“VARENICLINE TARTARATE ORODISPERSIBLE

TABLETS:DESIGN, OPTIMIZATION AND

EVALUATION”

A Dissertation submitted to

JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY, KAKINADA.

In Partial Fulfillment of the Curricular Requirements for the Degree Of

MASTER OF PHARMACY
IN
PHARMACEUTICS

By

BANDARU DURGA BHAVANI

[213M1S0303]
Under The Supervision of

V. KRISHNA VENI M. Pharm

Associate Professor

Department of Pharmaceutics

2022-2023

KORINGA COLLEGE OF PHARMACY

(Affiliated to JNTUK, Kakinada and Approved by AICTE & PCI, New Delhi)

Korangi-533461, Tallarevu (M), East Godavari (Dist), Andhra Pradesh.

 KORINGA COLLEGE OF PHARMACY

Tallarevu Mandal, Korangi-533461, East Godavari, A.P, India.

Affiliated to Jawaharlal Nehru Technology University,
Kakinada and Recognized by AICTE, India

CERTIFICATE

This is to certify that the thesis entitled “VARENICLINE TARTARATE ORODISPERSIBLE

TABLETS: DESIGN, OPTIMIZATION AND EVALUATION” is being submitted by
BANDARU DURGA BHAVANI (Regd no: 213M1S0303), in partial fulfillment of curricular
requirements of Master of Pharmacy degree from Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh is a record of bonafide work carried out by her under my supervision
during academic year 2022-2023. The results embodied in this thesis have not been submitted to
any other university or institute for award of any degree or diploma.

Station: Korangi

Date:

Signature of Supervisor

V. KRISHNA VENI
M. Pharm

Associate Professor
Department of Pharmaceutics
 KORINGA COLLEGE OF PHARMACY

Tallarevu Mandal, Korangi-533461, East Godavari, A.P, India.

Affiliated to Jawaharlal Nehru Technology University,
Kakinada and Recognized by AICTE, India

CERTIFICATE

This is to certify that the thesis entitled “VARENICLINE TARTARATE ORODISPERSIBLE

TABLETS: DESIGN, OPTIMIZATION AND EVALUATION” is being submitted by
BANDARU DURGA BHAVANI (Regd no: 213M1S0303), in partial fulfillment of curricular
requirements of Master of pharmacy degree from Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh under supervision of V. KRISHNA VENI, M. Pharm Associate Professor,
Department of Pharmaceutics during academic year 2022-2023. The work is original and has not
been submitted in part orfull for the award of any other degree or diploma.

Station: Korangi

Date:

PRINCIPAL

Dr. N. SUVARNA JYOTHI

M. Pharm, Ph. D
 DECLARATION
I, hereby declare that the subject matter embodied in this thesis “VARENICLINE
TARTARATE ORODISPERSIBLE TABLETS: DESIGN, OPTIMIZATION AND
EVALUATION” which is being submitted by me in partial fulfillment of curricular
requirements of Master of Pharmacy degree from Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh. The results of investigation carried out by me under supervision of
Dr. N. SUVARNA JYOTHI, M. Pharm, Ph. D Associate Professor and Principal of Koringa College of
Pharmacy, Korangi - 533461, during academic year 2022-2023. I further declare that the work is
original and has not been submitted in part or full for the award of any other degree or diploma.

Station: Korangi
Date: BANDARU DURGA BHAVANI

Register No: 213M1S0303

 KORINGA COLLEGE OF PHARMACY

Tallarevu Mandal, Korangi-533461, East Godavari, A.P, India.

Affiliated to Jawaharlal Nehru Technology University,
Kakinada and Recognized by AICTE, India

EVALUATION CERTIFICATE

This is to certify the dissertation work entitled “VARENICLINE TARTARATE

ORODISPERSIBLE TABLETS: DESIGN, OPTIMIZATION AND EVALUATION” is

being submitted by BANDARU DURGA BHAVANI (Regd no: 213M1S0303), is suitable for the partial

fulfillment of curricular requirements of Master of Pharmacy in 2022-2023 to the Jawaharlal Nehru

Technological University, Kakinada, Andhra Pradesh.

Station:Korangi

Date :

Evaluator’s Signature

External :

Internal :
 ACKNOWLEDGEMENT
I would like to express my most sincere appreciation to Professor V. KRISHNA VENI. I feel
so fortunate and pleasant to have her as my guide. My immensely thankful to him who brought
me into an amazing world of pharmacy and helped me throughout the work. I am very thankful
to Sri. D. Janardhan Rao, Chairperson Sri. P. Kanakaraju, Secretary and Correspondent,
Smt. P. Nagamani, Director, Sri. Ch. Kaliki Murthy, Director of Koringa College of
Pharmacy for providing all the facilities and support during our academic period of the
study.

We wish to express our deep sense of gratitude to Dr. N. Suvarna Jyothi Principal,
Koringa College of pharmacy for her constant encouragement throughout the entire period,
which helped us in successful completion of this work.

I am very grateful to Dr. N. SUVARNA JYOTHI (PROFESSOR AND PRINCIPAL), V. KRISHNA

VENI (ASSOSIATE PROFESSOR) for their helpful suggestions during my project work. My sincere
thanks to all other teaching and nonteaching staff of Koringa College of pharmacy for their kind
support.

I am very fortunate to have friends like Arshika Farzeen, C. Sarvani and B. Hema
who I am grateful for their help whenever and wherever required, also for their emotional
support and encouragement.

I would like to convey my thanks to my parents and friends who supported me

regarding my project work.

I would like to thank all whose blessings and wishes are always with me and the many
people, in many countries, who so generously contributed to the work presented in this thesis
and my apologies to everyone, for not being able to mention each one personally. Above all
“Thanks” to the almighty who gave me this opportunity to extend my gratitude to one and all
who helped and guided me throughout my life. I bow my head in complete submission before
him for the blessings poured on me.

(B. DURGA BHAVANI)

ABSTRACT
Varenicline is a prescription medicine which is used to quit smoking. To increase your chance of success,

use this medication with a stop-smoking program that includes education, support and counselling.

Quitting smoking lowers your risk of heart and lung disease, as well as cancer. Varenicline is a medicine

approved by the FDA which helps people to stop smoking. To improve bioavailability and patient

compliance, orodispersible drug delivery systems are used mostly because Orodispersible tablets are the

novel dosage form which quickly disintegrates in the mouth (1-3 min) without chewing upon oral

administration and without the need of water. As compared to conventional tablets and capsules

orodispersible tablets (ODT) are getting the attention from the last three decades because it has better

patient compliances, better solubility, and stability. Orodispersible tablets are the dosage forms which can

be prepared by different techniques. The choice of drug molecule and excipients is decided by the method

employed as all the drug candidates and the excipients are not suitable for the methods. The aim of the

present work is to statistically optimize the formulation parameters of the orodispersible tablets [ODT] of a

model drug, Varenicline Tartarate by using Design Expert Software. Varenicline Tartarate being a BCS

class I drug has high solubility and permeability which is widely used in smoking cessation. The

formulations are optimized with an aim of designing an optimum formulation for Varenicline Tartarate to

improve immediate release, therapeutic adherence and ease of administration. Varenicline works by

blocking nicotine's effects in the brain that make you want to smoke. Varenicline blocks the ability of

nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system,

believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking.

Keywords: Varenicline, smoking, orodispersible tablets, solubility, bioavailability, nicotine

 CONTENTS
S. No Page no
Abbreviations i

List of Tables ii

List of Figures iv
Aim and Objective 1
Plan of work 2
CHAPTER 1
Introduction
1.1 Oral drug delivery 3
1.2 Orodispersible tablets 3
1.3 Formulation of ODTs 4
1.4 Super disintegrants 5
1.5 Swelling 6
1.6 Porosity and capillary action – Wicking 6
1.7 Methods employed in formulation of ODTs and Evaluation 7
CHAPTER 2
Literature review
2.1 Literature review on Varenicline Tartarate 9
2.2 Literature review on Oro dispersible tablets 9
CHAPTER 3
Drugs and Excipients & Materials and Equipments used
3.1 Drug profile 11
3.2 Excipient profile 13
Materials and Equipments used
3.3 Materials used 24
3.4 Equipments used 25
CHAPTER 4
 Formulation Development & experimental work
4.1 Analytical Methodology 26
4.2 Experimental Design 26
4.3 Preparation of Varenicline Tartarate ODTs 27
4.4 Characterization and evaluation 28
4.5 Statistical Analysis 32
4.6 Kinetic model fitting 33
CHAPTER 5
Results and Discussion
5.1 Results 36
5.2 Discussions 49
CHAPTER 6
Summary and Conclusion
6.1 Summary 54
6.2 Conclusion 55
6.3 Significant contribution of the research project 55
CHAPTER 7
7 References 56
 List of abbreviations

