug Release (%CDR) and in-vitro comparative

dissolution profile of trial batches PT 1 to PT 3 shown in the table 7.7 and Fig 7.4

respectively.

Table 7.7: Result of In-vitro Release of trials using HPMC K100M

Time(hrs)% Cumulative drug Release

PT 1 PT 2 PT 3

1 24.21±0.6 22.18±0.4 19.26±0.5

3 50.86±0.5 45.72±0.6 41.89±0.3

5 69.84±0.3 63.89±0.3 60.87±0.6

7 89.50±0.4 80.68±0.6 78.24±0.1

9 99.72±0.1 94.67±0.7 90.12±0.4



Figure 7.4: Comparative dissolution profile of trials using HPMC K100M

The results of in-vitro dissolution study of trial batches PT1 to PT3 showed very

slower drug release as compared to the targeted drug release and as the percentage of

polymer decreased, the release of drug from tablet was increased. Formulations were

failed to generate sustained release of drug up to 20 hr and eroded before 15 hrs.

Hence formula with HPMC K100M alone was rejected and further study was

conducted using HPMC K 100M and HPMC K4M.

7.4 Formulation of ERT of Metoprolol Succinate with HPMC K 4M and HPMC

K 100M

Metoprolol Succinate ER Tablets were prepared by wet granulation technique. Drug,

HPMC and MCC were passed through 40# sieve. Aerosil and SSF were passed

through 60# sieve. Required amount of Polyethylene glycol was dissolved in IPA

until clear solution was achieved. Metoprolol Succinate, HPMC and MCC were

mixed for 10min. Wet granules were dried in FBD (Electrocraft Pvt. Ltd.) at 70-800C

for 40-45 min. Dried granules were passed through the sieve no #20. The dried

granules were mixed with rest of the portion of HPMC K 100 M in a polybag for 10

min. Extra granular part was added to retard the drug release in the last time points.

Add Aerosil and SSF into above mixture and mixed it for 3 min. The prepared blend

was compressed using tablet compression machine.

0102030405060708090

100

0 2 4 6 8 10

% C

umul

ativ

e D

rug

Rel

ease

Time (hrs)


PT 1

PT 2

PT 3



Table 7.8: Formulation of trial via wet granulation

7.4.1 Evaluation of Pre compressional parameters of trial via wet granulation

Preliminary trial batches of extended release tablet were evaluated for Angle of

repose, Bulk density, Taped density, Hausner’s ratio, Carr’s index, In-vitro

dissolution. Method to calculate the above parameters described in chapter 5.

Table 7.9: Evaluation of Powder Blend of trial via wet granulation

As per table 7.10 the results of angle of repose and compressibility index ranged from

21.64 to 24.84 and 12.59 to 16.80 respectively. The results of Hausner’s ratio ranged

from 1.14 to 1.20. Hence, it was concluded prepared blends were free flowing and

compressible. (Angle of repose < 300, Carr’s index < 1.5)

Ingredients MT1 MT2 MT3 MT4 MT5 MT6

Metoprolol Succinate 25 25 25 25 25 25

MCC pH 101 47.38 42.38 37.38 16 16 6

HPMC K 4M 3.62 3.62 3.62 10 10 20

HPMC K 100 M 10 10 20 20 30 40

PVP K 30 3 3 3 3 3 3

IPA q.s. q.s. q.s. q.s. q.s. q.s.

HPMC K 100 M 5 10 5 10 10 10

Aerosil 3 3 3 3 3 3

Sodium Steryl Fumarate 3 3 3 3 3 3

Tablet Weight(mg)100.0±

0.5100.4±

0.6100.9±

0.3100.1±

0.6100.2±

0.8101.0±

0.5

Powder

blend

Loose Bulk

Density(g/ml)

Tapped Bulk

Density(g/ml)

Carr’s

Index (%)

Hausner’s

Ratio

Angle of

Repose(0)

MT1 0.479±0.005 0.548±0.004 12.59±0.5 1.14±0.01 23.47±0.5MT2 0.489±0.004 0.564±0.005 13.30±0.1 1.15±0.04 22.14±0.4MT3 0.426±0.003 0.512±0.003 16.80±0.2 1.20±0.03 24.84±0.7MT4 0.457±0.001 0.534±0.002 14.41±0.5 1.16±0.02 21.64±0.8MT5 0.434±0.006 0.516±0.003 15.89±0.6 1.18±0.06 24.78±0.2MT6 0.465±0.008 0.556±0.003 16.36±0.2 1.19±0.07 23.44±0.7



7.4.2 Evaluation of Post compressional parameters of trial via wet granulation

Table 7.10: Evaluation of Tablets of trial via wet granulation

Hardness of the prepared tablets of batch MT 1 to MT 6 was 12 - 14 kP. All the tablet

formulations showed acceptable properties and complied with the Pharmacopoeial

specifications for weight variation, drug content, hardness, and friability.

In- Vitro Release Study of trial via wet granulation

Table 7.11: Result of In-vitro release of trial via wet granulation

Time(hrs)% Cumulative Release

MT 1 MT 2 MT 3 MT 4 MT 5 MT 60 0 0 0 0 0 0

111.25±

0.510.62±

0.410.17±

0.410.35±

0.69.18±

0.57.65±

0.4

226.94±

0.624.78±

0.624.32±

0.723.69±

0.422.33±

0.621.50±

0.5

4 48.84±0.4

46.11±0.4

45.20±0.5

44.29±0.6

39.40±0.4

38.84±0.5

654.61±

0.454.27±

0.753.53±

0.552.52±

0.751.00±

0.749.98±

0.6

868.60±

0.166.65±

0.865.75±

0.662.09±

0.758.67±

0.157.45±

0.3

1672.05±

0.474.03±

0.772.64±

0.571.86±

0.870.73±

0.770.05±

0.4

2093.79±

0.785.63±

0.383.42±

0.782.35±

0.380.77±

0.373.50±

0.5

2496.33±

0.396.03±

0.195.06±

0.592.21±

0.590.99±

0.486.08±

0.6

Table 7.12: USP Limit for drug release for Metoprolol Succinate ERT

Time(hour)%Drugrelease

1 NMT 20%4 20-40%8 40-60%

20 NLT80%

Trial Hardness Thickness(mm)

Friability Weightvariation

Assay

MT1 13.5±0.5 3.5±0.01 0.072±0.001 100.0±0.6 99.3MT2 12.8±0.6 3.48±0.05 0.069±0.006 100.4±0.5 99.6MT3 12.5±0.4 3.42±0.06 0.061±0.005 101.0±0.8 98.4MT4 13.7±0.1 3.55±0.04 0.072±0.004 101.0±0.9 97.6MT5 12.9±0.4 3.43±0.03 0.069±0.007 100.2±1.0 98.2MT6 13.8±0.7 3.45±0.08 0.061±0.001 102.0±0.7 99.1



Figure 7.5: Comparative dissolution profile of trial via wet granulation

Figure 7.6: Photographs of ERT of METO at Different time interval

0

20

40

60

80

100

120

0 10 20 30

%Cu

mul

ativ

e re

leas

e

Time(min)

Comparative Dissolution Profile

MT 1

MT 2

MT 3

MT 4

MT 5

MT 6

At 1st hour At 4th hour

At 8th hour At 20th hour



From the Table 7.11, it was concluded that as the concentration of HPMC was

increased, drug release was decreased. It may be due to the gelling property of

HPMC. Incorporation of a high concentration of HPMC controlled the drug release in

a better manner, which could be attributed to the decreased penetration of the solvent

molecules in the presence of hydrophilic polymer, leading to decreased diffusion of

the drug from the matrix. Form above observation table it can be concluded that

batches MT1 to MT4 shown the drug release which was greater than the limit.

Batches MT5 and MT6 was shown the drug release within the limit.

