FORMULATION AND PRODUCT DEVELOPMENT OF

AZITHROMYCIN TABLETS

Dissertation Submitted to
THE TAMIL NADU Dr. M.G.R. MEDICAL UNIVERSITY
Chennai-32

In Partial fulfillment for the award of the degree of

MASTER OF PHARMACY
IN
PHARMACEUTICS

Submitted by
Reg.No: 261210260

Under the guidance of

Mr. K. JAGANATHAN, M.PHARM.,

DEPARTMENT OF PHARMACEUTICS
J.K.K.NATTRAJA COLLEGE OF PHARMACY
KOMARAPALAYAM-638 183.
TAMIL NADU.
APRIL-2014
 CERTIFICATE

This is to certify that the dissertation entitled “FORMULATION

AND PRODUCT DEVELOPMENT OF AZITHROMYCIN
TABLETS‖ is a bonafied work done by Mr.RAJKUMAR T (Reg:No:
261210260), J.K.K. Nattraja college of pharmacy, in part and fulfillment of
the university rules and regulation for award of Master of Pharmacy in
Pharmaceutics under my guidance and supervision during the academic
year 2013-2014.

Mr. C. KANNAN, M. Pharm., Dr.R.SAMBATH KUMAR,M.Pharm.,Ph.D.,

Lecturer, Principal, Head of the Department,
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy,
J.K.K. Nattraja College of Pharmacy, Kumarapalayam —638 183,
Kumarapalayam —638 183. Tamil Nadu.
Tamil Nadu.

Dr.R.SAMBATH KUMAR,M.Pharm.,Ph.D.,
Principal, Head of the Department,
J.K.K. Nattraja College of Pharmacy,
Kumarapalayam —638 183.
Tamil Nadu.
 EVALUATION CERTIFICATE

This is to certify that the dissertation work entitled “FORMULATION AND

PRODUCT DEVELOPMENT OF AZITHROMYCIN TABLETS” submitted by the

student bearing Reg. No:261210260 to ―The Tamil Nadu Dr. M.G.R. Medical

University‖, Chennai, in partial fulfillment for the award of degree of MASTER OF

PHARMACY in PHARMACEUTICS was evaluated by us during the examination

held on……………………….

Internal Examiner External Examiner

 CERTIFICATE

This is to certify that the work embodied in this dissertation ―FORMULATION

AND PRODUCT DEVELOPMENT OF AZITHROMYCIN TABLETS”, submitted
to The Tamil Nadu Dr.M.G.R.Medical University, Chennai, was carried out by Mr.
T.RAJKUMAR [Reg. No. 261210260], for the Partial fulfillment of degree of
MASTER OF PHARMACY in Department of Pharmaceutics under the direct
supervision of Mr. K. JAGANATHAN, M.PHARM., Lecturer, Department of
Pharmaceutics, J.K.K.Natrajah College of Pharmacy, Komarapalayam, during the
academic year 2013-2014.

PLACE: Komarapalayam Dr. R.SAMBATH KUMAR, M.Pharm., Ph.D.,

DATE : Principal,
J.K.K.Nattraja college of Pharmacy,
Komarapalayam – 638183,
Tamil Nadu.
 CERTIFICATE

This is to certify that the work embodied in this dissertation ―FORMULATION

AND PRODUCT EVALUATION OF AZITHROMYCIN TABLETS”, submitted to
The Tamil Nadu Dr.M.G.R. Medical University, Chennai, in the requirement for the
award of degree of MASTER OF PHARMACY in pharmaceutics, is a bonafide work
carried out by Mr. T.RAJKUMAR [Reg. No. 261210260] during the academic year
2013-2014, under my guidance and direct supervision in the department of
Pharmaceutics, J.K.K.Nattraja College of Pharmacy, Komarapalayam.

Mr.K.Jaganathan,M.Pharm.,(Guide)

Lecturer,
Department of Pharmaceutics,
J.K.K. Nattaraja college of Pharmacy,
Komarapalayam-638183,
Tamil Nadu.