ABBREVIATIONS

IUPAC- International Union of Pure and Applied Chemistry

BCS - Biopharmaceutical Classification System

ODT - Orodispersible tablets

VT - Varenicline Tartarate

µg - Microgram

g - Grams

cm2 - Square centimeter

Kg - Kilogram

Mg - Milligram

Min - Minutes

mL - Milliliter

°C - Degree Celsius

RPM - Revolution per minute

s.d - Standard Deviation

UV - Ultra Violet

Koringa College of Pharmacy Page i

 List of tables

List of tables

S. No Table No. Title Page No.

1 3.1 Materials used in research work 24

2 3.2 Equipment used in research work 25

3 4.1 Coded and actual values of independent variables 28

4 4.2 Formulae of different formulations 28

5 4.3 Nature of flow based on angle of repose 29

6 4.4 Nature of flow based on compressibility index and 30

Hausner’s ratio
7 4.5 Constraints of dependent variables in optimization 33

8 4.6 Formulae of optimized formulations 33

9 4.7 Determination of the type of diffusion 35

Calibration curve for estimation of Varenicline Tartarate

10 5.1 36
in Phosphate buffer pH 6.8

Results of Pre compression and post compression

11 5.2 38
evaluation parameters of formulations

13 5.3 Summary of results of regression analysis for responses 39

14 5.4 ANOVA for the response, Disintegration time 39

15 5.5 ANOVA for the response, Wetting time 40

Koringa College of Pharmacy Page ii

 List of tables

List of tables

Proportions of factors in Optimized Varenicline

16 5.6 44
Tartarate ODTs

17 5.7 The values of responses of the optimized formulation 44

18 5.8 Relative error for optimized formulation 45

19 5.9 In vitro drug release profiles of pure drug and 46

optimized formulation

20 5.10 Correlation coefficient and kinetic model fitting of in 47

vitro drug release studies

Koringa College of Pharmacy Page iii

 List of figures

LIST OF FIGURES

S.No Figure Page no

Title
No.
1 1.1 A few mechanisms of disintegration by super Disintegrants 06

2 1.2 Disintegration by swelling and wicking mechanisms 07

3 1.3 Various Evaluation and characterization methods 07

4 3.1 Structure of Varenicline Tartarate 11

5 3.2 Structure of Crospovidone 14

6 3.3 Structure of PEG 4000 16

7 3.4 Structure of Starch 17

8 3.5 Structure of MCC 18

9 3.6 Structure of Magnesium stearate 19

10 3.7 Structure of Talc 20

11 3.8 Structure of Aspartame 21

12 3.9 Structure of Croscarmellose sodium 23

Standard calibration for the estimation of Varenicline Tartarate

6 5.1 36
in phosphate buffer of pH 6.8

7 5.2 3D surface plot and contour plot of AB term for Disintegration 41

Time
8 5.3 3D surface plot and contour plot of AB term for Wetting time 42

9 5.4 Perturbation plot and interaction plot of disintegration time 43

Koringa College of Pharmacy Page iv

 List of figures

10 5.5 Perturbation plot and interaction plot of wetting time 43

11 5.6 Overlay plot of optimized formulation OF 44

12 5.7 The desirability bar graph of all the terms of optimized 45

Formulation
13 5.8 The ramp graph of all the terms of optimized formulation 46

14 5.9 Dissolution profile of pure drug & optimized formulation 47

15 5.10 Kinetic model graphs of optimized formulation 48

Koringa College of Pharmacy Page v

 Aim and Objective

AIM AND OBJECTIVES OF WORK

The oral drug delivery systems are most widely used as they are most convenient means of

administration.

Aim

The aim of the present work is to statistically optimize the formulation parameters of the

orodispersible tablets [ODT] of a model drug, Varenicline Tartarate [VT] – a BCS class I

drug, using Design Expert Software. Varenicline Tartarate being a BCS class I drug has high

solubility and permeability which is widely used in smoking cessation. The formulations are

optimized with an aim of designing an optimum formulation for Varenicline Tartarate to

improve immediate release, therapeutic adherence and ease of administration.

Objectives

The objectives of the present work are

 Formulation of VT-ODT with super disintegrant.

 Statistical optimization of formulation parameters by Factorial Design.

 Evaluation and characterization of the formulated VT-ODT.

 Preparation of optimized formulation.

 In vitro evaluation of the optimized formulation. 

Koringa College of Pharmacy Page 1

 Aim and Objective

PLAN OF WORK

Formulation development

Preformulation studies
Standard calibration curve

Experimental design

Formulation of VT-ODT

Evaluation of VT- ODT

DISINTEGRATION TIME EFFERVESCENCE TIME

Statistical optimization of formulations

Formulation of optimised VT-ODT

In-vitro evaluation of the final optimised formulation

Conclusion

Koringa College of Pharmacy Page 2

 Introduction

1.1 ORAL DRUG DELIVERY [1-3]

Oral route remains as the most preferable route for the administration of the

drugs. Different factors like physiology, site of absorption, physicochemical factors of

the drug and residence time at the site of absorption should be considered for the

achievement of successful delivery of drug. Solubility of a drug and permeability can be

crucial in the effective delivery of the drug molecules.

Novel technologies are being employed in so that the performance can be

improved without compromising the patient compliance.

1.2 ORODISPERSIBLE TABLETS [4-9]

Also known as mouth dissolving tablets, ODTs differ from traditional tablets in

the region they are designed to be dissolved i.e., the tongue rather than GIT. The ODTs

serves as an alternative dosage form for patients who experience dysphagia (difficulty in

swallowing) or for where compliance is a known issue and therefore an easier dosage

form to take ensures therapeutic adherence.

1.2.1 Ideal characteristics

ODTs should depict some ideal characteristics to distinguish them from

traditional conventional dosage forms. Important desirable characteristics of these

dosage forms include

 No water requirement for administration.

 Provide pleasant feeling in the mouth.

 Be portable without fragility concern.

 Leave negligible or no residue in the mouth after oral administration.

 Exhibit low sensitivity to altered environmental conditions such as humidity and

temperature.

 Allow high drug loading.

Koringa College of Pharmacy Page 3

 Introduction

 Adaptable and amenable to conventional processing and packaging equipment at

nominal expenses.

1.2.2 Advantages

 ODT can be administered by people of all age groups and those with difficulty in

swallowing.

 They are known to improve therapeutic efficacy.

 As there is no requirement of water, they can be taken at any point of time.

 Cost effective and allows high drug loading

1.2.3 Disadvantages

 Hygroscopic in nature

 May sometimes leave taste in mouth

 At times may be fragile

1.2.4 Mechanism of drug release from ODT

The various mechanisms for drug release may include

⚫ Highly swellability and disintegration

⚫ Chemical reaction
⚫ Capillary action
1.3 FORMULATION OF ODTS [10, 11]
The main aim in formulating any ODT is fast disintegration and quick release.

Hence, the selection of drug as well as the excipients play a crucial role in the

formulation.

1.3.1 Selection of API

The following are the desirable characteristics of a drug molecule to be formulated as

ODT

 Acceptable taste

 Preferably small to moderate molecular size

Koringa College of Pharmacy Page 4

 Introduction

 Good solubility and permeability

 Partially unionized at oral cavity pH

1.3.2 Selection of excipients

Major adjuvants in ODTs are at least one disintegrant, a diluent, a lubricant, and

optionally, a swelling agent, sweeteners, and flavouring agents etc. Ideal properties may

include

 Must disperse and dissolve in the mouth within a few seconds without leaving

any residue

 Should mask the unacceptable taste of drug, if any and leave a pleasant mouth

feel.

 Enables sufficient drug loading and remains relatively unaffected by changes in

humidity or temperature

1.4 SUPER DISINTEGRANTS [5-7, 12]

Disintegrants are the excipients which aid the process of disintegration of the

tablets once they enter the GIT. The superdisintegrants are used for immediate

disintegration of the formulation and thus widely used as major and significant excipient

in the ODTs.

1.4.1 Mechanism of action of superdisintegrants

The major mechanisms employed by the superdisintegrants to aid disintegration

process include

 Swelling

 Wicking

 Deformation

 Enzymatic reaction

 Particle repulsive forces

Koringa College of Pharmacy Page 5

 Introduction

 Heat of wetting

 Combination of wicking and swelling

Figure 1.1: A few mechanisms of disintegration by super Disintegrants

The major mechanisms of superdisintegrants employed in the current research is

swelling and wicking.

1.5 SWELLING

Swelling is believed to be a mechanism in which certain disintegrating agents

impart the disintegrating effect. When in contact with water, the adhesiveness of other

ingredients in a tablet is overcome causing the tablet to fall apart.

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 again slows down.

1.6 POROSITY AND CAPILLARY ACTION – WICKING

Effective disintegrants that do not swell are believed to impart their disintegrating

action through porosity and capillary action. Tablet porosity provides pathways for the

penetration of fluid into tablets. The disintegrate particles (with low cohesiveness &

compressibility) themselves act to enhance porosity and provide these pathways into the

Koringa College of Pharmacy Page 6

 Introduction

tablet. Liquid is drawn up or “wicked” into these pathways through capillary action and

rupture the interparticulate bonds causing the tablet to break apart.

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/excipient 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.

Figure 1.2: Disintegration by swelling and wicking mechanisms

1.7 METHODS EMPLOYED IN FORMUATION OF ODTS AND EVALUATION

[13-21]

1.7.1 The methods of formulation include

 Wet granulation

 Dry granulation

Koringa College of Pharmacy Page 7

 Introduction

 Direct Compression

The choice of drug molecule and excipients is decided by the method employed as all the

drug candidates and the excipients are not suitable for the methods.

1.7.2 Evaluation

The ODTs are evaluated for general precompression parameters and post

compression parameters of tablets. They include

 Flow properties

 General appearance

 Size & Shape

 Unique identification marking

 Organoleptic properties

 Hardness and Friability

 Disintegration time

 Dissolution

The ODTs are specifically evaluated for the following parameters in the current

research

 Effervescent time

 Content uniformity

 Moisture content

 Disintegration time

Koringa College of Pharmacy Page 8

 Literature review

2.1. LITERATURE REVIEW ON VARENICLINE TARTARATE

 [22]
Amin et al., (2023) have performed the preformulation studies of varenicline for

formulating as oral disintegrating film and concluded that the drug molecule is

suitable to be administered orally. they observed that the drug molecule is stable in

solid as well as the liquid states.

 [23]
Kwak SS et al., (2022) formulated immediate release tablet of the drug molecule

and performed the pharmacokinetic studies on humans. They concluded that the wet

granulation method was preferred for tablet preparation. Their results indicated the

bioequivalence of the optimized formula and the marketed product.

2.2. LITERATURE REVIEW ON ORODISPERSIBLE TABLETS

 [24]
Fukami et al., (2006) prepared rapidly disintegrating tablets using glycine as a

disintegrant. They evaluated the disintegration behavior of tablets in oral cavity and

concluded that the fastest disintegration is due to excellent wetting property. They

also studied the effect of ethanzamide and ascorbic acid on disintegration time and

depicted the influence of ascorbic acid on disintegration.

 [25]
Udupa et al., (2001) formulated Nimesulide dispersible tablets by direct

compression method, using microcrystalline cellulose as directly compressible

vehicle, starch and sodium starch glycollate combination as super disintegrant. They

reported that the optimized formula showed less disintegration time and more

dissolution than marketed product.