7.5 Optimization of formulation by using 32 full factorial designs:

In the present study, a 32 full factorial design was employed to study the effect of

independent variables, i.e. concentration of HPMC K4M (X1) and Concentration of

HPMC K 100M (X2) on dependent variables, % drug release at 1 hour (Q1), 8 hour

(Q8), 20 hour (Q20), 24 hour (Q24), T50% and T80%. A statistical model (see equation)

incorporating interactive and polynomial terms was utilized to evaluate the responses.

Y = b0 + b1X1+b2X2 + b12X1X2 + b11X12 + b22X22

Where, Y is the dependent variables, b0 is the arithmetic mean response of the nine

runs, and b1 is the estimated coefficient for the factor X1.

The main effects (X1 and X2) represent the average result of changing one

factor at a time from its low to high value. The interaction terms (X1X2) show how

the response changes when two factors are simultaneously changed. The polynomial

terms (X12 and X22) are included to investigate non-linearity. The results indicate

that all the dependent variables are strongly dependent on the selected independent

variables as they show a wide variation among the nine batches (F7 to F15). The fitted

equations (Full model) relating the responses, i.e., % drug release at Q1,Q8,

Q20,Q24,T50% and T80% are shown in Table 7.18. The polynomial equation can be

used to draw conclusions after considering the magnitude of coefficient and the

mathematical sign it carries, i.e. positive or negative. The high values of correlation

coefficient for the dependent variables indicate a good fit. The equation may be used

to obtain estimate of the response because small error of variance was noticed in the

replicates.



Table No. 7.13: 32 Full Factorial Design Layouts

Batch No.Independent Variables

X1 X2MT7 -1 -1

MT8 -1 0

MT9 -1 1

MT10 0 -1

MT11 0 0

MT12 0 1

MT13 1 -1

MT14 1 0

MT15 1 1

Concentration of Independent VariablesLevel Concentration of HPMC

K4MConcentration of HPMC

K100M-1 0 30

0 10 40

1 20 50

Table No. 7.14: Formulation of ERT using 32 Full Factorial Design

Ingredients MT7 MT8 MT9 MT10 MT11 MT12 MT13 MT14 MT15

MetoprololSuccinate

25 25 25 25 25 25 25 25 25

MCC pH101

36 26 16 26 16 6 16 6 0

HPMC K4M

0 10 20 0 10 20 0 10 20

HPMC K100 M

25 25 25 25 25 25 25 25 25

PVP K 30 3 3 3 3 3 3 3 3 3

IPA q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

HPMC K100 M

5 5 5 15 15 15 25 25 25

Aerosil 3 3 3 3 3 3 3 3 0

SodiumSteryl

Fumarate3 3 3 3 3 3 3 3 2

TabletWeight(mg)

100.3±0.5

100.5±0.5

100.2±0.7

100.1±0.1

100.6±0.4

100.7±0.5

100.7±0.3

100.7±0.6

100.1±0.2



7.5.1 Evaluation of Pre compressional parameters of ERT using 32 Full Factorial

Design

Table 7.15: Evaluation of Powder Blend of ERT using 32 Full Factorial Design

As per table 7.15 the results of angle of repose and compressibility index ranged from

21.64 to 24.84 and 12.59 to 16.80 respectively. The results of Hausner’s ratio ranged

from 1.14 to 1.20. Hence, it was concluded prepared blends were free flowing and

compressible. (Angle of repose < 300, Carr’s index < 1.5)

7.5.2 Evaluation of Post compressional parameters of ERT using 32 Full

Factorial Design

Table 7.16: Evaluation of ERT using 32 Full Factorial Design

Hardness of the prepared tablets of batch MT7 to MT15 was 12 - 14 kP. All the tablet

formulations showed acceptable properties and complied with the Pharmacopoeial

specifications for weight variation, drug content, hardness, and friability.

Powderblend

Loose BulkDensity(g/ml)

Tapped BulkDensity(g/ml)

Carr’sIndex(%)

Hausner’sRatio

Angle ofRepose(0)

MT7 0.436±0.034 0.520±0.045 16.15±0.4 1.19±0.045 25.67±0.5

MT8 0.454±0.042 0.523±0.034 13.19±0.3 1.15±0.034 23.69±0.7

MT9 0.444±0.045 0.516±0.065 13.95±0.2 1.16±0.067 24.67±0.3

MT10 0.457±0.056 0.534±0.034 14.41±0.6 1.16±0.052 21.64±0.6

MT11 0.434±0.021 0.516±0.056 15.89±0.6 1.18±±0.063 24.78±0.7

MT12 0.465±0.034 0.556±0.023 16.36±0.3 1.19±0.045 23.44±0.3

MT13 0.489±0.067 0.564±0.034 13.30±0.7 1.15±0.056 22.14±0.8

MT14 0.426±0.067 0.512±0.034 16.80±0.3 1.20±0.031 24.84±0.2

MT15 0.479±0.023 0.548±0.023 12.59±0.2 1.14±0.012 23.47±0.3

Batches Hardness(kg/cm2)

Thickness(mm)

Friability(%)

Weightvariation(mg)

Assay(%)

MT7 12.6±0.5 3.5±0.196 0.072±0.026 100.60±0.10 99.3MT8 12.8±0.4 3.48±0.217 0.069±0.017 100.3±0.23 99.6MT9 13.2±0.4 3.42±0.167 0.061±0.010 100.7±0.41 98.4

MT10 13.6±0.7 3.55±0.212 0.072±0.005 100.1±0.56 97.6MT11 12.9±0.5 3.43±0.577 0.069±0.0017 100.9±0.78 98.2MT12 12.7±0.6 3.45±0.564 0.061±0.005 100.2±0.1 99.1MT13 13.6±0.4 3.51±0.454 0.078±0.016 100.4±0.9 97.1MT14 12.6±0.5 3.48±0.325 0.064±0.02 100.7±0.12 98.8MT15 12.8±0.7 3.43±0.543 0.058±0.021 100.2±0.67 99.3



Figure 7.7: Effect of concentration of Polymers on Hardness

Hardness of different batches were analysed by hardness tester and found around in

the range as per IP requirement. Hardness varies from 12.6 – 13.6 Kg/cm2. All the

formulations gave hardness sufficient enough to decrease friability and resulted in

fruitful output in terms of hardness.

Figure 7.8: Effect of concentration of Polymers on Friability

Tablets of each batch were evaluated for percentage friability and the data’s were

shown in the Table 7.15. The average friability of all the formulation came in the

range of 3.42±0.005 to 3.58±0.005% which was less than 1% as per official

requirement of IP indicating a good mechanical resistance of tablets.

12

12.5

13

13.5

14

MT7 MT8Har

dnes

s(K

g/cm

2)

0

0.02

0.04

0.06

0.08

Fri

abili

ty(%

)













MT7 MT8 MT9 MT10 MT11 MT12 MT13 MT14 MT15Formulation

Formulation















Figure 7.9: Effect of concentration of Polymers on Assay of Tablet

The percentage drug content of all the tablets was found between 97.1 to 101.1 of

Metoprolol succinate, which was within the acceptable limits. This result indicates

that there was uniform distribution of the drug throughout the batch.

Figure 7.10: Effect of concentration of Polymers on Weight variation

Tablets of each batch were evaluated for Weight variation and the Weight variation of

all the formulation came in the range of 100.0±0.5 to 101.2±0.3 mg which was in the

limit as per official requirement of IP indicating a good mechanical resistance of

tablets.

94

96

98

100

102

Ass

ay(%

)

99.5

100

100.5

101

Wei

ght v

aria

tion

(mg)











tablets.

Formulation

Fromulation











tablets.



FTIR Spectra:

The Extended release Tablet of Metoprolol Succinate contains Metoprolol and

HPMC. The HPMC contains number of hydroxyl groups in a molecule which is

indicated by broad hump at 3500 cm-1 which is the expected place wherein many

hydroxyl groups can observe. Similarly, to above instead of aromatic C-H number of

aliphatic C-H are observed near 2900 cm-1. In ERT of Metoprolol when the drug is

formulated along with the polymer HPMC the IR of this of this batch did not exhibit

any extra peaks only peaks which are present in the drug and the HPMC are repeated

indicating that during the process of formulation no chemical reaction has taken

place. Only hydrogen bonding between the drug molecule and HPMC has taken

place. This is a reversible bonding, hence HPMC can carry the drug to the local of its

action and can be released for the purpose to which it is administered.