.
 DECLARATION

I hereby declare that the dissertation entitled ―Formulation and product development of
azithromucin tablets‖ was carried out by me, under the guidance of MR.K.Jeganathan,
M.Pharm., lecturer, for submission to ―Dr.MGR Medical University‖Chennai, in partial
fulfillment for the award of degree of master of pharmacy in pharmaceutics, the work is
original and has not been submitted in part (or) any degree of this (or) any other
university. The information furnished in this dissertation is genuine to best of my
knowledge and belief.

PLACE: Komarapalayam T.RAJKUMAR

DATE: Reg.No : 261210260
 ACKNOWLEDGEMENT

I would like to thank first and foremost my parents who instilled in me the
desire to do my best at whatever I attempt, and that with hard work I was capable of
anything. Without them I would not be there I am now.

I express whole hearted gratitude to my guide Mr. K. Jaganathan, M.Pharm.,

Lecturer, Department of Pharmaceutics, for suggesting solution to problems faced by me
and providing indispensable guidance, tremendous encouragement at each and every step
of this dissertation work. Without his critical advice and deep-rooted knowledge, this
work would not have been a reality.

I am proud to dedicate my deep sense of gratitude to the founder, (Late) Thiru

J.K.K. Nataraja chetttiar, providing us the historical institution to study.

My sincere thanks and respectful regards to our reverent Chairperson Smt. N.

Sendamaraai, B.Com., Managing Director Mr. S. Omm Sharravana, B.Com., LLB.,
and Executive Director Mr. S. Omsingarravel, B.E., M.S. J.K.K. Nattraja Educational
Institutions, Komarapalayam for their blessings, encouragement and support at all times.

It is most pleasant duty to thank our beloved Principal Dr. R. Sambath

kumar, M.Pharm., Ph.D., principal. J.K.K. Nataraja College of Pharmacy,
Komarapalayam for ensuring all the facilities were made available to me for the smooth
running of this project.

My heartful thanks to Dr. K. Sengodan, M.B.B.S., for encouraging us in a

kind and generous manner to complete this work.

My sincere thanks to Mrs.S. Bhama, M.Pharm., Assistant professer,

Mr.V.Kamalakannan, Lecturer, Mr.K.Kannan lecturer, Mr. M. kanagasabai,
B.Pharm., M.Tech Assistant Professor, Department of Pharmaceutics for their valuable
suggestions and co-operation and help during my project work.
 My sincere thanks to Mr. V. Sekar, M.Pharm., Ph.D Professor and Head of
the Department, Mr. Jayaselan, M.Pharm., Assistant Professor, Mr.
D. Boopathy, M.Pharm., Assistant Professor and Mr. S. Senthilraja M.Pharm.,
Assistant Professor, Department of Pharmaceutical Analysis for their valuable
suggestions and co-operation and help during my project work.

My sincere thanks to Dr. R.Shanmugasundaram, M.Pharm., Ph.D

Professor and Head of the Department, Mr. Sritharan, M.Pharm.,Lecturer,
Mr. Venketesh, M.Pharm., Ph.D lecturer Department of Pharmacology for their
valuable suggestions and co-operation and help during my project work.

My sincere thanks to Mr.Vijayabaskaran M.Pharm., Ph.D Asst.Professor

and Head of the Department, Mrs.Vasuki, M.Pharm.,Lecturer, Mrs.
Gomathi, M.Pharm., lecturer Department of Pharmaceutical chemistry for their
valuable suggestions and co-operation and help during my project work.

My sincere thanks to Mr.Mahadevan M.Pharm., Ph.D., Professor and Head

of the Department, Mrs.Balasubramaniyam, M.Pharm.,Lecturer,
Mrs. Mena prabha, M.Pharm., lecturer Department of Pharmacocnosy for their
valuable suggestions and co-operation and help during my project work.

My sincere thanks to Mr.Venkateshwara moorthy M.Pharm., Ph.D.,

Professor and Head of the Department, Dr.Senthil kumar, M.Pharm., Ph.D., prtofesser,
Mrs. Krishnaveni, M.Pharm., lecturer Department of Pharmacy practice for their
valuable suggestions and co-operation and help during my project work.