 [26]
Ohkuma et al., (2001) prepared and evaluated a fast disintegrating tablet

containing Nicordial and suggested that formulation had masking effect against the

bitter taste and irritation of the drug.

 [27]
Sreenivas et al., (2005) prepared Ondansetron hydrochloride mouth

disintegrating tablets using various disintegrant like crospovidone, croscarmellose

Koringa College of Pharmacy Page 9

 Literature review

sodium, pre-gelatinized starch, sodium starch glycolate and low-substituted hydroxyl

propyl cellulose (L-HPC) by direct compression method. They concluded that

formulation with 10% concentration of crospovidone and croscarmellose sodium

were best for Ondansetron hydrochloride mouth disintegrating tablets.

Koringa College of Pharmacy Page 10

 Drug and excipient profiles & Materials and Equipment used

3.1. Drug Profile [28 -34]

Name of the drug : Varenicline tartarate

Chemical Name : 7,8,9,10-tetra hydro -6, 10- methano -6H-

pyrazino[2,3- h][3] benzazepine, (2R,3R) -2, 3-

dihydroxybutanedioate (1:1)

Structure

Figure 3.1: Structure of Varenicline tartarate

Molecular Formula : C13H13N3 • C4H6O6

Molecular Weight : 361.35

Synonyms : Vareniclina, vareniclinum

Category : Smoking Cessation

Description: Varenicline, as the tartrate salt, is a powder

which is a white to off-white to slightly yellow

solid

Solubility : 0.0877mgmL

Koringa College of Pharmacy Page 11

 Drug and excipient profiles & Materials and Equipment used

logP : 1.39

Dose : 0.5mg to 1mg

Clinical Pharmacology

Pharmacodynamics

Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate

this system while displacing nicotine at its sites of action in the brain.

Mechanism of action

Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist.

The drug shows high selectivity for this receptor subclass, relative to other nicotinic

receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma

delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively

inhibits the ability of nicHFotine to bind to and activate the alpha-4 beta-2 receptor. The

drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it

is presumed that this activation eases withdrawal symptoms.

Pharmacokinetics

Absorption: Maximum plasma concentrations of varenicline typically occur within 3-4

hours after oral administration. Varenicline exhibits linear pharmacokinetics over the

recommended dosing range after single or repeated doses.

Distribution: Plasma protein binding of varenicline (less than 20%) is independent of age

and renal function of the person.

Metabolism Varenicline has minimal metabolism, with 92% of the drug excreted

unchanged in the urine. The elimination half-life (t1/2) of varenicline is around 24 hours.

Koringa College of Pharmacy Page 12

 Drug and excipient profiles & Materials and Equipment used

Excretion: varenicline is primarily eliminated via the kidney through glomerular filtration

along with active tubular secretion, possibly through the organic cation transporter, OCT2

Dosing: Varenicline is taken as a tablet and comes in 0.5 mg and 1 mg strength oral tablets

Toxicity: There are currently no antidotes to varenicline. If there are serious adverse effects,

including psychiatric conditions or skin hypersensitivity reaction, discontinue varenicline

immediately. Varenicline therapy may stop abruptly with no side effects, and there is no

need for a taper. Evaluation of prolonged exposure to varenicline in adults has not revealed

any alteration of hematological, biochemical, and anatomicopathological parameters.

Varenicline is removed by dialysis in patients with end-stage renal disease; however, there is

no experience in dialysis following an overdose.

Side effects:

Stop using varenicline if you have

 Seizure (convulsions)

 Thoughts about suicide or hurting yourself;

 Strange dreams, sleepwalking, trouble sleeping;

 New or worsening mental health problems--mood or behavior changes,

depression, agitation, hostility, aggression;

 Heart attack symptoms--chest pain or pressure, pain spreading to your jaw or

shoulder, nausea, sweating;

 Stroke symptoms--sudden numbness or weakness (especially on one side of the

body), slurred speech, problems with vision or balance.

3.2. EXCIPIENT PROFILE

3.2.1. Crospovidone [35, 36]

Koringa College of Pharmacy Page 13

 Drug and excipient profiles & Materials and Equipment used

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

practically tasteless, odorless or nearly odorless, hygroscopic powder.

Synonyms: Crosslinked povidone; E1202; Kollidon CL-M; polyplasdone XL;

polyplasdoneXL-10; Polyvinylpolypyrrolidone; PVPP; 1-vinyl-2-pyrolidone homopolymer.

Figure 3.2: Structure of Crospovidone

Physical and Chemical Properties

Form : Powder

Odour : Nearly odourless

Colour : White to creamy white

pH value : 5.0-8.0 (1%w/v aqueous slurry)

melting point : 150 °C

Boiling point : The product is a non-volatile solid.

Bulk density : Approx. 0.35g/cm3

Vapour density : The product is a non-volatile solid.

Solubility : Practically insoluble in water and most common organic

solvents

Evaporation rate : The product is a non-volatile solid

Koringa College of Pharmacy Page 14

 Drug and excipient profiles & Materials and Equipment used

Handling and Storage:

Precautions for safe handling

Handle in accordance with good industrial hygiene and safety practice. Closed containers

should only be opened in well-ventilated areas.

Conditions for safe storage, including any incompatibilities

Further information on storage conditions: Keep container tightly closed and dry. Protect

against heat.

Swelling capacity: The swelling of disintegrants depends on several factors such as

chemical structure, degree of crosslinking, and porosity.

Incompatibilities: Crospovidone is compatible with most organic and inorganic

pharmaceutical ingredients. When exposed to a high water level, crospovidone may form

molecular adducts with some materials.

Uses:

 It is medically used for the treatment of some intestinal disorders as solubilizing

excipients to improve the bioavailability of drugs and as germicides in wound

treatment.

 It is also commonly used as a clarifier in alcoholic and non alcoholic beverages.

3.2.2. PEG 4000 [37, 38]

Description: PEG-4000 is a water soluble, waxy solid that is used extensively in the several

industries such as rubber etc.

Structure:

Koringa College of Pharmacy Page 15

 Drug and excipient profiles & Materials and Equipment used

Figure 3.3: Structure of PEG 4000

Nonproprietary name:

BP: Macrogols

JP: Macrogol 4000, Macrogol 1500, Macrogol 1500, Macrogol 6000, Macrogol 20000

PhEur: Macrogols; USP-NF: Polyethylene glycol

Synonym: Carbowax, carbowax sentry, lipoxol

Chemical name: a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl)

pH: 3.6-10.0

Density: 1.11-1.14 g/cm3 at 25 °C

Melting point: 53-58 °C

Solubility: Soluble in water, acetone, alcohols, benzene, glycerin and glycols.

Incompatibilities: PEG is incompatible with phenol.

Uses:

 Used in a variety of pharmaceutical formulations, including parenteral, topical,

ophthalmic, oral, and rectal preparations.

 It has laxative effect.

3.2.3. Starch [39, 40]

Koringa College of Pharmacy Page 16

 Drug and excipient profiles & Materials and Equipment used

Description: Starch is a soft, white, tasteless powder that is insoluble in cold water, alcohol,

or other solvents. Starch is a polysaccharide comprising glucose monomers joined in a 1,4

linkages.

Structures:

Figure 3.4: Structure of starch

Non proprietary name: Amylum

Synonym: Cellulose, dextrin, dextrose, fructose, galactose, glucose

Colour: white

Taste: tasteless

Odour: odorless powder

Solubility: Insoluble in cold water or alcohol.

pH: 7

Bulk density: 0.50 - 0.58 g/cc

Melting point range: 256 – 258 °C

Incompatibilities: Starch is incompatible with strongly oxidizing substances. Coloured

inclusion compounds are formed with iodine. Uses: Used in industries like agrochemical,

food, medical, textile etc.

3.2.4. MCC [41]

Koringa College of Pharmacy Page 17

 Drug and excipient profiles & Materials and Equipment used

Description: It is purified, partially depolarized cellulose that occurs as a white, odourless,

tasteless, crystalline powder composed of porous particles.

Structure:

Figure 3.5: Structure of MCC

Non proprietary name:

BP: Microcrystalline cellulose

JP: Microcrystalline cellulose

PhEur: Cellulose, Microcrystalline

USP-NF: Microcrystalline cellulose

Synonym: Avicel pH, celex, cellulose gel, celphere,emocel.

Emperical formula: (C6H10O5)n

Molecular weight: Approximately 36000.

Category: Absorbent, suspending agent, tablet and capsule diluent, tablet disintegrant.

Bulk density: 0.32g/cm3 for Avicel pH-101

Solubility: Slightly soluble in 5% w/v sodium hydroxide, practically insoluble in water,

dilute acids and most organic solvents. Incompatibilities: Microcrystalline cellulose is

incompatible with strong oxidizing agents.

Uses: Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a

binder/diluent in oral tablet and capsule formulations.

Koringa College of Pharmacy Page 18

 Drug and excipient profiles & Materials and Equipment used

3.2.5. Magnesium stearate [42, 43]

Description: It is a very fine, light white, precipitated or milled, impalpable powder. It is

greasy to touch and readily adheres to skin.

Structure:

Figure 3.6: Structure of Magnesium stearate

Non proprietary name:

BP: Magnesium stearate

JP: Magnesium stearate

PhEur: Magnesium stearate

USPNF: Magnesium stearate

Synonym: Dibasic magnesium stearate, magnesium distearate, magnesium octadecenoate,

octadecanoic acid, magnesium salt etc.

Chemical name: Octadecanoic acid magnesium salt

Formula: C36H70MgO4

Molecular weight: 591.24

.Bulk Density: 0.159g/cm3

Solubility: Practically soluble in ethanol, ether and water and slightly soluble in warm

benzene and warm ethanol (95%).

Incompatibilities: Incompatible with strong acid, alkalis and iron salts. Avoid mixing with

strong oxidizing materials.

Koringa College of Pharmacy Page 19

 Drug and excipient profiles & Materials and Equipment used

Uses: It is primarily used as a lubricant in capsule and tablet manufacture

Handling Safe Handling:

• Wear safety glasses. Avoid contact with eyes.