Figure 7.11: FTIR of Metoprolol Succinate ER tablet formulation

DSC Thermogram:When the drug was taken in ERT along with HPMC, the batch was obtained in good

yield. This purified batch was subjected for DSC measurements which have showed a

wide range of melting process which has started at around 139ºC and

completed at around 148ºC with a range of 9ºC suggesting that formulation was a

mixture of drug and HPMC but not the reaction product. Hence, drug in ERT batch

had remained in an unreacted form. The HPMC present along with the drug in ERT

was responsible for prolonged melting range of the formulation.



100.00 200.00 300.00Temp [C]

0.00

10.00

20.00

30.00

40.00

mWDSC

62.91x100C71.35x100C

85.52x100C

89.86x100C

111.18x100C

119.82x100C

142.66x100C

157.23x100C

178.08x100C

192.55x100C

205.22x100C

216.34x100C

226.98x100C

236.86x100C 255.77x100C261.50x100C

269.98x100C

277.60x100C

Figure 7.12: DSC of Metoprolol Succinate ERT Formulation

In vitro drug release study for factorial batches:

Table 7.17: In vitro drug release study for factorial batches

Time(min) MT7 MT8 MT9 MT10 MT11 MT12 MT13 MT14 MT15

125.65±

0.20.2

16.65±0.3

8.51±0.4

18.54±0.2

9.18±0.6

6.21±0.5

11.46±0.8

7.65±0.1

5.22±0.4

238.54±

0.231.78±

0.623.67±

0.530.00±

0.522.33±

0.420.68±

0.322.49±

0.421.51±

0.419.68±

0.2

451.92±

0.648.96±

0.744.28±

0.642.39±

0.439.41±

0.536.93±

0.336.95±

0.838.84±

0.536.64±

0.1

659.87±

0.457.41±

0.452.50±

0.552.84±

0.853.67±

0.848.95±

0.151.65±

0.149.98±

0.548.20±

0.5

870.33±

0.564.34±

0.458.75±

0.666.02±

0.459.57±

0.555.15±

0.756.14±

0.257.46±

0.354.49±

0.3

16 86.03±0.9

87.00±0.5

71.81±0.6

71.95±0.5

70.75±0.4

67.54±0.5

78.92±0.5

70.05±0.3

68.40±0.5

20 99.20±0.4

93.61±0.6

87.25±0.5

95.59±0.4

88.34±0.4

84.20±0.2

89.63±0.4

85.30±0.3

83.00±0.5

24100.35±

0.199.11±

0.297.34±

0.599.95±

0.598.97±

0.697.96±

0.595.15±

0.394.17±

0.493.92±

0.8

f2 value 51.52 60.43 74.03 67.08 79.20 69.13 76.04 72.57 66.32



Table 7.18: Effect of Independent variable on dependent variable by 32 full factorial

design of Metoprolol Succinate for Extended Release

Batchcode

IndependentVariables

Dependent VariablesX Y Q1 Q8 Q20 Q24 t50% t80%

MT7 -1 -1 25.65 70.33 99.196 100.35 6.45 14.93

MT8 0 -1 16.65 64.31 93.639 99.14 7.52 15.7

MT9 1 -1 8.51 58.75 87.358 97.341 9.39 18.04

MT10 -1 0 18.56 66.02 95.526 99.931 8.16 16.45

MT11 0 0 9.18 59.65 88.772 98.999 9.48 17.85

MT12 1 0 6.21 55.12 84.172 97.934 10.25 18.83

MT13 -1 1 8.46 58.12 86.522 95.046 9.62 18.18

MT14 0 1 7.65 57.46 85.509 94.086 9.89 18.46

MT15 1 1 5.22 54.49 83.331 93.976 10.42 19.09

From the in vitro drug release study it could be seen that in batch MT7 the cumulative

drug release at 1 hour was more than the 20% and at the 4 hours the drug release was

more than the limit which was 20 to 40%. After those 8 hours the cumulative drug

release was in the limit. While in batch MT8, MT9 and MT10 the cumulative drug

release at 1 hour was less than 20% but more than 40% at 4 hour. So batches failed in

the dissolution study. In batches MT12 to MT15 the cumulative drug releases were in

the limit at 1, 4, 8 and 20 hours as per the limit described in USP.

Table 7.19: Summary of regression analysis of Metoprolol Succinate tablet forExtended release

Coefficients b0 b1 b2 b12 b11 b22 R2

Q1 10.59 -5.45 -4.91 3.48 0.94 0.71 0.988

Q8 60.24 -4.35 -3.89 1.99 -1.0 0.30 0.977

Q20 89.46 -4.39 -4.13 2.16 0.04 -0.23 0.975

Q24 98.94 -1.01 -2.29 0.48 -0.02 -2.30 0.996

T50% 9.240 0.97 1.09 -0.53 0.08 -0.41 0.988

T80% 17.54 1.06 1.18 -0.055 0.25 -0.31 0.977

7.5.3 Response R1: Drug release at 1st hour

Final Equation in terms of Coded Factors:

Drug release at 1st hour (Q1)= +10.69-5.46 A-4.91 B+3.48 A B+0.94A2+0.71 B2

Final Equation in terms of Actual Factors:



Drug release at 1st hour (Q1)= +61.94556-2.12383HPMCK4M-1.40417HPMC

K100M+0.034750HPMCK4M*HPMCK100M+9.41667HPMCK4M2+7.06667HPM

C K100M2

Drug release at 1st hr (Q1) gives correlation co-efficient 0.98115978. The P value for

variable X1 and X2 were 0.0033 and 0.0044 respectively (P<0.05), it indicate that

both variables shows significant effect on drug release and combination efficient was

positive but the P value was less than 0.05, which indicates that combination of

independent variable show significant effect at 1st hr.

7.5.4 Response R2: Drug release at 8th hour


Drug release at 8th hour (Q8) = +60.26-4.35A-3.89B+1.99AB-1.000003A2+0.3 B2


Drug release at 8th hour (Q8)= +60.26-4.35HPMCK4M-

3.89HPMCK100M+1.99HPMCK4M*HPMCK100M-1.987HPMCK4M2+0.3HPMC

K100M2

Drug release at 8th hr (Q8) gives correlation co-efficient 0.97734979. The P value for



positive but the P value was greater than 0.05, which indicates that combination of

independent variable does not show significant effect at 8th hr.



Drug release at 20th hr (Q20) = +89.46-4.40A-4.14B+2.16AB+0.044A2-0.23B2


Drug release at 20th hr (Q20) = +115.40956-1.31325* HPMC K4M-0.44536*

HPMC K100M+0.021618* HPMC K4M * HPMC K100M+4.41667E-004* HPMC

K4M2-2.30833E-003* HPMC K100M2







independent variable does not show significant effect at 20th hr.



Drug release at 24th hr (Q24) = +98.94-1.01* A-2.29* B+0.48* A * B+0.021* A2-2.30* B2


Drug release at 24th hr (Q24) = +101.18033-0.90777HPMCK4M+0.31551

HPMCK100M+0.017597HPMCK4M*HPMCK100M-6.62000HPMCK4M2-

9.81500E-003 HPMC K100M2





independent variable also does not show significant effect at 24th hr.

7.5.7 Response R5: T50%


Time for 50% concentration (T50%) =+9.13+0.89* A+1.07* B-0.50* A * B+0.060*

A2-0.39* B2


Time for 50% concentration (T50%) =-4.13333+0.27700*HPMC

K4M+0.46483*HPMC K100M-5.0000 *HPMCK4M* HPMC K100M+6.000*HPMC

K4M2-3.8500* HPMC K100M2

Time for 50% concentration (T50%) gives correlation co-efficient 0.9883000. The P

value for variable X1 and X2 were 0.0021 and 0.0014 respectively (P<0.05), it

indicate that both variables shows significant effect on drug release and combination

efficient was negative but the P value was less than 0.05, which indicates that

combination of independent variable show significant effect at T50%.