I greatly acknowledge the help rendered by Mrs. K. Rani, Office

Superintendent, Mr. K. Sakthivel, Clerical Assistant, Miss. V.V Prabha, typist, Mrs.
V. Gandhimathi, M.A., M.L.I.S., Librarian for their co-operation.

My sincere thanks to Ms.Gayathri MCA.,Mrs.Jayakala B.A,

Mr.Venketesan, Mr.manikandan, Mrs.Shanthi for their helpful support through out
the project work.

My special thanks to all the Departments, technical and non-technical staff

members of the institute for their precious assistance and help. I am extremely thankful
to all my friends and my parents for their co-operation, encouragement, support and
help throughout my work.

Its very difficult task to acknolwdge the services to thank all those gentle
people.so I would like to thank all those people who helped me directely or indirectely to
complete this project work successfully.

Place: Komarapalayam Mr. T.RAJKUMAR

Date : Reg. No: 261210260

 Abbreviation

Abbreviations:

NMT : Not More Than

NLT : Not Less Than
SS : Stainless Steel
mg : Milligrams
Qty : Quantity
MFC : Master Formula Card
BMR : Batch Manufacturing Record
mm : Millimeters
o
C : Degrees Centigrade
% w/w : Percentage weight/weight
QC : Quality Control
QA : Quality Assurance
BP : British Pharmacopoeia
IH : In House
USP-NF : United State Pharmacopoeia and National formulary
gm : Gram
USP : United State Pharmacopoeia
N : Newton
RH : Relative Humidity
Q.S. : Quantity sufficient
SOP : Standard Operating Procedure
D.T. : Disintegration Time
API : Active Pharmaceutical Ingredient
Kg : Kilogram
IP : Indian Pharmacopeia
Ph.Eur : European Pharmacopeia
LOD : Loss on Drying
NA : Not Applicable

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 CONTENTS

Chapter PAGE
TITLE
No. No.

1 INTRODUCTION 1-45

2 DRUG PROFILE 46-53

3 AIM AND OBJECTIVE 54-55

4 LITERATURE REVIEW 56-65

5 FORMULATION DEVELOPMENT 66-73

6 PRODUCT OPTMIZATION 74-86

7 MATERIAL AND METHODS 87-101

8 RESULT AND DISCUSSION 102-110

9 CONCLUSION 111

10 BIBLIOGRAPHY 112-115
Chapter 1 Introduction

CHAPTER - 1
INTRODUCTION
The main goal of pharmaceutical formulation is to achieve better therapeutic
activity in the shortest possible time by using smallest quantity of drug administered
by the most suitable route1.
Drugs can be administered through different routes; however, of all the
routes of administration, oral route of administration is most convenient for
administering drugs for systemic effect because of ease of administration and dosage
adjustments2. Parenteral route is not routinely used because of difficulty in self-
administration and hence hospitalization may be required. Topical route is recently
developed and is employed for only few drugs like nitroglycerine, scopolamine, for
systemic effect. Topical route has limitations in its ability to allow effective drug
absorption for systemic drug action. Parenteral administration is employed in case of
emergency and in which the subject is comatose or cannot swallow. Nevertheless it
is possible that at least 90% of all drugs used to produce systemic effect are
administered by oral route3.
Oral route of drug administration has wide acceptable and of the drugs
administered orally in solid dosage forms represents the preferred class of products.
The reasons are follows: ―tablets and capsules represent unit dosage forms in which
one usual dose of drug has been accurately placed‖.
Solid dosage forms of tablets and capsules are more commonly employed,
the tablets have advantages than capsules in that they are tamper resistant and any
adulterant of the tablet after its manufacture is almost certain to be observed. The
adulteration can be easily found if it is done in either liquid form or solid form since
deformation takes place, if it is done in liquid form and powders cannot be added to
the tablet if once they are formed. The major disadvantage of capsules over tablet is
their higher cost. The capsules either hard capsule or soft capsule they are
susceptible to breakage if they are not stored properly.