• Keep away from oxidizing agents, excessive heat and sources of ignition.

• Empty containers pose a fire risk. Evaporate the residue under a fume hood.

• Ground all equipment containing material.

• Do not breathe dust.

Storage Requirements for Storage Areas and Containers: Store in a cool, dry location, in

a sealed container in a well ventilated area.

3.2.6. Talc [44]

Description: Talc is a very fine, white to grayish white, odorless, impalpable, crystalline

powder. It is soft to touch and free from grittiness.

Structure:

Figure 3.7: Structure of Talc

Non proprietary name:

BP: Purified talc

JP: Talc

PhEur: Talc

Synonym: Mussolinite, Agalite, Asbestine, Snowgoose, Soapstone

Molecular weight: 379.27 g/mol

Koringa College of Pharmacy Page 20

 Drug and excipient profiles & Materials and Equipment used

Emperical formula: Mg6(Si2O5)4(OH)4

Odour: Odour less

Colour: Grey white powder

Acidity/alkalinity: pH= 7-10 for a 20% w/v aqueous dispersion

Solubility: Practically insoluble in dilute acids and alkalis, organic solvents and water.

Incompatibilities: Incompatible with quaternary ammonium compounds.

Safety: Nontoxic material, intranasal or intravenous abuse of products containing talc can be

caused granulomas in body tissues, particularly the lungs.

Uses: Used orally as lubricant and diluent. Dissolution retardant in the development of

controlled- release products.

3.2.7. Aspartame [45]

Description: Aspartame is a dipeptide obtained by formal condensation of the alpha-

carboxy group of L-aspartic acid with the amino group of methyl L-phenylalaninate.

Commonly used as an artificial sweetener. It has a role as a sweetening agent, a

nutraceutical, a micronutrient, a xenobiotic, an environmental contaminant, an apoptosis

inhibitor and an EC 3.1.3.1 (alkaline phosphatase) inhibitor. It is a dipeptide, a carboxylic

acid and a methyl ester. It is functionally related to a L-aspartic acid and a methyl L-

phenylalaninate. It occurs as white, almost odorless crystalline powder.

Structure:

Figure 3.8: Structure of Aspartame

Koringa College of Pharmacy Page 21

 Drug and excipient profiles & Materials and Equipment used

Synonyms: Aspartyl phenyl amine Methyl Ester, Canderel, NutraSweet, Sancta, Tri-Sweet

Formula: C14H18N2O5

Functional category: Sweetening agent.

Applications: It is used as an intense sweetening agent in tablets powder mixes and vitamin

preparations. It enhances flavor systems, can be used to mask some unpleasant taste, and has

sweetening power of 180-200 times that of sucrose.

kSolubility: Slightly soluble in ethanol (95%), sparingly soluble in water. Solubility

increasesat higher temperature and more acidic pH

Stability: It is stable in dry conditions. In presence of moisture, hydrolysis occurs.

Degradation also occurs during prolonged heat treatment.

Storage conditions: Bulk material should be kept in a well-closed container and stored in a

cool dry place.

Incompatibilities: Incompatible with dibasic calcium phosphate & also with magnesium

stearate.

Safety: The WHO has set an acceptable daily intake of 40mg/kg body weight.

Hazards:

 Causes effects on fluid intake

 Degenerative changes to brain, and effects on phosphatases and true cholinesterase

in acute oral studies of rats

 An eye and mucous membrane irritant

 May cause irritation

3.2.7. Cross Carmellose Sodium [46]

Koringa College of Pharmacy Page 22

 Drug and excipient profiles & Materials and Equipment used

Structure:

Figure 3.9: Structure of croscarmellose sodium

Nonproprietary name:

BP: Croscarmellose sodium.

PhEur: Carmellosum natricum conexum

USPNF: Croscarmellose

Synonym: Ac-Di-sol, crosslinked carboxymethylcellulose sodium; Explocel; modified

cellulose gum; Nymcel ZSX; pharmacel XL; primellose; solutab; vivasol

Chemical name: Carboxymethyl ether, sodium salt,

Description: Croscarmellose sodium occurs as an odorless, white or grayishwhite powder.

pH = 5.0-7.0 in aqueous dispersions.

Density:0.529g/cm3 for Ac-Di-Sol

Melting point: 90℃

Solubility: CCS derived from wood pulp has lower MW, higher water solubility, a slightly

lower pH, decreased water capacity and swelling rate compared to CCS made from cotton

linters.

Swelling capacity: It is soluble in water, although it rapidly swells to 4-8 times its original

volume on contact with water.

Incompatibilities: The efficacy of disintegrants, such as croscarmellose sodium, may be

slightly reduced in tablet formulations prepared by either the wet-granulation or direct

Koringa College of Pharmacy Page 23

 Drug and excipient profiles & Materials and Equipment used

compression process that contain hygroscopic excipients such as sorbitol. Croscarmellose

sodium is not compatible with strong acids or with soluble salts of iron and some other

metals such as aluminium, mercury, and zinc.

Uses: Croscarmellose (CMC) that is widely used as an additive in pharmaceutical and non-

pharmaceutical industry, in particular, it is used in oral pharmaceutical formulations as a

disintegrant for capsules, tablets and granules.

3.3 MATERIALS USED

Table 3.1: Materials used in research work

S. NO MATERIALS MANUFACTURER

1 Varenicline Tartarate Gift Sample

2 Crosspovidone Sigma Aldrich

3 Microcrystalline cellulose Sigma Aldrich

4 PEG 4000 Sigma Aldrich

5 Aspartame Sigma Aldrich

6 Magnesium stearate S.D Fine Chem, Ltd Mumbai

7 Talc S.D Fine Chem, Ltd Mumbai

8 Potassium di hydrogen S.D Fine Chem, Ltd Mumbai

phosphate

9 Sodium hydroxide S.D Fine Chem, Ltd. Mumbai

Other chemicals used are of analytical grade.

Koringa College of Pharmacy Page 24

 Drug and excipient profiles & Materials and Equipment used

3.4 EQUIPMENTS USED

Table 3.2: Equipment used in research work

S.NO EQUIPMENT MANUFACTURER / MODEL

1 Tablet punching machine 16 punch

2 UV/visible spectrophotometer double Elico SL159

Beam
3 Dissolution test apparatus- U.S.P. Electro lab TDT 08L
Standards
4 Single pan digital balance Citizen

5 Hardness tester Monsanto, Electronics India

6 Friability apparatus Electronics India/1902

7 Disintegration test apparatus Electronics India/ 2901

Koringa College of Pharmacy Page 25

 Experimental Work

4.1 ANALYTICAL METHODOLOGY

4.1.1 Standard calibration curve of Varenicline Tartarate

4.1.1.1. Preparation of buffer pH 6.8

Solution of phosphate buffer of pH 6.8 was prepared by taking 250 mL of 0.2M potassium

dihydrogen phosphate and 112 mL of 0.2M sodium hydroxide in a volumetric flask. The

final volume was then made up to 1000 mL with distilled water.

4.1.1.2 Preparation of stock for standard curve in phosphate buffer pH 6.8

A fixed quantity 10 mg of the drug was weighed and taken into a 10 mL volumetric flask.

The volume was made up to the mark with phosphate buffer of pH 6.8. This was named as

stock I. From stock I, 5 mL of solution was taken and made up to 50 mL with buffer. This

was named as stock II. From this 0.3 mL, 0.6 mL, 0.9 mL, 1.2 mL and 1.5 mL solution was

taken and made up to 10mL with buffer to obtain 3 µg/mL, 6 µg/mL, 9 µg/mL, 12 µg/mL

and 15 µg/ml concentrations respectively. The absorbance was checked at 237 nm in UV

spectrophotometer.

A calibration curve was constructed by plotting the absorbance against the concentration of

drug. A regression equation was derived from the plot, which was used for the estimation of

drug against phosphate buffer pH 6.8. The regression equation is in the form of, y = mx ±c.

4.2 EXPERIMENTAL DESIGN [47, 48]

A face centered Central Composite Design was used for the design, development of

Venlafaxine loaded ODTs by formulation parameter optimization.

Three factors were evaluated at 3 levels (+1, 0, -1) and experimental trials were

conducted for the 13 combinations. The percentage of Crospovidone (X1 or A) and CCS (X2

Koringa College of Pharmacy Page 26

 Experimental Work

or B) were selected as independent variables. Disintegration Time (Y 1) and Wetting time

(Y2) were selected as dependent variables to optimize the response data.

The polynomial equation given below was used to study the effect of variables on different

evaluation responses (Y), where the coefficients in the equation (𝛽0, 𝛽1, 𝛽2, 𝛽12, 𝛽23, 𝛽31, 𝛽11,

𝛽22, 𝛽33) were related to the effects and interactions of the factors.

Y= 𝛽0+ 𝛽1X1+ 𝛽2X2+ 𝛽12 X1X2 + 𝛽11X1X1+ 𝛽22X2X2

Where,

Y is the dependent variable; 𝛽0 is the arithmetic mean response of the 13 runs; 𝛽1 and 𝛽2 are

the estimated coefficients for the factors X1, and X2 respectively. The main effect (X1 and

X2) represents the average result of changing one factor at a time from its low to high value.

The interaction term (X1X2) shows how the response changes when two factors are changed

simultaneously. The polynomial terms (X1X1 and X2X2) are included to investigate

nonlinearity. The formulations coded values and actual values are given from Table 4.1 and

4.2.

4.3 PREPARATION OF VARENICLINE TARTARATE ODTS [49]

Fast dissolving tablets of Varenicline tartrate were prepared by direct compression method,

using synthetic disintegrants crospovidone and croscarmellose sodium in different ratios

and directly compressible MCC (PH-102) as diluent and mannitol to enhance the mouth

feel. According to the formulae given in Table 4.1, All the ingredients were passed through

#60 mesh separately. The drug and MCC (PH-102) were mixed by the small portion of both

each time and blending it to get a uniform mixture and kept aside. Then the ingredients were

weighed and mixed in geometrical order. The mixed blend of excipients was compressed

into tablet.