7.5.8 Response R6: T80%


Time for 80% concentration (T80%) = +17.31+0.78* A+1.17* B-0.35* A * B+0.098*

A2-0.31* B2



Figure 7.13: Contour plot and 3 D surface showing effect of HPMC K4M and

HPMC K100M on the cumulative drug release at 1st hour

Figure 7.14: Contour plot and 3 D surface plot showing effect of HPMC K4M and

HPMC K100M on the cumulative drug release at 8th hour



Design-Expert® SoftwareFactor Coding: ActualQ1

Design points above predicted valueDesign points below predicted value25.65

5.22

X1 = A: HPMC K4MX2 = B: HPMC K100M

30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

5

10

15

20

25

30

Q1

A: HPMC K4M B: HPMC K100M



54.49


30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

50

55

60

65

70

75

Q8




83.331


30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

80

85

90

95

100

105

Q2

0





Time for 80% concentration (T80%) = +5.55111+0.19883*HPMC

K4M+0.40175*HPMCK100M-3.52500E-003*HPMCK4M*HPMC

K100M+9.83333E-004* HPMC K4M2-3.11667E-003* HPMC K100M2

Time for 80% concentration (T80%) gives correlation co-efficient 0.9776283. The P

value for variable X1 and X2 were 0.0052 and 0.0039 respectively (P<0.05), it

indicate that both variables shows significant effect on drug release and combination

efficient was negative but the P value was greater than 0.05, which indicates that

combination of independent variable does not show significant effect at T80%.

Figure 7.16: Contour plot and 3 D surface showing effect of HPMC K4M and


Figure 7.17: Contour plot and 3 D surface plot showing effect of HPMC K4M andHPMC K100M on the T50%



89.976


30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

85

90

95

100

105

110

Q

24


Design-Expert® SoftwareFactor Coding: ActualT50%


6.45


30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

5

6

7

8

9

10

11

T5

0%





HPMC K100M on the T80%

Figure 7.19: Overlay of contour plot of all Responses

Design-Expert® SoftwareFactor Coding: ActualT80%


14.93


30.00

35.00

40.00

45.00

50.00

0.00

5.00

10.00

15.00

20.00

13

14

15

16

17

18

19

20

T

80

%




7.5.9 Validity of Regression Equations of 32full factorial design (Check point

Batch)

Table 7.20: Composition of final Optimized Formula M16

Table 7.21 : Comparison between the Experimental (E) and Predicted (P) values

for the most probable optimal formulation

OptimizedFormulati

-on

Dependent Variables

%Cumulat-ive Releaseat 1st hour

(Q1)

%Cumulat-ive Releaseat 8th hour

(Q8)


(Q20)


(Q24)

(T50%) (T80%)

Predicted 10.39 59.99 89.20 99.08 9.09 17.20Experimen

tal10.20 58.87 90.5 97.48 9.18 17.54

RelativeError (%)

1.83 1.87 1.43 1.61 0.98 1.89

Full factorial design gives regression equation for response for selected variables

within range selected for those variables. But validity of these equation are confirmed

within those selected range by taking one or more check point batches at particular

value of those selected variables. Here we found that relative error was less than 2%

for all responses like %cumulative Release at 1st hour (Q1), %cumulative Release at

8th hour (Q8), %cumulative Release at 20th hour (Q20), %cumulative Release at 24th

hour (Q24), T50% and T80% for both level. So equations obtained for selected responses

Ingredients Quantity (mg/tab)

Metoprolol Succinate 25

MCC pH 101 16.01

HPMC K 4M 12.84

HPMC K 100 M 32.15

PVP K 30 3

IPA q.s.

HPMC K 100 M 5

Aerosil 3

Sodium Steryl Fumarate 3

Tablet Weight(mg) 100.0



are validated in selected range of variables. Thus these regression equations are

further useful for deriving the desired response from selected range of variables.

7.6 Result and Discussion:

For the preparation of Metoprolol Succinate extended release tablet, polymer HPMC

K100M alone and direct compression method used. Batches gave the good result of

Precompressional parameters but the dissolution was limited to 9 hour, tablet eroded

after that. So the batches failed in the dissolution limit. After that both HPMC K4M

and HPMC K 100M and direct compression method used, but as in ago batches same

problem was observed. Tablet had not given the dissolution profile as we needed.

In batches MT1 to MT6, both polymer HPMC K4M and HPMC K10OM

and Wet granulation used. Tablet gave the good Precompressional and Post

compressional parameters. Batches MT1 to MT3, gave the good dissolution profile

but not in the limit described in USP. While MT4 to MT6 batches gave the drug

release in the limit, at 1st hour-not more than 20%, at 4 hour-20 to 40%, at 8 hour-40

to 60% and at 20 hour-not less than 80%.

A two factor, there level 32 factorial design was used for the For the

optimization of Extended release tablet using stastical software, Design expert

7,(state- Ease Inc., MN). For the optimization two factor HPMC K4M and HPMC

K100M concentration selected and 9 batches prepared. In vitro drug release profile of

these batches using USP type 2 apparatus was performed.

For the optimization 6 differ responses like Q1 means drug release at 1

hour,Q8 mean drug release at 8th hour, Q20 mean drug release at 20th hour, Q24 mean

drug release at 24th hour, T 50% mean time required for the 50% drug release and

t80% mean time required for the 80% drug release. Q1, Q8, Q20, Q24, T50% and

T80% was calculated and from the design expert software regression analysis of

variables was calculated.

The Q1 value in the range of 25.65% to 5.22%, Q8 value in the range of

70.33% to 54.59%, Q20 value in the range of 99.3-% to 83%, Q24 value in the range

of 100.35% to 93.92%, T50% in the range of 6.45 to 10.42 hour and T80% value in

the range of 14.93 to 19.09 hour was obtained. The fitted design was analyzed as

polynomial model in quadratic order by the software design expert 7 trail version. The



data clearly indicate that the dependent variables were strongly dependent on

independent variables.

The R- square value for Q1 0.988, Q8 0.977, Q20 0.975, Q24 0.996, T50%

0.988 and T80% 0.977 and p value less than 0.05 was obtained. Value of p is less than

0.05 indicate model is significant. By the optimization option in the design expert 7

solution was obtained, from that one batch was taken as check point batch for the

validation of factorial study. Actual values were obtained near to the predicted values.

The in vitro drug release profile was compared to check point batch by f2 value.

Batch MT11 gave the f2 value 79.20 which was the maximum than the other batches.

So batch MT11 could be selected as optimize formulation of extended release tablet

of Metoprolol Succinate tablet.

7.7 Conclusion:

In the present work, an attempt has been made to develop Extended release Tablet of

Metoprolol Succinate.

Amongst the polymer used in the study, tablets that were formulated using HPMC

K4M and HPMC K100M by wet granulation method exhibited 24 hours drug release

study and also in the limit as described in USP. Formulation MT11 was the optimized

formulation having maximum f2 value when compared with Check Point batch.



7.8 References:

Deshmukh VN, Singh SP, Sakarkar DM, Formulation and Evaluation of Sustained

Release Metoprolol Succinate Tablet using Hydrophilic gums as Release modifiers.

International Journal of PharmTech Research, 2009; 1(2): pg no: 159-163.

Jain N.K. Adv. in Controlled and Novel Drug Delivery, CBS publications, 2001, pg

no: 268-269.

Jantzen GM, Robinson JR. Sustained- and controlled-release drug delivery systems.

In: Banker GS, Rhodes CT, editors, Modern pharmaceutics. 3rd edi, Marcel Dekker

Inc; New York, 1996, pg no: 575-609.