Dept. of Pharmaceutics 1 JKK Nattraja College of Pharmacy

Chapter 1 Introduction

1.1 TABLETS:
Tablets may be defined as solid pharmaceutical dosage forms containing
drug substances with or without suitable diluents and prepared either by
compression or molding methods. In European pharmacopoeia tablets are also
defined as ―Solid preparations each containing a single dose of one or more active
ingredients and obtained by compressing uniform volume of particles‖. They have
been in widespread use since the latter part of the 19th century and their popularity
continues1, 2.
Tablets remain popular as a dosage form because of the advantages, afforded
both to the manufacturer [e.g.: simplicity & economy of preparation, stability and
convenience in packing, shipping, and dispensing] and the patient [e.g.: accuracy of
dosage, compactness, post ability, blandness of taste and ease of administration].
Although tablets are more frequently discoid in shape, they also may be
round, oval, oblong, cylindrical or triangular. They may differ greatly in size and
weight depending on the amount of drug substance present and the intended method
of administration.
a) Properties of Tablets1:
The attributes of an acceptable tablet are as follows:
 The tablet must be sufficiently strong and resistance to shock and
abrasion and to withstand handling during manufacturing, packing,
shipping, and use. Hardness and friability tests measure this property.
 Tablet must be uniform in weight and in drug content of the individual
tablet. This is measured by the weight variation and content uniformity
tests.
 The drug content of the tablet must be bioavailability. This property is
measured by the dissolution test. Accurate bioavailability can be obtained
from the drug levels of the drug after its administration.
 Tablets must be elegant in appearance and must have characteristic
shape, color, and other markings necessary to identify the product.
 Tablets must retain all these functional attributes, which include drug
stability and efficacy.

Dept. of Pharmaceutics 2 JKK Nattraja College of Pharmacy

Chapter 1 Introduction

b) Advantages of Tablets2:
 They are easy to administer.
 They are a unit dosage form, and they offer the greater capabilities of all
oral dosage forms for the greatest dose precision and the least content
variability.
 Their cost is lowest of all oral dosage forms.
 They are the lightest and most compact of all oral dosage forms.
 Product identification is potentially the simplest and cheapest, requiring
no additional processing steps when employing an embossed or
monogrammed punch face.
 They are in general the easiest and cheapest to package and ship of all
oral dosage forms.
 They may provide the greatest ease of swallowing with the least tendency
for ―hang-up‖ above the stomach. Especially when coated, provided that
tablet disintegration is not excessively rapid.
 They lend themselves to certain special release profile products, such as
enteric or delayed release products.
 They are better suited to large-scale production than other unit oral
forms.
 They have the best-combined properties of chemical, mechanical and
microbiological stability of all the oral forms.
 One of the major advantages of tablet over capsules is that the tablet is
essentially ―tamperproof dosage form‖.

Dept. of Pharmaceutics 3 JKK Nattraja College of Pharmacy

Chapter 1 Introduction

c) Disadvantages of Tablets2:
 Some drugs resist compression into dense compacts, owing to their
amorphous nature or flocculent, low-density character.
 Drugs with poor wetting, slow dissolution properties, intermediate to
large dosages, optimum absorption high in the gastrointestinal tract, or
any combination of these features may be difficult or impossible to
formulate and manufacture as a tablet that will still provide adequate or
full drug bioavailability.
 Bitter tasting drugs, drugs with objectionable odor or drugs that the
sensitive to oxygen or atmosphere moisture may require encapsulation or
a special type of coating with may increase the most of the finished
tablets.
d) Types of Tablets1:
Tablets are classified according to their route of administration or function.
The following are the 5 main classification groups:

 Tablets ingested orally

 Compressed tablets
 Multiple compressed tablets
 Multilayered tablets
 Sustained action tablets
 Enteric coated tablets
 Sugar coated tablets
 Film coated tablets
 Chewable tablets
 Tablets used in the oral cavity
 Buccal tablets
 Sublingual tablets
 Lozenge tablets and torches
 Dental cones
 Tablets administered by other routes
 Implantation tablets
Dept. of Pharmaceutics 4 JKK Nattraja College of Pharmacy
Chapter 1 Introduction