Koringa College of Pharmacy Page 27

 Experimental Work

Table 4.1: Coded and actual values of independent variables

Name Coded Actual (%)

-1 5
Crospovidone 0 7.5
+1 10
-1 5
CCS 0 7.5
+1 10

Table 4.2: Formulae of different formulations

o
Formulation A- CP B- CCS Aspar Mg.
CP CCS MCC Starch Talc
Code (%) (%) tame Stearate
F1 10 5 10 5 61 5 2 1 1
F2 7.5 5 7.5 5 66 5 2 1 1
F3 7.5 7.5 7.5 7.5 61 5 2 1 1
F4 7.5 7.5 7.5 7.5 61 5 2 1 1
F5 7.5 10 7.5 10 56 5 2 1 1
F6 7.5 7.5 7.5 7.5 61 5 2 1 1
F7 5 5 5 5 71 5 2 1 1
F8 10 10 10 10 51 5 2 1 1
F9 10 7.5 10 7.5 56 5 2 1 1
F10 7.5 7.5 7.5 7.5 61 5 2 1 1
F11 5 10 5 10 61 5 2 1 1
F12 7.5 7.5 7.5 7.5 61 5 2 1 1
F13 5 7.5 5 7.5 66 5 2 1 1

4.4 CHARACTERIZATION AND EVALUATION [50-57]

4.4.1. Pre Compression Parameters – Flow properties:

Koringa College of Pharmacy Page 28

 Experimental Work

4.4.1.1 Angle of Repose

The maximum angle, which is formed between the surface of pile of powder and horizontal

surface is called the angle of repose. Mostly, the angle of repose values ranges from 25 to 45°,

with lower values indicating better flow characteristics. The type of flow based on the angle of
ℎ
repose is presented in Table 4.3. Angle of repose can be calculated using formula, tan 𝜃 =
𝑟

Where, h is the height of the heap and r is the radius of the heap

Table 4.3: Nature of flow based on angle of repose

S. No Flow Property Angle of Repose

1 Excellent 25-30º
2 Good 31-35º
3 Fair 36-40º
4 Passable 41-45º
5 Poor 46-55º
6 Very poor 56-65º
7 Very very poor >66 º

4.4.1.2 Bulk Density

Predetermined quantity of powder was taken (W1) and poured in to a measuring cylinder and the
𝑊1
volume was noted (V1). The bulk density was calculated. Bulk Density =
𝑉1

4.4.1.3 Tapped density

Predetermined quantity of powder was taken (W1) into a measuring cylinder. The cylinder was

tapped for 100 times and volume was measured after the tapings (V2).

The tapped density was calculated using formula, Tapped Density = 𝑊1

𝑉2

4.4.1.4 Carr's index

Koringa College of Pharmacy Page 29

 Experimental Work

Compressibility or Carr's index of a powder can be defined as the ability to decrease in volume

under pressure. It is calculated by the following formula

𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦−𝐵𝑢𝑙k 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

Carr's index = ×100
𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

4.4.1.5 Hausner's Ratio

The Hausner ratio is a number that is correlated to the flowability of a powder or granular

material. The Hausner ratio is calculated by the formula where is the freely settled bulk density

of the powder, and is the tapped bulk density of the powder. The flow property based on

compressibility index and the Hausner’s ratio is represented in Table 4.4.

Hausner's ratio=𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

𝐵𝑢𝑙k 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

Table 4.4: Nature of flow based on compressibility index and Hausner’s ratio

Compressibility
Flow property Hausner’s ratio
index
≤ 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

4.4.2 Post Compression Evaluation [17]

4.4.2.1 Hardness

The force needed to fracture the tablet by diametrical compression is referred as crushing

strength of tablet. The hardness of the six tablets from each formulation batch was

determined using Monsanto type hardness tester. Results are expressed as mean value ±SD.

Koringa College of Pharmacy Page 30

 Experimental Work

4.4.2.2 Friability

The tablets were rotated in the Friabilator for 4 minutes for 100 revolutions. At the end of test

tablets were dusted off and reweighed, the loss in the weight of the tablet was measured.

𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑊𝑒𝑖𝑔ℎ𝑡 − 𝐹𝑖𝑛𝑎𝑙 𝑊𝑒𝑖𝑔ℎ𝑡

𝐹𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = × 100
𝐼𝑛𝑖𝑡𝑖al 𝑊𝑒𝑖𝑔ℎ𝑡

4.4.2.3 Drug Content

The tablet was crushed and dissolved in 100 mL of phosphate buffer pH 6.8. The drug content

was determined spectrophotometrically with appropriate dilutions at 237 nm.

4.4.2.4 Wetting time

A piece of tissue paper (10.75 × 12 mm) folded twice was placed in a culture dish (d = 6.5 cm)

containing 6 ml of simulated saliva (phosphate buffer pH 6.8). A tablet was carefully placed on

the surface of tissue paper and the time required for simulated saliva to reach the upper surface

of the tablet was noted as the wetting time.

4.4.2.4 Water Absorption Ratio

A test was done with the same procedure as that of wetting time. In this test, initial weight of

the tablet was noted before placing it on a Petridish. After complete wetting, the wetted tablet

was then weighed. The water absorption ratio ‘R’ was determined using the equation

𝑊𝑏 − 𝑊𝑎
𝑅= × 100
𝑊𝑏

Wa: Weight of tablet before the study, Wb: Weight of tablet after the study

4.4.2.5 Disintegration Time

Water at 37 ± 1℃ was used as the disintegration medium. Six tablets were placed in each

tube of the cabinet and the apparatus was operated. The time taken for complete

disintegration of tablet without any leftover residue in the tubes was recorded.

Koringa College of Pharmacy Page 31

 Experimental Work

4. 4. 3 In vitro dissolution studies

The drug release studies were performed using the USP dissolution test apparatus type I.

The dissolution test was performed using 900 ml of phosphate buffer pH 6.8 maintained at

37±0.5℃ and paddle speed of 100 rpm. The test was performed pure drug, optimized

formulation and the marketed product. At regular time intervals Samples (5 ml) were

collected into a test tube. After every sample with drawl, fresh medium of same volume is

replenished. The samples were then filtered through 0.45 µm membrane filter and analyzed

by using UV spectrophotometer at 237 nm.

4.5 STATISTICAL ANALYSIS

The data obtained from factorial design study was subjected to multiple regression

analysis using Design Expert DX 12 software and were fitted in the equation:

Y= 𝛽0+ 𝛽1X1+ 𝛽2X2 + 𝛽12 X1X2 + 𝛽11X1X1+ 𝛽22X2X2

The effect of the variables was interpreted by considering the magnitude of correlation

and the mathematical sign it carried (positive or negative). The adequacy of the fitted model

was checked by analysis of variance (ANOVA). To study the main and interaction effects of

the independent variables, response surface plots were constructed using software Design

Expert® DX 12. Response surface plots were constructed using software to study the main

and interaction effects of the independent variables. From the above statistical analysis two

formulations were optimized with specified constraints are shown in the Table 4.5 and the

formula for optimized formulation was presented in Table 4.6.

Koringa College of Pharmacy Page 32

 Experimental Work

Table 4.5: Constraints of dependent variables in optimization

S. No Dependent variable Constraints (Minimize)

1 Y1 30-50
2 Y2 20-30

Table 4.6: Formulae of optimized formulations

Code % CP % CCS
OF 5 10

The optimized formulation which as one of the initial 13 formulations, was prepared

based on the given formulae and the evaluation tests were repeated and the % relative error

of the predicted and the experimental values was calculated.. The formula for calculating the

relative error:

𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑 𝑣𝑎𝑙𝑢𝑒 − 𝐸𝑥𝑝𝑒𝑟𝑖𝑚𝑒𝑛𝑡𝑎𝑙 𝑉𝑎𝑙𝑢𝑒

𝑅𝑒𝑙𝑎𝑡𝑖𝑣𝑒 𝑒𝑟𝑟𝑜𝑟 % (𝑜𝑟) 𝐵𝑖𝑎𝑠 % = × 100
𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑 𝑉𝑎𝑙𝑢𝑒
4.6 Kinetic model fitting [58]

Several theories/kinetics models describe drug dissolution from immediate and modified

release dosage forms. To compare dissolution profiles between two drug products model

dependent (curve fitting), statistic analysis and model independent methods can be used. The

kind of drug, its polymorphic form, crystallinity, particle size, solubility and amount in the

pharmaceutical dosage form can influence the release kinetics.

4.6.1 Zero order kinetics

Koringa College of Pharmacy Page 33

 Experimental Work

Pharmaceutical dosage forms following this profile release same amount of drug by unit of

time and it is the ideal method of drug release in order to achieve a pharmacological

prolonged action. The following relation can, in a simple way, express this model

Q1=Q0+K0t

Where,

Q is the amount of drug dissolved in time t,

Q0 is the initial amount of drug in the solution

K is the zero order release constant.

4.6.2 First order kinetics

The following relation can also express this model

log Qt = log Q0+ K1t

2.303

Where,

Qt is the amount of drug release in time t

Q0 is the initial amount of drug in the solution

K is the first order release constant

4.6.3 Higuchi model

Higuchi T (1973) developed models to study the release of water soluble and low soluble

drugs incorporated in semi-solid and/or solid matrixes. Mathematical expressions were

obtained for drug particles dispersed in a uniform matrix behaving as the diffusion media.

To study the dissolution from a planar system having a homogenous matrix, the relation

obtained was the following

ft= Q= √D(2C − Cs)CsT

Koringa College of Pharmacy Page 34

 Experimental Work

Where,

Q is the amount of drug released in time t per unit area

C is the initial concentration of the drug

Cs is the drug solubility in the media

D is the diffusivity of the drug molecules (diffusion constant) in the matrix

4.6.4 Korsmeyer-Peppas model

Korsmeyer et al (1983) developed a simple, semi-empirical model, relating exponentially

the drug release to the elapsed time (t)

Mt
= atn
M∞

Where,

a is a constant incorporating structural an geometric characteristics of the drug

dosage form

n is the release exponent, indicative of the drug release mechanism

Mt
the function of t is (fractional release of drug)
M∞

The type of diffusion determination is given in Table 4.7.