Lee TW, Robinson JR. In Remington: The science and practice of pharmacy;

Gennaro, Ed. Baltimore. Lippincott Williams and Wilkins; 2000 ;( 2), pg no: 903-929.

Lauretta M, Evelyn M, Maria T, and Ubaldo Conte., Formulation of biphasic release

tablets containing slightly soluble drugs, Eur J Pharma Biopharma 1999; 48, pg no:

37-42.

Xiaoling Li, Bhaskara JR. Design of controlled release drug delivery system. 2001, pg

no: 120-121.

Yie WC., Rate controlled drug delivery systems; Marcel Dekker; New York, Revised

and expanded, 2005; 2, pg no: 210.

Chapter 8: Formulation and Development of Granules and Tablet in Capsule Dosage form


8. FORMULATION AND DEVELOPMENT OF GRANULES AND TABLET IN

CAPSULE DOSAGE FORM:

8.1 Analytical Method for the Estimation of Metoprolol Succinate and Olmesartan

Medoxomil in Combine Dosage form by HPLC (Kevin H. Vachhani et al, 2012)

8.1.1 Apparatus

RP-HPLC instrument equipped with a UV-Visible detector and a photodiode array

detector, (Shimadzu, LC-2010CHT, Japan,), auto sampler, Phenomenex (Torrance,

CA) C18 column (250 mm × 4.6mm id, 5 µm particle size) and LC-solution

software were used.

Analytical balance (Sartorius CP224S, Germany)

Triple distillation unit consisting of borosilicate glass

Digital pH meter (LI 712 pH analyzer, Elico Ltd., Ahmadabad)

Corning volumetric flasks ( 10, 50, 100 ml)

Ultra sonic cleaner (Frontline FS 4, Mumbai, India)

8.1.2 Materials and Reagents:

Metoprolol Succinate and Olmesartan Medoxomil were kindly supplied as a gift

samples from Acme pharmaceutical and Zydus cadila Pharmaceutical respectively.

HPLC grade methanol (Merck Ltd., Mumbai, India).

HPLC grade acetonitrile (Finar Chemicals Ltd.,Mumbai, India).

The water for RP-HPLC was prepared by triple glass distillation and filtered through

a nylon 0.45 µm – 47 mm membrane filter.

Nylon 0.45 µm – 47 mm membrane filters (Gelman Laboratory, Mumbai, India).

Whatman filter paper no. 41. (Whatman International Ltd., England).

8.1.3 Preparation of solutions & Reagents:

Preparation of METO and OLME standard solutions

A mixed standard solution of METO (100 ug/m1) and OLME (100 ug/m1) was prepared

by accurately weighing METO (10 mg) and OLME (10 mg) and dissolving in methanol

and diluted to 100 ml with methanol in the same volumetric flask.

Preparation of working standard solutions

An aliquot of stock solution 25 ml was transferred in 50 ml volumetric flask and adjusted

up to mark with methanol having concentration (50 µg/m1)



Preparation of sample solution

Twenty tablets were weighed and powdered. The powder equivalent to 25 mg METO and

20 mg OLME was transferred to 100 ml volumetric flask. Methanol (50 ml) was added to

it and sonicated for 20 mm. The volume was adjusted up to the mark with methanol after

filtration of sonicated solution.

Preparation of pH 3.0 Buffer solution

Potassium dihydrogen phosphate (20 mM, 2.72 gm) in 1000m1 of mille equivalent water

was solubilised and adjusted the pH to 3.0 ±0.05 with ortho phosphoric acid solution

(10%).

8.1.4 Chromatographic Condition

Stationary phase: Thermo C18 column (150 mm x 4.6 mm i.d., 5 µm particle size)

was used at ambient temperature.

Mobile Phase: Acetonitrile: Phosphate Buffer 20 mM (pH 3.0) [40:60 v/v] Flow

rate: 1.0 mL/min

Injection volume: 20 µL

Detection: The elution was monitored at 223 nm using PDA detector.

8.1.5 Determination of analytical wavelength

The standard solution of METO and OLME were injected under the chromatographic

condition described above. Detection was carried out at different wavelength best

response was achieved at 223 nm with PDA detector. So both drugs were detected at this

analytical wavelength.

Fig. 8.1: Overlain zero-order absorption spectra of METO and OLME in Phosphate

buffer pH 6.8



Fig.: 8.2 Chromatogram of Standard Solution of METO and OLME at 223 nm

Table 8.1 System Suitability Parameters of Chromatogram for METO and

OLME

ParametersMETO ± RSD

(n = 7)OLME ± RSD

(n = 7)

Retention time (mm) 2.65 ± 0.11 6.35 ± 0.06

Tailing factor 1.23 ± 1.44 0.84 ± 0.99

Theoretical plates 2125 ± 0.78 4948 ± 0.51

Resolution 11.457 ± 0.56

8.1.6 Calibration Curve (Linearity)

Calibration curves were constructed by plotting peak areas Vs concentrations of METO

and OLME, and the regression equations were calculated. The calibration curves were

plotted over the concentration range 0.5-25 pg/m1 for METO and OLME. Accurately

measured working standard solutions of METO and OLME (0.1. 0.2. 1.0, 2.0, 3.0. 4.0

and 5.0 ml) were transferred to a series of 10m1 of volumetric flasks and diluted to the

mark with mobile phase. Aliquots of 20 µL samples were injected under the

chromatographic condition described above.



Table 8.2: Result of linearity study

Sr

No.

Conc. of

METO µg/ml

Conc. of

OLME µg/ml

Area of

METO at

223nm

Area of

OLME at

223nm

1 2 2 117834 186416

2 5 5 180830 271815

3 10 10 571917 884453

4 15 15 936043 1360110

5 20 20 1241979 1821588

6 25 25 1567187 2337773

7 30 30 1718204 27636962

Correlation coefficients(R2) 0.994 0.995

Slope of regression line 65366 93607

Y - intercept 71855 73388

Figure 8.3: Calibration curve of METO and OLME at 223 nm

y = 65366x - 71855R² = 0.994

0200000400000600000800000

10000001200000140000016000001800000

0 10 20 30

Are

a (m

AU

)

Concentration(ug/ml)

Calibration curve ofMetoprolol Succinate at

223nm

y = 93607x - 73388R² = 0.995

0

500000

1000000

1500000

2000000

2500000

3000000

0 10 20 30 40

Are

a (m

AU

)

Cocentration(ug/ml)

Calibration curve ofOlmesartan Medoxomil at

223nm



8.2 Formulation of granules and tablet in capsule dosage form of METO and

OLME (Carla Lopes M et al, 2006):

The formulation process of Granules and tablet-in-capsule systems can be divided into

three steps:

The formulation/production of tablet

Filling of these tablets into hard gelatin or HPMC capsules.

Formulation and Filling of granules-mini-tablets-in-capsule systems.

Granules and Tablet in capsule device was formed by filling size “0” capsule with two

formulations, one of Optimized formulation of Extended release mini tablet of

Metoprolol Succinate MT11, and other Optimized formulation of Immediate release

Granules of Olmesartan Medoxomil F3.

8.3 Evaluation of Granules and Tablet in Capsule dosage form:

1. Weight variation of capsule

To study weight variation, 20 capsule of formulation were weighted using an electronic

balance and average weight is calculated.

Table 8.3: Weight variation limit as per IP

Avg. weight of content % deviation allow

<300 10%

>300 7.5%

If more than 2 but less than 6 net weights determined by the test deviate by more than

10% but less than 25%, the net content are determined for additional 40 capsules and the

average is calculated for entire 60 capsules. The requirements are met, if the difference

does not exceed 10% of the average in more than 6 of the 60 capsule and if in no case any

difference exceeds 25%.

2. Dispersion time

This test is applicable for the dispersible dosage form. Place 2 capsule in 100 ml of water

and stir gently until completely disperse the granules in water. A smooth dispersion is

obtained is obtain which passes through a sieve screen with nominal mesh aperture of

710 mm (sieve no. 16).