 Vaginal tablets
 Tablets used to prepare solutions
 Effervescent tablets
 Molded tablets or tablet triturates (TT)
 Dispensing tablets (DT)
 Hypodermic tablets (HT)
1.2 TABLET MANUFACTURING4:
Tablets are compressed powders and their manufacturing is a complex,
multistep process. The ultimate aim is to easily disperse in gastrointestinal fluid and
in complete absorption of API and at the same time, offer stability to the
formulation.
The tablet manufacturing process can be broadly classified as:
1) Granulation method
a. Wet granulation method
b. Dry granulation method
2) Direct compression method
Oral dosage forms mainly solid dosage forms are more popular than other
dosage forms but suffer from problems like solubility, absorption Viz.
bioavailability, therefore patient compliance. Immediate release/conventional dosage
form is one of the approach to achieve the above goal. As dissolution rate is related
to absorption and bioavailability, increased dissolution rate will increase absorption
to give faster onset of action.
The enhancement of oral bioavailability of poorly water soluble drugs
remains one of the challenging aspects of drug development together with the
permeability. The solubility behavior of a drug is key determinate of its oral
bioavailability. There have always been certain drugs for which solubility has
presented a challenge to the development of a suitable formulation for oral
administration. The most important property of a dosage form is its ability to deliver
the active ingredient to its site of action in an amount sufficient to elicit the desired
pharmacological response. This property of the dosage form has been referred to as
its physiological availability.
Bioavailability is defined more precisely as the rate and extent of absorption
of a drug from its dosage form into the systemic circulation. Accordingly the
Dept. of Pharmaceutics 5 JKK Nattraja College of Pharmacy
Chapter 1 Introduction

absorption of an intravenously administered drug is instantaneous and complete.

However, for reasons of convenience and stability, most drugs are administered
orally offer first being formulated into dosage forms usually tablets and capsules.
The rate and extent of absorption from such dosage forms is usually not precisely
known as it is affected by a number of factors related to the drug, dosage form and
patient.
Solid dosage form
GI Barrier

Dissolution
Disintegration
Drug in solution Drug in
Blood, other
Dissolution
at the fluids &
Tissues
Granules Absorption site

Dissolution

Fine particles

Fig No. 1: Dissolution and Absorption of Drugs from Solid Dosage Forms3
When a drug is administered orally in a solid dosage form such as tablet,
capsule it must be released from the dosage form and dissolved in the gastro
intestinal fluid before it can be absorbed3. The bioavailability of many poorly water
soluble drugs is limited by their dissolution rates, which are in turn controlled by the
surface area that they present for dissolution6. Two consecutive transport processes
can be identified to describe the oral absorption of drugs from solid dosage forms.
1. Dissolution of the drug in vivo to produce a solution
2. Transport of the dissolved drug across the gastrointestinal membrane.
Each process can be characterized by a rate constant. If the rate of
dissolution of the drug is significantly slower than the rate of absorption, the
dissolution of the drug becomes the rate-limiting step in the absorption process, and
the particle size of the drug is of greater importance in the transport from the
gastrointestinal (GI) tract to the site of action Most drugs are passively absorbed and
their rates of absorption are dependent upon the concentration gradients in each
case; by increasing the dissolution rate in GI tract, the absorption rate increases, so
long as the dissolution rate is still the limiting step5. This commonly occurs for
drugs with limited water solubility.

Dept. of Pharmaceutics 6 JKK Nattraja College of Pharmacy

 Chapter 1 Introduction

Permeation
Solid Disintegration Solid drug Dissolution Drug in across the Drug in blood
dosage particles solution at the biological circulation
form absorption site membrane