Table 4.7: Determination of the type of diffusion

Diffusion exponent Drug diffusion mechanism
0.45 Fickian diffusion
0.45<n<0.89 Non-fickian diffusion
0.89 Case II transport
>0.89 Super Case II transport

Koringa College of Pharmacy Page 35

 Results and Discussion

5.1. RESULTS

5.1.1. Standard calibration curve

The standard calibration curve for Varenicline Tartarate (VT) in Phosphate buffer pH 6.8

was established and the results were presented in the Table 5.1 and Figure 5.1.

Table 5.1: Calibration curve for estimation of Varenicline Tartarate in Phosphate

buffer pH 6.8

Concentration(µg/ml) Absorbance
2 0.095 ± 0.0035
4 0.281 ± 0.017
6 0.475 ± 0.004
8 0.726 ± 0.005
10 0.995 ± 0.0035
Intercept -0.1589
Slope 0.1122
Correlation coefficient (r) 0.9964
All the values are expressed as mean ± SD (n=3)

Standard Calibration Curve

1.2

0.8
Absorbance

0.6

0.4
y = 0.1122x - 0.1589
R² = 0.9929
0.2

0
0 2 4 6 8 10 12
Concentration (mcg/mL)

Figure 5.1: Standard calibration curve of Varenicline Tartarate in Phosphate

buffer pH 6.8

Koringa College of Pharmacy Page 36

 Results and Discussion

The formulations obtained from the Design Expert Software were prepared and

evaluated for responses and other parameters.

5.1.2. Characterization and Evaluation

The formulations were evaluated for various pre compression and post compression

parameters and the results are reported in Table 5.2. The hardness of all the formulations

from F1 to F 13 was found to be in the range of 2-4 kg/cm2. The percentage weight loss

in the friability test for the formulations was found to be less than 0.5%.

Koringa College of Pharmacy Page 37

 Results and Discussion

Table 5.2: Results of Pre compression and post compression evaluation parameters of formulations

Formulation Angle of Carr’s Hausner’s Drug Wetting Water Absorption Disintegration

code Repose Index Ratio Content time Ratio Time
F1 23.32 ± 0.25 8.32 ± 0.49 1.06 ± 0.02 98.22 ± 0.66 28.05 ± 2.67 96.45 ± 3.71 65.04 ± 2.87
F2 20.01 ± 0.77 9.36 ± 0.16 1.03 ± 0.07 96.54 ± 0.49 35.14 ± 1.93 97.87 ± 0.49 73.15 ± 2.65
F3 19.86 ± 0.84 11.34 ± 0.26 1.05 ± 0.03 97.56 ± 0.44 30.15 ± 2.22 99.04 ± 2.61 69.35 ± 1.43
F4 23.36 ± 0.58 9.95 ± 0.47 1.07 ± 0.04 97.99 ± 0.64 28.06 ± 1.09 98.74 ± 1.86 68.12 ± 1.41
F5 20.55 ± 0.71 7.42 ± 0.38 1.1 ± 0.04 97.54 ± 0.35 18.15 ± 2.79 112.35 ± 1.31 53.41 ± 1.39
F6 23.22 ± 0.40 10.35 ± 0.29 1.05 ± 0.04 99.54 ± 0.37 35.36 ± 2.56 98.32 ± 1.99 62.29 ± 0.92
F7 19.54 ± 0.29 11.11 ± 0.57 1.04 ± 0.03 97.32 ± 0.79 42.49 ± 2.18 99.85 ± 3.63 65.32 ± 1.21
F8 20.05 ± 0.98 9.42 ± 0.39 1.03 ± 0.03 96.54 ± 0.2 24.72 ± 1.24 106.25 ± 4.12 41.36 ± 2.42
F9 14.85 ± 0.35 6.54 ± 0.55 1.04 ± 0.05 98.11 ± 0.79 29.12 ± 1.01 100.14 ± 4.25 51.32 ± 1.29
F10 23.06 ± 0.53 9.35 ± 0.63 1.06 ± 0.02 99.22 ± 0.88 31.35 ± 2.22 101.86 ± 3.72 65.85 ± 1.03
F11 15.05 ± 0.55 10.22 ± 0.19 1.07 ± 0.05 97.73 ± 0.44 18.45 ± 0.98 118.46 ± 2.72 31.15 ± 1.17
F12 20.01 ± 0.45 12.55 ± 0.40 1.05 ± 0.03 99.02 ± 0.74 36.97 ± 2.81 99.85 ± 0.86 64.14 ± 1.13
F13 20.22 ± 0.99 14.32 ± 0.53 1.02 ± 0.09 99.21 ± 0.92 25.32 ± 1.09 104.87 ± 1.16 47.03 ± 2.16

Koringa College of Pharmacy Page 38

 Results and Discussion

5.1.3. Statistical analysis

5.1.3.1. Suggested model

The statistical analysis was performed after the input of the results obtained in

characterization process into DOE software and the suggested models and fitted model

was presented in Table 5.3.

Table 5.3: Summary of results of regression analysis for responses

Models R2 Adjusted R2 Predicted R2 SD % CV Remarks

Disintegration Time
Linear model 0.5562 0.4675 0.1649 9.10
Second order 0.5710 0.4280 -.5305 9.43
Quadratic model 0.9606 0.9325 0.7751 3.24 5.56 Suggested
Wetting Time
Linear model 0.5162 0.4374 0.00979 509
Second order 0.7429 0.6572 0.4967 4.11 13.92 Suggested

5.1.3.2. Analysis of variance

The analysis of variance (ANOVA) for the responses are given in the Table 5.4 and 5.5.

Table 5.4: ANOVA for the Response, Disintegration Time

Source SS Df F value p value Remark

Model 1791.05 5 34.13 < 0.0001 Significant
A 33.70 1 3.21 0.1162 Not Significant
B 1003.37 1 95.61 < 0.0001 Significant
AB 27.51 1 2.62 0.1495 Not Significant
A² 600.18 1 57.19 0.0001 Significant
B² 1.12 1 0.1066 0.7536 Not Significant
Lack of Fit 40.51 3 1.64 0.3150 Not significant

Koringa College of Pharmacy Page 39

 Results and Discussion

Table 5.5: ANOVA for the Response, Wetting Time

Source SS Df F value p value Remark

Model 438.38 3 8.67 0.0051 Significant
A 3.18 1 0.1888 0.6741 Not Significant
B 327.97 1 19.45 0.0017 Significant
AB 107.23 1 6.36 0.0327 Significant
Lack of Fit 97.08 5 1.42 0.3777 Not significant

5.1.3.3 Regression equation of the fitted model

The regression equation Final equation in terms of coded factors and the actual terms

1. Disintegration Time - Coded Values

Disintegration Time = 65.369 + 2.37 * A + -12.9317 * B + 2.6225 * AB + -

14.7414 * A2 + -0.636379 * B2

2. Disintegration Time – Actual Values

Disintegration Time = -17.7434 + 33.1803 * Crospovidone + -6.79236 * CCS +

0.4196 * Crospovidone*CCS + -2.35862 * Crospovidone2 + -0.101821 * CCS2

3. Wetting Time – Coded Values

Wetting Time = 29.4869 + -0.728333 * A + -7.39333 * B + 5.1775 * AB

4. Wetting Time – Actual Values

Wetting Time = 100.449 + -6.50433 * Crospovidone + -9.17033 * CCS + 0.8284 *

Crospovidone*CCS

5.1.3.4. Plots showing effect of variables on responses

The plots for various responses are given from Figure 5.2 to 5.5.

Koringa College of Pharmacy Page 40

 Results and Discussion

Figure 5.2: 3D surface plot and contour plot of AB term for Disintegration Time

Koringa College of Pharmacy Page 41

 Results and Discussion

Figure 5.3: 3D surface plot and contour plot of AB term for Wetting time

Koringa College of Pharmacy Page 42

 Results and Discussion

Figure 5.4: Perturbation plot and interaction plot of disintegration time

Figure 5.5: Perturbation plot and interaction plots of wetting time

Koringa College of Pharmacy Page 43

 Results and Discussion

5.1.4.5 Overlay plots of optimized formulation

The optimized amounts and ratio of factors for preparing optimized formulation are

given in Table 5.6 and the overlay plot of the optimized formulation is given in Figure

5.6.

Figure 5.6: Over lay plot of optimized formulation OF

Table 5.6: Proportions of factors in Optimized Varenicline Tartarate ODTs

Code Crospovidone CCS

OF1 5 10

5.1.5. Characterization of optimized formulations

The optimized formulation was characterized for various parameters stated and for the

responses considered. The results are tabulated in Table 5.7.

Table 5.7: The values of responses of the optimized formulation

Parameter OF
Disintegration time 31.85 ± 0.43
Wetting time 17.96 ± 0.52

All the values are presented as Mean ± sd (n=3)

Koringa College of Pharmacy Page 44

 Results and Discussion

5.1.6. Model validation and final formulation identification

The relative error was calculated to validate the model. The relative error was calculated

for the and the values are presented in Table 5.8.

Table 5.8: Relative error for optimized formulations

Code Response Predicted values Experimental values Relative error (%)

Disintegration time 32.07 31.85 0.69
OF
Wetting time 17.64 17.96 -1.81

The desirability bar graph and ramp graph of all the terms of optimized formulation are

given in Figure 5.7 and 5.8 respectively.

Figure 5.7: The desirability bar graph of all the terms of optimized formulation

Koringa College of Pharmacy Page 45

 Results and Discussion

Figure 5.8: The ramp graph of all the terms of optimized formulation

5.1.7. In vitro drug release study of optimized formulation

The dissolution study was performed and the results are given in Table 5.9 and Figure

5.9.