3. Fourier transforms infrared (FTIR) Spectroscopic analysis

The FTIR spectrum of moisture free sample of formulation GT was recorded on IR

spectrophotometer by potassium bromide (KBr) pellet method. The scanning range was

4000 – 400 cm-1 and the resolution was 1 cm-1

4. Differential Scanning Colorimetric (DSC) Analysis

DSC scan of about 5mg accurately weighed sample and optimized formulations were

performed by using an automatic thermal analyzer system (DSC60 Shimadzu

Corporation, Japan) and spectrum was recorded.

5. In- vitro drug release study:

Conducting in vitro drug release studies assessed the “Granules and Tablet in capsule”

device to release the drug in two pulses with immediate first pulse as loading dose and

remaining second pulse after the required lag time. Drug release studies were carried out

using a USP XXIII dissolution rate test apparatus (Apparatus1, 50 rpm, 37 °C) for 2 hr in

0.1 M Hcl (900 ml) as the average gastric emptying time is about 2 hr. Then the

dissolution medium was replaced with pH 6.8 phosphate buffer (900 ml) for remaining

hours and tested for drug release up to complete drug release. At the end of the time

period 10 ml of the samples were taken and analyzed for Metoprolol Succinate and

Olmesartan medoxomil content. A 10 ml volume of fresh and filtered dissolution medium

was added to make the volume after each sample withdrawal. Sample was analyzed using

Shimadzu HPLC.

6. Accelerated Stability study:

Reproduce large scale batch in blister pack (PVDC – Alu blister packing), was placed for

stability study at 40˚C/75% RH for 3 months. Sample was collected after 1 month

interval and evaluated for dissolution in 6.8 pH phosphate buffer, USP- I basket

apparatus, 50 rpm.

7. Mathematical model fitting of obtained drug release data:

To analyze the mechanism of the drug release rate kinetics of the dosage form, the data

obtained were plotted as:

1) Cumulative percentage drug released Vs time (In-Vitro drug release plots)

2) Cumulative percentage drug released Vs Square root of time (Higuchi‘s plots)

3) Log cumulative percentage drug remaining Vs time (First order plots)



4) Log percentage drug released Vs log time (Pappas plots)

Zero order release rate kinetics:

To study the Zero – order release kinetics the release rate data are fitted to the following

equation.

F=K.t

Where,F is the fraction of drug release,

K is the release rate constant, and

t is the release time.

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

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

Higuchi release model:

To study the Higuchi release Kinetics, the release rate data were fitted to the following

equation,

F = K .t1/2

Where,F is the amount of drug release,

K is the release rate constant, and


When the data is plotted as a cumulative drug released versus square root of time, yields

a straight line, indicating that the drug was released by diffusion mechanism.

The slope is equal to ‘K‘.

Korsmeyer and Pappas release model:

The release rate data were fitted to the following equation,

Mt/M∞ = K. tn

Where,Mt/M∞ is the fraction of drug release,

K is the release rate constant,


n is the diffusion exponent for the drug release that is dependent on the shape of

the matrix dosage form.

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

with a slope equal to ‘n‘ and the ‘K‘ can be obtained from Y- intercept. For non Fickian



release the ‘n‘values falls between 0.5 and 1.0, while for Fickian (case І) diffusion n = 0.5

and zero order release (case ІІ transport) n=1.0.

8.4 Result and Discussion:

Evaluation of Granules and Tablet in Capsule dosage form:

1. Weight variation of capsule (Nagaraju R et al, 2002):

Average wt of capsule material:-211mg

As per USP specification the no capsule is out of range ±10% (i.e. 204.42 to 237.57mg)

As per weight variation test 20 capsule weight and average weight is determine which

was less than 300 mg. So as per IP 10% deviation allow to weight the powder. If more

than 2 capsules are outside the range, test will not comply with the specific requirement

of this test as per IP. All capsules come in these criteria. Not more than 2 capsule outside

the range. So this test was complying with requirement of as per IP.

2. Dispersion time

Hard gelatin capsule formulation is dispersed within 3 min. When capsule come in the

contact with 100 ml water it becomes soften. So it is break and a release granule into the

solution that time is called as dispersion time. All the capsules were disintegrating in the

range of 2.19 to 3 min.

3. In- vitro drug release study

Table 8.4: Drug release study of Granules & tablet in Capsule dosage form

Time(hour)%Cumulative Release of

Metoprolol Succinate%Cumulative Release ofOlmesartan Medoxomil

0 0 0

1 10.12 76.30%

2 21.32 100%

4 37.4 -

6 56.00 -

8 58.57 -

16 69.75 -

20 87.34 -

24 95.97 -



Figure 8.4 Dissolution profile of Granules and Tablet in capsule dosage form of

METO AND OLME

4. Differential Scanning Colorimetric (DSC) Analysis

100.00 200.00 300.00Temp [C]

0.00

10.00

20.00

30.00

40.00

mWDSC

62.91 x100C71.35 x100C

85.52 x100C

89.86 x100C

111.18 x100C

119.82 x100C

142.66 x100C

157.23 x100C

178.08 x100C

192.55 x100C

205.22 x100C

216.34 x100C

226.98 x100C

236.86 x100C 255.77 x100C261.50 x100C

269.98 x100C

277.60 x100C

Figure 8.5: DSC Spectra of Granules and Tablet in capsule dosage form of METO

AND OLME

The melting point of Metoprolol Succinate is 142-1450C and Olmesartan medoxomil is

180-1850C. From the above DSC spectra it can be seen that no change in the melting

point of both drug was observed. The result shows that there is no interaction between the

0

0.2

0.4

0.6

0.8

1

1.2

0

20

40

60

80

100

120

0 5 10 15 20 25 30

%Cu

mul

ativ

e dr

ug r

elea

se

Time(hour)

%CDR Vs Time

Metoprolol

Olmesartan



drug and other excipients and thermal degradation of drug was not occurred, so it can be

concluded that formulations is stable.

5. Fourier transforms infrared (FTIR) Spectroscopic analysis

Figure 8.6: FTIR Spectra of Granules and Tablet in Capsule dosage form

6. Mathematical model fitting of obtained drug release data:

The in-vitro release studies data was quantified to determine the release mechanism, to fit

various mathematical models and to determine which the best-fit model was. The various

parameters like the time exponent (n), the release rate constant (k) and the regression co-

efficient (R2) were also calculated. In a set of data, the model showing the highest value

to R2 was taken as the best-fit model.

Table 8.5: Data of various parameters of model fitting for Granules and Tablet in

Capsule Dosage form of METO and OLME

Formulation Zero order First order Higuchi Pappas

Final

Formulation

R2

0.952 0.785 0.994 0.993



From the above observation table in can be concluded that the Granules and Tablet in

Capsule device follows Higuchi Kinetic drug release.