RLS for
RLS for
hydrophilic
lipophilic
drugs
drugs

Fig No. 2: The Two Rate limiting Steps in the Absorption of Drugs from orally
administered formulations3
1.3. THEORIES OF DISSOLUTION:
Dissolution rate may be defined as the amount of drug substance that is
dissolved per unit time under standardized conditions of liquid-solid interface,
temperature and solvent composition. Dissolution can be considered a specific type
of heterogeneous reaction in which a mass transfer results a net effect between the
escape and deposition of solute molecules at a solid surface. The most common
theory for dissolution, the film theory, also known as the diffusion layer model
accepts the assumption that dissolution belongs to a type of heterogeneous reaction
where the rate is determined by the transport process3.
The following is the brief interpretation of this as well as some other
important dissolution theories.
a. Noyes-Whitney and Nernst-Brunner Equations:
Noyes and Whitney in 18976 stated that the rate at which a solid substance
dissolved in its own solution is proportional to the difference between the
concentration of that solution and the concentration of the saturated solution.
Mathematically it can be expressed as
dc
 K (Cs  Cb )
dt
Where: dc = the dissolution rate
K = proportionality constant
Cs = the solubility of the solute
Cb = the concentration at any time, t
The Noyes - Whitney equation can be explained as:

Dept. of Pharmaceutics 7 JKK Nattraja College of Pharmacy

Chapter 1 Introduction

A thin layer of saturated solution is formed at the surface of the solid and the rate of
dissolution is governed by the rate of diffusion from this layer to the bulk of the solution.
There is negligible change in the surface area with time during dissolutions.
Noyes-Whitney, Brunner7 and Tolloczko8 revised the equation assuming, that
under well-defined conditions of temperature and agitation, the dissolution rate is
proportional to the surface area ‗S', giving.
dc
 K1 (Cs  Cb )
dt
Where: K1 = called the intrinsic dissolution rate constant.
Applying Fick's law of diffusion to Nernst9 and Brunner10 equation
dc DS
 (Cs  Cb )
dt hv
Where: D = the diffusion coefficient of the solute.
h = the thickness of the diffusion layers.
V = the volume of the dissolution medium.
S= surface area
This has been referred to as film theory of Nernst Brunner, which applies to some
situations.
b. Cube root law:
Hixson and Crowell12 introduced the concept of changing surface area during
dissolution and derived the "Cube root law" given by.

  NP 
1/ 3
2 Dcs t
(WO )1/ 3  (W1 )1/ 3   
 6  hp
Where: W0 = the initial weight of solid.
W1 = the weight of solid at time, t.
N = the number of particles.
P = the density of the solid.
This equation is based on a number of assumptions:
1. Dissolution takes place normal to the surface of the dissolving solid particles.
2. No stagnation of liquid occurs in any region.
3. The same effect of agitation is observed on all areas of the solid surface.
4. Solid particles remain intact during the dissolution process and
5. The stagnant or diffusion layer thickness is independent of the particle diameter

Dept. of Pharmaceutics 8 JKK Nattraja College of Pharmacy

Chapter 1 Introduction

1.4. FACTORS INFLUENCING DRUG ABSORPTION FROM ITS DOSAGE

FORM3,5:
1. Pharmaceutical factors: Include factors relating to the physicochemical
properties of the drug and dosage form characteristic and pharmaceutical
ingredients.
a) Physicochemical properties of the drug substances
 Drug solubility and dissolution rate
 Particle size and effective surface area
 Polymorph and amorphism
 Pseudo polymorphism
 Salt form of the drug
 Lipophilicity of the drug
 Pka of the drug and pH
 Drug stability
b) Dosage Form Characteristics
 Disintegration time
 Dissolution time
 Manufacturing variables
 Pharmaceutical ingredients (excipients / adjuvants)
 Nature and type of dosage form
 Product and storage conditions
2. Patient Related Factors: Include factors relating to the anatomical,
physiological and pathological characteristics of the patient
 Age
 Gastric emptying time
 Intestinal transit time
 Gastro intestinal pH
 Disease states
 Blood flow through the GIT
 Gastrointestinal contents
 Pre-systemic metabolism