Table 5.9: In vitro drug release profiles of pure drug and optimized formulation
5
Time % Cumulative Drug Release
(Min) Pure drug Optimized Formulation
0 0 0

5 13.65 ± 0.91 22.04 ± 1.14

15 27.44 ± 0.77 40.40 ± 1.36

30 32.96 ± 0.90 59.08 ± 1.20

45 46.52 ± 1.43 88.34 ± 1.79

60 56.84 ± 1.36 99.68 ± 0.31

All the values are presented as Mean ± sd (n=3)

Koringa College of Pharmacy Page 46

 Results and Discussion

Dissolution Profile
Pure Drug OF

100

90

80
% CUMULATIVE DRUG RELEASE

70

60

50

40

30

20

10

0
0 10 20 30 40 50 60 70 80
TIME (MINUTES)

Figure 5.9: Dissolution profile of pure drug & optimized formulation

5.1.8. Kinetic Model Fitting

The drug release data was subjected to kinetic model fitting. The results are given in

Table 5.10 and Figure 5.10.

Table 5.10: Correlation coefficient and kinetic model fitting of in vitro drug release

studies

Zero order First order Higuchi Korsmeyer and Peppas

r 0.9921 0.9013 0.99 0.9951

n 0.8975

Koringa College of Pharmacy Page 47

 Results and Discussion

Figure 5.10: Kinetic model graphs of optimized formulation

Koringa College of Pharmacy Page 48

 Results and Discussion

5.2 DISCUSSION

5.2.1. Analytical methodology

5.2.1.1. Construction of calibration curve in Phosphate buffer pH 6.8

The calibration curve was constructed by preparing 2 µg/mL, 4 µg/mL, 6 µg/mL,

8 µg/mL and 10 µg/mL, concentrations as the serial dilutions and then finding the

corresponding absorbance values spectrophotometrically at 237 nm. The data is

represented in Table 5.1. The slope and intercept values were found to be 0.1122 and -

0.1589 respectively and the correlation coefficient was 0.9964.

The calibration curve is represented in Figure 5.1. From the slope and intercept

values it is observed that the curve is having a positive slope. The coefficient of

correlation value of 0.9964 is good. From the data it is evident that the concentration

range from 2µg/ml to 10µg/mL is within the linearity range as per the Beer’s Lamberts

law.

5.2.2. Varenicline Tartarate ODT preparation & evaluation

The formulations obtained from the Design Expert Software were prepared and

evaluated for responses and other parameters.

5.2.3 Experimental design

The formulae of the Varenicline Tartarate ODT (VTO) to be prepared were

designed experimentally by using Design Expert software. The range is given in Table

4.1.

5.2.3. Preparation of VTO

The proportion of ingredients used in t]-he preparation of VTO were tabulated and

shown in Table 4.2. By varying the CP and CCS, various formulations from F1 to F13

were prepared.

Koringa College of Pharmacy Page 49

 Results and Discussion

5.2.4. Characterization and evaluation of VTO

The pre compression parameters and the post compression parameters were

evaluated and represented in Table 5.2.

The angle of repose was found to be in the range of 14.85 ± 0.35 to 23.36 ± 0.58,

which indicate that the flow is excellent.

The Carr’s index was found to be in the range of 6.54 ± 0.55 to 14.32 ± 0.53,

which indicate that the flow is from excellent to good.

The Hausner’s ratio as found to be in the range of 1.02 ± 0.09 to 1.1 ± 0.04,

which indicate that the flow is excellent.

The Hardness and friability was found to be in the limits as per official

compendia. The drug content as found to be in the range of 96.54 ± 0.2 to 99.54 ± 0.37,

which indicates that the values are within the IP limits of 95-105%.

The wetting time was found to be in the range of 18.15 ± 2.79 to 42.49 ± 2.18

seconds, while the water absorption ratio was found to be in the range of 96.45 ± 3.71 to

118.46 ± 2.72.

The disintegration time was found to be in the range of 31.15 ± 1.17 to 69.35 ±

1.43 seconds.

5.2.5. Data analysis, optimization and cross validation

In this CCD, two numeric factors were evaluated at 3 levels (+1, 0, -1) and % of

CP and % CCS (X2 or B) were selected as independent variables. The dependent

variables were subjected to statistical optimization and fitted to linear, interactive and

quadratic models. The summary of statistics is presented in Table 5.3. The comparative

R2, adjusted R2, predicted R2, S.d, F- values and P-values were determined using the

Design Expert Software. A suitable polynomial model for describing the data was

Koringa College of Pharmacy Page 50

 Results and Discussion

selected based on coefficient of determination R2. The responses followed quadratic

model. These models show higher R2 and F-values and lower P-values.

The results of the response surface model fitting in the form of ANOVA are given in

Table 5.4 and 5.5 for all responses.

 The F value of the model for response, Disintegration time, was observed to be 34.13 for

the VTO, which indicate that the model is significant. The values of p less than 0.05 for

all the responses except A, AB and B2 indicated the significance of parameters except A,

AB and B2 on Disintegration time.

 The F value of the model for response, wetting time, was observed to be 8.67 for the

VTO, which indicate that the model is significant. The values of p less than 0.05 for all

the responses except A indicated the significance of the model and insignificance of

variable A on defining wetting time.

From the equations given in Section 5.1.3.3, it can be analyzed that coefficient with

one factor indicate the effect of that particular factor, while the coefficients with more

than one factor and those with second order terms represent the interaction between

those factors and the quadratic nature of the phenomena respectively. Positive sign of the

term indicates positive (additive) effect, while negative sign indicates negative

(antagonistic) effect of the factor on the response.

All the terms except A and AB have negative impact on Disintegration time, while

the term AB have negative impact on wetting time.

The contour plots are built to evaluate the relationship between independent

factors and their effect on dependent factors. Similarly, response surface plots were also

generated to establish the effect of factors on response.

Koringa College of Pharmacy Page 51

 Results and Discussion

The plots showing the effect of CP and CCS and their effect on dependent factors

i.e., responses disintegration time and wetting time of VTO are given from Figure 5.2 to

Figure 5.5.

With increase in the % CP, the disintegration time increased initially and further

increase decreases disintegration time. The % CSS caused decrease in disintegration

time with increase in its percent. With increase in the % CSS, the wetting time decreased

initially and further increase decreases wetting time. The % CP caused decrease in

wetting time with increase in its percent.

5.2.6. Optimization

The constraints for optimization are presented in Table 4.5 and the formulae in

Table 4.6. In this experimental design optimization is done both numerically and

graphically. In numerical optimization the desired character for the response was

selected, automatically software will choose the solutions with desired characters and

limits. Among different solutions, it also suggests the solution with desirability near to 1.

Graphical optimization was done by desirability plot and overlay plot, which contains

optimal values of independent variables. The higher the desirability more suitable is the

formulation. The overlay plot with optimized formula is given in Figures 5.6.

5.2.7. Preparation of optimized VTO:

The optimized VTO was prepared as per the suggestions given by the software.

The proportions of all the components are tabulated in Table 5.7.

5.2.8. Evaluation of optimized VTO:

The optimized formulation was characterized for various parameters stated and for the

responses considered. The results are tabulated in Table 5.8. The desirability bar graph

and the ramp graph of the optimized formulation are presented as Figure 5.7 and Figure

5.8.

Koringa College of Pharmacy Page 52

 Results and Discussion

5.2.10 In vitro drug release study

The results of the study are presented in Table 5.9 and Figure 5.9. The results conclude

that the optimized formulation released 99.68 % drug in 60 minutes while the cumulative

% drug release of pure drug was just 56.84%. It can be concluded that the dissolution is

improved by VTO.

5.2.11 Kinetic model fitting

The results are tabulated in Table 5.10 and Figure 5.10. It can be concluded from the

results that, the release followed zero order kinetics and from the slope of Korsemeyer -

Peppas model, it can be conclude that the release is by Super case II transport.

Koringa College of Pharmacy Page 53

 Summary and
Conclusion

6.1. SUMMARY

Oral dispersible tablets are the dosage forms which can be prepared by various

techniques. Direct compression with the use of super disintegrants is the technique

employed in the preparation where the percentage of crospovidone and CCS, the super

disintegrants employed, are crucial in determining the product quality and efficiency.

Thus, the current work was started with an aim to optimize these parameters using the

model drug Varenicline Tartarate. It is a highly soluble and highly permeable drug and

is an ideal candidate for formulating as oro dispersible tablet.

The design of the formulation started with the CCD to optimize the independent

variables like concentration of the superdisintegrants, the key ingredients in the

formulation of VTOs. Formulation batches of VTOs were prepared in accordance with

CCD.

The VTOs were prepared based on the formulae given by the software and

evaluation tests were performed. It was observed that the independent parameters

concentration show impact performance of VTOs with disintegration time and

wetting time.

The data obtained in the experiments was used for plotting response-surface

and contour plots and data was analyzed by ANOVA. Optimized formulae were

given by the software.

The optimized formulation were prepared and evaluated. The formulation has

low relative error (<2%).

Thus, the optimum proportion of the formulation parameters in the preparation of

ODTs was optimized for the model drug.

Koringa College of Pharmacy Page 54

 Summary and
Conclusion

6.2. CONCLUSION

Optimization of the formulation parameters and evaluating its influence on

the performance of ODTs is the main aim of the present research.

The present work is focused on development of ODT, which serves the

purpose of improved performance of model drug. The concentration of

superdisintegrants is the important parameter in the formulation of VTO.

Using Design Expert Software various proportions of the % of CP and % of

CSS on performance of VTO was studied. The VTO were formulated and evaluated.

The parameters like disintegration time and wetting time were considered as

responses and analyzed by Design Expert Software.

It was observed that the formulation prepared with 5% of CP and 10% of CSS

produce effective formulations with desired responses. The disintegration time and

wetting time of OF was found to have 31.85 ± 0.43 seconds and 17.96 ± 0.52

seconds respectively.

Optimized formulation released 99.68 ± 0.31 % drug in 60 minutes while the

cumulative % drug release of pure drug was found to be 56.84 ± 1.36 % in same

time. The release followed Zero order kinetics and release of drug is by supercase II

transport.

6.3. SIGNIFICANT CONTRIBUTION OF THE RESEARCH PROJECT

 The formulation developed is useful for the improvement of Release of the

drug

 The patient compliance can be enhanced.