Figure 8.7: Plot showing zero order and first order kinetics of formulation

Figure 8.8: Plot showing Higuchi and Pappas model of formulation

y = 0.026x + 1.434R² = 0.785

0

0.5

1

1.5

2

2.5

0 10 20 30log

%cu

mul

ativ

e dr

ug r

elea

se

Time

First order

y = 1.863x - 2.342R² = 0.993

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 1 2 3

log

%cu

mul

ativ

e dr

ug r

elea

se

log t

Korsmayer

y = 3.158x + 25.22R² = 0.952

0

20

40

60

80

100

120

0 10 20 30

%cu

mul

ativ

e dr

ug r

elea

se

Time

Zero order Release

y = 19.89x - 0.662R² = 0.994

0

20

40

60

80

100

120

0 2 4 6

%cu

mul

ativ

e dr

ug r

elea

se

t1/2

Higuchi



7. Accelerated Stability study

Table 8.6: Result of Accelerated stability study

Pack PVDC – Alu Blister

Condition 40˚C/75%RH

Batch Name MO

In – Vitro Drug Release

Time

(hr)

Initial After 1 Month

Metoprolol Olmesartan Metoprolol Olmesartan

0 0 0 0 0

1 10.12 76.30% 9.15 75.12%

2 21.32 100% 22.55 100%

4 37.4 - 36.45 -

6 56.00 - 55.67 -

8 58.57 - 57.89 -

16 69.75 - 68.80 -

20 87.34 - 86.24 -

24 95.97 - 96.88 -

Fig. 8.9: In – Vitro Drug Release study of Accelerated stability study at initial







Batch Name MO


Time

(hr)



0 0 0 0 0

1 10.12 76.30% 9.15 75.12%

2 21.32 100% 22.55 100%

4 37.4 - 36.45 -

6 56.00 - 55.67 -

8 58.57 - 57.89 -

16 69.75 - 68.80 -

20 87.34 - 86.24 -

24 95.97 - 96.88 -








Batch Name MO


Time

(hr)



0 0 0 0 0

1 10.12 76.30% 9.15 75.12%

2 21.32 100% 22.55 100%

4 37.4 - 36.45 -

6 56.00 - 55.67 -

8 58.57 - 57.89 -

16 69.75 - 68.80 -

20 87.34 - 86.24 -

24 95.97 - 96.88 -




Fig. 8.10: In – Vitro Drug Release study of Accelerated stability study at 1Month

The result of accelerated stability study showed that there was no change in the

formulation after 3 month. The drug release throughout 20 hours obtained within range of

targeted release profile. The related substance results showed that individual maximum

impurity below 0.5% and total maximum impurity below 1.0%. After 3 month

accelerated stability study the assay result was stable. From the stability result, concluded

that there was no change in the formulation after 3 month accelerated stability study. It

indicates that prepared formulation of Metoprolol Succinate and Olmesartan medoxomil

was stable.

8.5 Conclusion:

In the present work, an attempt had been made to develop Granules and Tablet in Capsule

dosage form of Metoprolol Succinate and Olmesartan Medoxomil.

Formulation GT showed the optimum desired dissolution range as well as other

parameters for both the drugs.

The stability studies revealed that there was no significant change in formulation

properties with aging at different storage condition.

0

0.2

0.4

0.6

0.8

1

1.2

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24

%Cu

mul

ativ

e dr

ug r

elea

se

Time(hour)

%CDR Vs Time

Metoprolol

Olmesartan



8.6 References:

Carla Lopes M, Jose Manual Souza Lobo, Jaao Pinto F, Paulo, Costa, Compressed mini-

tablet as a biphasic drug delivery system, Int. J. Pharm. 2006; 323: 93-100.

Kevin H. Vachhani*, Satish A. Patel, Himanshu H. Vachhani, development and

validation of rp-hplc method for the simultaneous estimation of metoprolol succinate and

olmesartan medoxomil in tablet dosage form, Int Jl of Institutional Pharmacy and Life

Sciences 2(2): March-April 2012.

Nagaraju R. Meera DS. Kaza R. Arvind V, Venkateswarlu V. Core-in-cup tablet design

of metoprolol succinate and its evaluation for controlled release, Curr Drug Discov

Technol. 2009; 6(4): pg no: 299-305.

Patent number: EP 2521540A2, Solid oral dosage form containing Olmesartan

medoxomil, publication 2012.

Chapter 9: Summary


9. SUMMARY:

The ultimate objective of any research done in the field of pharmaceuticals is to

serve the society's needs by developing a formulation that is highly efficient and most

effective. For the research to be successful, the work to be done should be logically and

properly based upon the literature surveyed. The objective of the present research is

formulation and evaluation of Granules and Tablet in Capsule dosage form of

antihypertensive drug combination. The aim of the study is to formulate and evaluate the

Granules and Tablet in Capsule dosage form containing Immediate release Granules of

Olmesartan Medoxomil 20 mg and Extended release tablet of Metoprolol Succinate 25

mg for treatment of Hypertension.

Prepared calibration curve of Olmesartan medoxomil in 0.1 N HCL and got sharp

peak of drug at absorbance maxima at 255 nm. Preliminary trail batches of Immediate

release granules of Olmesartan medoxomil were prepared using sodium starch glycolate

as a disintegrant by wet granulation and evaluated by various parameters like Angle of

repose, Carr’s index and Hausner’s rario. Sodium starch glycolate (SSG) in 3.5% got

maximum cumulative drug release after increasing concentration of SSG the cumulative

drug release was decrease. On comparison with Crosspovidone(CP) and cross carmellose

sodium(CCS) as same concentration of SSG, at 45 min 90.99% drug release obtain in

granules containing CP while 76.23% and 79.44% cumulative drug release obtained in

granules containing CCS and SSG respectively. So, 3.5% concentration of Cross

povidone was taken optimum for the immediate release granules of Olmesartan

medoxomil.

Calibration curve of Metoprolol Succinate was prepared in 0.1 N HCL and

phosphate buffer pH 6.8 and got sharp peak of drug at absorbance maxima at 222 nm.

Preliminary trail batches was prepared using HPMC K100M alone and HPMC K4M and

HPMC K100M in combine with using direct compression method and evaluated for

various parameters. Batches were failed to give dissolution for 24 hour. After that other

batches were prepared with using polymer HPMC K4M and HPMC K100M by wet

granulation method. And investigated that batches MT5 and MT6 gave the drug release

in the limit described in USP for Metoprolol extended release 24 hour.

Chapter 9: Summary


Optimization was done using two different factors by factorial design. Two

different factors are X1 is HPMC K4M concentration, X2 is HPMC K100M

concentration. Take six different response values like Q1, Q8, Q20, Q24, t50% and t80%. In

optimization all factor have p values less than 0.05 so they have significant effect on the

response value. On basis of regression equation factor X1 and X2 have negative effect on

Q1, Q8, Q20, Q24 and positive effect on t50% and t80%.

For all Factorial batches performed the evaluation parameters like flow property

(Carr’s index, Hausner’s ratio , angle of repose),weight variation, assay of METO,

dispersion time, kinetic drug release and In-vitro drug release . In flow property test all

batches have good Carr’s index, Hauser’s ratio, angle of repose. All the batches passed

the weight variation test and drug content in range of 97.41 % to 104.59 % and also

dispersion time came in the range of 2.19 min to 3 min. based on the optimization option

give in the Design expert check point batch was prepared and on comparison with check

point batch MT11 was found to have maximum f2 value 79.05 than other batches. So,

MT11 batch was taken as optimize batch for the preparation of Extended release tablet of

Metoprolol Succinate tablet.

Granules and Tablet in capsule device was formed by filling size “0” capsule with

two formulations, one of Optimized formulation of Extended release mini tablet of

Metoprolol Succinate MT11, and other Optimized formulation of Immediate release

Granules of Olmesartan medoxomil F3. HPLC method was done for the combine

estimation of METO and OLME. As per USP METO gave release NMT 20 % in first hr,

20% to 40% after 4 hr and after 8 hr 40 to 60% and after 20 hour not less than 80% drug

release and OLME gave the drug release 100% in 2 hr. So, granules and Tablet in capsule

dosage form of METO and OLME could be developed for large scale production.

List of Tables


List of Tables

Table

No.Title

Page

No.