Dept. of Pharmaceutics 9 JKK Nattraja College of Pharmacy

 Chapter 1 Introduction

1.5. METHODS AVAILABLE TO ENHANCE THE DISSOLUTION RATE:

As far as the definition of bioavailability is concerned, a drug with poor
bioavailability is the one with, poor aqueous solubility and / or slow dissolution rate
in the biologic fluids, poor stability of the dissolved drug at the physiological pH,
inadequate partition coefficient and thus poor permeation through the bio-membrane
and extensive pre-systemic metabolism.
The three major approaches in overcoming the bioavailability problems due
to such causes are,
 The Pharmaceutical Approach
 The Pharmacokinetic Approach
 The Biological Approach
1. The Pharmaceutical Approach: This involves modification of formulation,
manufacturing process or the physicochemical properties of the drug without
changing the chemical structure.
2. The Pharmacokinetic Approach: In which the pharmacokinetics of the
drug is altered by modifying its chemical structure.
3. The Biological Approach: Where by the route of administration may be
changed such as changing from oral to parentral route.
Methods available to enhance the Dissolution Rate of poorly soluble drugs

Method Examples of drug

Methods which increases solubility of the drug
a. Buffering the pH of the environment Buffered Aspirin tablets
b. Use of salts of weak acids and bases
c. Use of solvates and hydrates Sodium, potassium and Calcium salts of P-amino
salicylic acid
d. Use of selected polymorphic forms Ampicillin hydrate, solvated forms of succinyl
Complexation sulfathiazole,Novobiocin,
e. Pro drug approach Chloramphenicol palmitate Benzocaine – Caffeine
f. Use of surfactants complex
Prodrugs of Ampicillin in Pirampicillin
Hydrocortisone - Tween 80
Tolbutamide - Tween 20
Methods which increase the surface area of the drug.
a. Micronization Griseofulvin, Digoxin, Phenacetin
(Particle size reduction to increase the
surface area)
b. Use of surfactants Phenacetin
(to increase effective surface area by
facilitating proper wetting)
c. Solvent deposition Oxyphenbutazone, Predinisolone, Indomethacin
(Deposition of poorly soluble drugs on inert
materials) Griseofulvin – PVP, Reserpine – PVP
d. Solid Dispersions
(Dispersion of poorly soluble drug in a
solid matrix of water soluble carrier).

Dept. of Pharmaceutics 10 JKK Nattraja College of Pharmacy

 Chapter 1 Introduction

DISEASE PROFILE:

1.6 (I) Community Acquired Pneumonia

Definition
Community acquired pneumonia (CAP) refers to a serious infection or
inflammation of the lungs that is generally acquired outside of a hospital or long
term care facility. When this infection is acquired, the air sacs in your lungs fill
with pus or other liquid, making it difficult for oxygen to penetrate through your
lungs to reach your bloodstream. If CAP is not treated properly with antibiotics
or spreads throughout your body, it can result in death, especially in the elderly
or in people with weakened immune systems
Causes
Community acquired pneumonia is spread by close person-to-person contact—
usually when an infected person coughs or sneezes on another person. CAP can
be caused by several different organisms, including bacteria, viruses, and fungi.
The most common organism responsible for CAP is the bacterium known as
Streptococcus pneumoniae. Although several "bugs" or organisms have been
confirmed to be causes of CAP, about 30% to 50% of pneumonia cases are
reported to have an unknown cause—meaning the exact "bug" responsible for
the infection is unknown or is not identified via laboratory testing.
About CAP
In the United States, CAP (combined with influenza or "the flu") is the eighth
leading cause of death and the number one cause of death from infectious
diseases. It is estimated that approximately 5.6 million cases of CAP occur
annually and of these 1.1 million require hospitalization. Anyone can be
susceptible to CAP, but it more commonly occurs in very young (less than 2
years of age) or elderly people. CAP is also more common in people who smoke
or have other severe illnesses, such as chronic obstructive pulmonary disease
(COPD), alcoholism, cancer, organ transplants, kidney disease, and immune
system disorders.