Thus, this research work, the formulation technique used was effective,

reproducible and the formulations were safe and efficient in improving

therapeutic efficacy of drug.

Koringa College of Pharmacy Page 55

 References

References

1. Tiwari S, Batra N. Oral drug delivery system: a review. Am. J. Life. Sci. Res.

2014;2(1):27-35.

2. Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery–

a review. Pharmaceutical science & technology today. 2000 Apr 1;3(4):138-45.

3. Gupta H, Bhandari D, Sharma A. Recent trends in oral drug delivery: a review. Recent

patents on drug delivery & formulation. 2009 Jun 1;3(2):162-73.

4. Kuchekar B, Atul S, Badhan C, Mahajan, HS et al., Mouth dissolving tablets: A novel

drug delivery system. International Journal of Applied Biosciences. Pharma Tech. 2003;

35:7-9.

5. Wilson CG et al., The behavior of a fast-dissolving dosage form (Expidet)

6. Fix JA et al., Advances in quick-dissolving tablets technology employing Wowtab. In IIR

Conference on Drug Delivery Systems. 1998.

7. Allen LV, Wang B et al., Particulate Support Matrix for making a rapidly dissolving

tablet.1997, US patent 5595761.

8. Devrajan PV, Gore S., Express pharm plus. 2003,7(1):16.

9. Chang R, Guo X, Burnside BA, Couch R et al., Fast dissolving tablets, Pharma Tech.

2000;24(6): 52‐58.

10. Reddy LH, Ghosh B, Rajneesh A et al., Fast dissolving drug delivery systems: A review

of the literature. Indian Journal of Pharmaceutical Sciences. 2002;7(8):331-336.

11. Bansal AK et al., Improved excipients by solid-state manipulation. The Industrial

Pharmacy. 2003;31; 9-12.

Koringa College of Pharmacy Page 56

 References

12. Zao N, Augsburger LL et al., The influence of swelling capacity of superdisintegrants in

different pH media on the dissolution of hydrochlorothiazide from directly compressed

tablets.American association of Pharmaceutical Science and Technology. 2005;6(1):120-

126.

13. Bandari S, Mittapali R, Rao YM, Gannu R et al., Orodispersible tablets : An overview.

Asian Journal of Pharmacy. 2008:2-11.

14. Mizumoto T, Masuda Y, Yamamoto T, Yonemochi E, Tarada et al., Formulation design

of a novel Fast-Disintegrating Tablet. International Journal of Pharmaceutics.

2005;306:83-90.

15. Lachman L, Liberman HA, Kanig PL. Tablets, The theory and practice of industrial

pharmacy, 3rd Indian edition, Bombay; Verghese publishing house, 1987:317-20.

16. Lachman L, Lieberman HA, Kanig JL. Theory & practice of industrial pharmacy. 3rd ed.

Mumbai: Varghese publishing house; 1991:296-302.

17. Indian pharmacopoeia, 4th ed. Vol-II. New Delhi: The controller of publications;

1996;7,112,736.

18. Wiwattana patapee et al. Effervescent fast-disintegrating bacterial Formulation. Journal

of controlled release. 2007;119:229-235.

19. Kusuma et al., Design of miniature cabinet for compounding vitamin-C effervescent

tablet. International Journal of Applied Pharmaceutics. 2018;10(3):157-161.

20. Jacob, Sherry et al., Preparation and evaluation of fast-disintegrating effervescent tablet.

Drug Development and Industrial Pharmacy. 2009;35(3):321-328.

21. Purkayastha et al., formulation and evaluation of oral fast disintegrating tablet of

Ibuprofen. International Journal of Current Pharmaceutical Research. 2017;9(4):92-95.

Koringa College of Pharmacy Page 57

 References

22. Amin P, Patel M. Preformulation Studies of Varenicline for Formulation and

Development of a Novel Orally Disintegrating Film. Journal of Pharmaceutical Research

International. 2023 Jul 7;35(17):31-40.

23. Kwak SS, Lee ES, Yoon HY, Kim CH, Goo YT, Kang MJ, Lee S, Lee BS, Jeon HR, Oh

CH, Choi YW. Immediate release tablet formulation of varenicline salicylate and

comparative pharmacokinetic study in human volunteers. Drug Design, Development and

Therapy. 2018 Oct 9:3377-92.

24. Jinichi Fukami et al., Evaluation of rapidly disintegrating tablets containing glycine and

carboxy methyl cellulose. International Journal of Pharmaceutics. 2006;310(2):101-109.

25. Udupa et al., Nimusulide dispersible tablets from direct compression method. Journal of

India drugs. 2001;38(4):208-210

26. Jin Y, Ohkuma H, Wang CF, Natsume H, Sugibayashi K, Morimoto Y et al.,

Pharmaceutical evaluation of fast-disintegrating tablet containing Nicorandil-loaded

particles. Yao Xue Xue Bao. 2001;36 (7):535-538.

27. Sreenivas SA, Gadad AP, Dandagi PM, Mastiholimath VS, Patil MB et al., Formulation

and evaluation of Ondansetron hydrochloride directly compressed mouth disintegrating

tablets. Indian Drugs. 2005;43(1):35-38.

28. https://go.drugbank.com/drugs/DB01273 , accessed as on 10th December, 2022.

29. https://go.drugbank.com/salts/DBSALT000548 , accessed as on 10th December, 2022.

30. https://www.webmd.com/drugs/2/drug-144328/varenicline-oral/details, accessed as on

15th January, 2023.

31. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021928s008lbl.pdf, accessed as

on 21st January, 2023.

Koringa College of Pharmacy Page 58

 References

32. https://www.cdc.gov/tobacco/campaign/tips/quit-smoking/quit-smoking-

medications/which-quit-smoking-medicine-is-right-for-you/varenicline.html, accessed as

on 24th January, 2023.

33. https://www.ncbi.nlm.nih.gov/books/NBK534846/, accessed as on 31st January, 2023.

34. https://www.drugs.com/mtm/varenicline.html, accessed as on 2nd February, 2023.

35. https://www.usp.org/sites/default/files/usp/document/harmonization/excipients/2011-02-

25crospovidone.pdf, accessed as on 2nd February, 2023.

36. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-

science/crospovidone#:~:text=Crospovidone%20is%20a%20cross%2Dlinked,wet%20an

d%20dry%20granulation%20methods., accessed as on 2nd February, 2023.

37. https://go.drugbank.com/drugs/DB11077, accessed as on 2nd February, 2023.

38. https://pubchem.ncbi.nlm.nih.gov/compound/Polyethylene-Glycol-400, accessed as on

2nd February, 2023.

39. https://www.britannica.com/science/starch, accessed as on 2nd February, 2023.

40. https://www.sciencedirect.com/topics/nursing-and-health-professions/starch, accessed as

on 2nd February, 2023.

41. Raymond CR, Paul JS, Sia et al., Properties of microcrystalline cellulose. Handbook of

pharmaceutical excipient. 2006;(5):37, 180, 184, 354, 581.

42. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655391/, accessed as on 3rd March,

2023.

43. https://www.praannaturals.com/downloads/msds/MSDS_Magnesium_Stearate.pdf,

accessed as on 3rd March, 2023.

44. https://pubchem.ncbi.nlm.nih.gov/compound/Talc, accessed as on 3rd March, 2023.

Koringa College of Pharmacy Page 59

 References

45. https://pubchem.ncbi.nlm.nih.gov/compound/Aspartame, accessed as on 3rd March, 2023.

46. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-

science/croscarmellose-sodium, accessed as on 3rd March, 2023.

47. Section 1 designing your experiment; Handbook for Experimenters 2016 Stat-Ease, Inc.

48. W. J. Diamond textbook of stats.

49. Tanuwijaya J. Karsono. The effects of crospovidone and croscarmellose sodium as

superdisintegrants on the characteristics of piroxicam nanoparticles ODT (orally

disintegrating tablet). Int J PharmTech Res. 2013;5(4):1590-7.

50. Srilatha M, Naresh K, Vishnu Vamshi Y, Srikanth J. Formulation and evaluation of

acyclovir orodispersible tablets using sublimation method. J en Pract. 2015;3(208):2.

51. Azharuddin M, Kamath K, Shabaraya AR. Design and evaluation of fast dissolving

tablets of carvedilol using sublimation technique. International Journal of Pharmaceutical

Sciences and Research. 2012 Oct 1;3(10):3788.

52. Bhadkwade N, Rawat S, Galgatte U. Formulation and evaluation of oral disintegrating

tablets of lornoxicam by 32 factorial design. Journal of Applied Pharmaceutical Science.

2013 Sep 18;3(8,):S42-52.

53. Nagendrakumar D, Keshavshetti GG, MOGALE P, BHALKE N. Design and evaluation

of fast dissolving tablets of ergotamine tartarate. International Journal of Current

Pharmaceutical Research. 2015;7(2):101-4.

54. Ainurofiq A, Choiri S. Development and optimization of a meloxicam/β-cyclodextrin

complex for orally disintegrating tablet using statistical analysis. Pharmaceutical

Development and Technology. 2018 May 28;23(5):464-75.

Koringa College of Pharmacy Page 60

 References

55. Chen YD, Liang ZY, Cen YY, Zhang H, Han MG, Tian YQ, Zhang J, Li SJ, Yang DS.

Development of oral dispersible tablets containing prednisolone nanoparticles for the

management of pediatric asthma. Drug Design, Development and Therapy. 2015 Nov

20:5815-25.

56. Xu J, Bovet LL, Zhao K. Taste masking microspheres for orally disintegrating tablets.

International journal of pharmaceutics. 2008 Jul 9;359(1-2):63-9.

57. Mishra SM, Rohera BD. An integrated, quality by design (QbD) approach for design,

development and optimization of orally disintegrating tablet formulation of

carbamazepine. Pharmaceutical development and technology. 2017 Oct 3;22(7):889-903.

58. Hina K S, Kshirsagar.R.V, et al; Mathematical models for drug release characterization;

World Journal of Pharmacy and Pharmaceutical Sciences; 2015; 4(4); 324-338.

Koringa College of Pharmacy Page 61