2.1 Classification of "Superdisintegrants 8

2.2

Typical viscosity values for 2% (w/v) aqueous solutions of Methocel

Typical viscosity values for 2% (w/v) aqueous solutions of Methocel

(Dow Chemical Co.). Viscosities measured at 20°C

38

4.1 Materials used in the present investigation 46

4.2 Equipments / Machine used in the present investigation 47

5.1 Effect of Carr’s Index and Hausner’s Ratio on flow property 49

5.2 Effect of Angle of repose (ф) on Flow property 49

5.3 Result of Preformulation study of Metoprolol Succinate 50

5.4 Result of Preformulation study of Olmesartan Medoxomil 50

5.5 FTIR Spectrum bands of Metoprolol Succinate 53

5.6 FTIR Spectrum bands of Olmesartan Medoxomil 53

6.1 Absorbance values of OLME in 0.1 N Hcl 58

6.2 Ingredients and their function 59

6.3 Formulation for Preliminary trials using SSG 59

6.4 Result of Evaluation of Powder Blend of preliminary trials 61

6.5 Result of In-vitro Release of Preliminary trials 63

6.6 formulation of batches F1 to F3 64

6.7 Result of Evaluation of Powder Blend of Trial Batches F1 to F3 65

6.8 Result of In-vitro Release of Batches F1 to F3 66

6.9 formulation of batches using cross povidone 67

6.10 Result of Evaluation of Powder Blend of batches containing CP 68

6.11 Result of In-vitro Release of batches using cross povidone 69

7.1 Abs. values of Metoprolol in 0.1 N Hcl & pH 6.8 72

7.2 Ingredients and their function 74

7.3 Formulation trials using HPMC K100M 74

7.4 Weight Variation Specification as per IP 75

List of Tables


7.5 Result of Precompression parameters of trials using HPMC K100M 76

7.6 Result of Post compression parameters of trials using HPMC K100M 77

7.7 Result of In-vitro Release of trials using HPMC K100M 77

7.8 Formulation of trial via wet granulation 79

7.9 Evaluation of Powder Blend of trial via wet granulation 79

7.10 Evaluation of Tablets of trial via wet granulation 80

7.11 Result of In-vitro release of trial via wet granulation 80

7.12 USP Limit for drug release for Metoprolol Succinate ERT 80

7.13 32 Full Factorial Design Layouts 83

7.14 Formulation of ERT using 32 Full Factorial Design 83

7.15 Evaluation of Powder Blend of ERT using 32 Full Factorial Design 84

7.16 Evaluation of ERT using 32 Full Factorial Design 84

7.17 In vitro drug release study for factorial batches 88

7.18Effect of Independent variable on dependent variable by 32 full

factorial design of Metoprolol Succinate for Extended Release89

7.19Summary of regression analysis of Metoprolol Succinate tablet for

Extended release89

7.20 Composition of final Optimized Formula M16 95

7.21Comparison between the Experimental (E) and Predicted (P) values

for the most probable optimal formulation95

8.1System Suitability Parameters of Chromatogram for METO and

OLME101

8.2 Result of linearity study 103

8.3 Weight variation limit as per IP 104

8.4 Drug release study of Granules & tablet in Capsule dosage form 106

8.5Data of various parameters of model fitting for Granules and Tablet

in Capsule Dosage form of METO and OLME108

8.6 Result of Accelerated stability study 110

List of Figures


List of Figures

Figure

No.Title

Page

No.

2.1 Granules and Tablets-in-a capsule technology 7

2.2 Size of the capsule to fill weight 9

2.3

Characteristic representation of plasma concentration of a

Conventional immediate release (IR), Sustained release and Zero

order Controlled release (ZOCR)

9

2.4 Chemical structure of Metoprolol Succinate 17

2.5 Chemical structure of Olmesartan Medoxomil 20

2.6 Chemical structure of Hypromellose 23

2.7 Chemical structure of sodium starch glycolate 25

2.8 Chemical structure of croscarmellose sodium 27

2.9 Chemical structure of Crospovidone 28

5.1 FTIR of Metoprolol Succinate 51

5.2 FTIR of Olmesartan Medoxomil 52

5.3 FTIR of Metoprolol Succinate + Olmesartan Medoxomil 52

5.4 DSC of Metoprolol Succinate 54

5.5 DSC of Olmesartan medoxomil 54

5.6 DSC of Metoprolol Succinate + Olmesartan Medoxomil 55

6.1 UV spectra of Olmesartan medoxomil 57

6.2 Calibration curve of OLME in 0.1 N Hcl 58

6.3 Comparative dissolution profile of Preliminary trails 64

6.4 Comparative dissolution profile of F1 to F3 67

6.5 Comparative dissolution profile of batches using cross povidone 70

6.6 FTIR of Olmesartan Medoxomil granules formulation 70

6.7 DSC of Olmesartan medoxomil Granules Formulation 71

7.1 UV spectra of Metoprolol Succinate 72

7.2 Calibration curve of METO in 0.1 N Hcl 73

7.3 Calibration curve of METO in phosphate buffer pH 6.8 73

7.4 Comparative dissolution profile of trials using HPMC K100M 78

List of Figures


7.5 Comparative dissolution profile of trial via wet granulation 81

7.6 Photographs of ERT of METO at Different time interval 81

7.7 Effect of concentration of Polymers on Hardness 85

7.8 Effect of concentration of Polymers on Friability 86

7.9 Effect of concentration of Polymers on Assay of Tablet 86

7.10 Effect of concentration of Polymers on Weight variation 86

7.11 FTIR of Metoprolol Succinate ER tablet formulation 87

7.12 DSC of Metoprolol Succinate ERT Formulation 88

7.13Contour plot and 3 D surface showing effect of HPMC K4M and

HPMC K100M on the cumulative drug release at 1st hour92

7.14Contour plot and 3 D surface plot showing effect of HPMC K4M

and HPMC K100M on the cumulative drug release at 8th hour92


and HPMC K100M on the cumulative drug release at 20th hour92

7.16Contour plot and 3 D surface showing effect of HPMC K4M and

HPMC K100M on the cumulative drug release at 24th hour93


and HPMC K100M on the T50%

93


and HPMC K100M on the T80%

94

7.19 Overlay of contour plot of all Responses 94

8.1Overlain zero-order absorption spectra of METO and OLME in

Phosphate buffer pH 6.8100

8.2Chromatogram of Standard Solution of METO and OLME at 223

nm101

8.3 Calibration curve of METO and OLME at 223 nm 102

8.4Dissolution profile of Granules and Tablet in capsule dosage form

of METO AND OLME107

8.5DSC Spectra of Granules and Tablet in capsule dosage form of

METO AND OLME107

8.6 FTIR of Granules and Tablet in Capsule formulation 108

8.7 Plot showing zero order and first order kinetics of formulation 109

8.8 Plot showing Higuchi and Pappas model of formulation 109

List of Figures


8.9In – Vitro Drug Release study of Accelerated stability study at

initial110

8.10In – Vitro Drug Release study of Accelerated stability study at

1Month111

List of Abbreviations



Abbreviation Full Form

ER Extended Release

PEG Polyethylene glycol

DDS Drug delivery system

HPMC Hydroxypropylmethylcellulose

Css,max Maximum steady state concentration

Css,min Minimum steady state concentration

MTC Minimum Toxic Concentration

MEC Maximum Effective Concentration

Vd Volume of Distribution

USP United States Pharmacopoeia

API Active pharmaceutical ingredient

HPLC High performance liquid chromatography

TD Tapped density

BD Bulk density

MCC Micro crystalline cellulose

RH Relative Humidity

DSC Differential scanning colorimetric

UV Ultra violet

%CDR Percentage Cumulative Drug Release

BD Bulk Density

API Active Pharmaceutical Ingredient

AUC Area Under Curve

BCS Biopharmaceutical Classification System.

C-max Maximum Peak Plasma Concentration

DT Disintegration Time

FDA Food and Drug Administration of the USA

HPLC High Performance Liquid Chromatography

MCC Microcrystalline Cellulose

IPA Isopropyl Alcohol



SSF Sodium Steryl Fumarate

Kp Kilo pound

pH The Negative Logarithm of the Hydrogen ion concentration

pKa The Negative Logarithm of the Dissociation constant

Ppm Parts Per Million

Rpm Revolution Per Minute

T-max Time to achieve Peak Plasma Concentration

ERT Extended Release Tablet

IR Immediate release

CP Crospovidone

METO Metoprolol Succinate

OLME Olmesartan Medoxomil

Documents

FORMULATION AND EVALUATION OF GRANULES AND ...gnu.inflibnet.ac.in/bitstream/123456789/891/1/MT-584-Khartri... · Use of Metoprolol Succinate and Olmesartan ... 7 FORMULATION AND OPTIMIZATION