Dept. of Pharmaceutics 11 JKK Nattraja College of Pharmacy

 Chapter 1 Introduction

Risk Factors
Risk factors are characteristics that may increase the chance for developing a
condition. The more risk factors present, the more likely you are to develop the
condition. You are at an increased risk for developing CAP if you:
 Are 65 years or older
 Have other medical conditions or a combination of conditions such as:
1. Chronic obstructive lung disease (COPD) or other chronic lung disorders
2. Diabetes mellitus
3. Chronic kidney disease
4. Heart failure
5. Coronary artery disease
6. Cancer
7. Chronic liver disease
8. Cystic fibrosis
 Are a smoker
 Are exposed to certain chemicals or pollutants such as those used for agriculture,
construction, or industrial chemicals. Exposure to these pollutants can sometimes
cause damage to the lungs and contribute to lung inflammation—thus leaving the
lungs more susceptible to infection.
 Suffer from alcoholism and have a weakened immune system
Symptoms
CAP sometimes presents after a cold, the flu, or any condition that damages the
defenses of the airways that would allow bacteria to infect them. The symptoms
of CAP can vary and generally overlap with other symptoms of the common
cold or flu. This variability makes it sometimes difficult to recognize pneumonia.
Many people attribute it to a cold that just won‘t go away. However, CAP can be
life-threatening if it is not properly treated.
``Some symptoms that you may notice with community acquired pneumonia
include, but are not limited to:
 Shaking and chills ,Fever
 A cough that produces sputum—usually rust colored (or burnt orange)
 Shortness of breath and Chest pain worsened by deep breathing or
coughing and Night sweats
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Treatment
Treatment for CAP varies according to the organism responsible for the
infection. If the cause is bacterial, then the goal of treatment is to cure the
infection with antibiotics, which can typically be taken orally at home if the
infection is not severe. If the infection is severe, if the person is having difficulty
breathing, or has other chronic medical conditions, then intravenous (IV—
injected into a vein) antibiotics may be needed and are usually administered in a
hospital. If the infection is viral, the goal is to alleviate any signs and symptoms
of the infection through supportive care (such as fever reduction with
acetaminophen) since there is no cure for a virus.
Because several treatment guidelines are available, the specific drug(s) that your
doctor may use to treat your CAP may vary. Clinical expertise/preference and
antibiotic drug resistance in a particular area are two factors that may affect a
doctor‘s drug of choice for treating CAP.
At the initial visit to the doctor, he or she will question you about your past
medical history and perform a physical examination. It may be necessary to
perform a chest X-ray. Next, your doctor will determine how much your
infection places your life at risk. Your doctor may need to send samples of your
sputum, blood or urine to the laboratory to confirm your CAP diagnosis. Doctors
will usually prescribe "empiric therapy"—prescribing therapy based on the
suspected cause (bacteria, virus, or fungi) using clinical or practical expertise—
because the specific organism responsible for the infection is usually not yet
identified before treatment is started. After the organism is identified, therapy
can be tailored to treat that specific organism. The following chart describes the
guidelines from the Infectious Diseases Society of America and American
Thoracic Society for patients that don't need to be hospitalized.

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 Chapter 1 Introduction

1.7 (ii) Toxoplasmosis

Definition

Toxoplasmosis is an infectious disease caused by the one-celled protozoan

parasite Toxoplasma gondii. Although most individuals do not experience any
symptoms, the disease can be very serious, and even fatal, in individuals with
weakened immune systems.

Description

Toxoplasmosis is caused by a one-celled protozoan parasite known as

Toxoplasma gondii. Cats, the primary carriers of the organism, become infected
by eating rodents and birds infected with the organism. Once ingested, the
organism reproduces in the intestines of cats, producing millions of eggs known
as oocysts, which are excreted in cat feces daily for approximately two weeks. In
the United States, it is estimated that approximately 30% of cats have been
infected by T. gondii. Oocysts are not capable of producing infection until
approximately 24 hours after being excreted, but they remain infective in water
or moist soil for approximately one year. When cattle, sheep, or other livestock
forage through areas with contaminated cat feces, these animals become carriers
of the disease. Fruits and vegetables can also become contaminated when
irrigated with untreated water that has been contaminated with cat feces. In
humans and other animals, the organisms produce thick-walled, dormant
structures called cysts in the muscle and other tissues of the body.

Most humans contract toxoplasmosis by eating cyst-contaminated raw or

undercooked meat, vegetables, or milk products. Humans can also become
infected when they come into contact with the T. gondii eggs while cleaning a
cat's litterbox, gardening, or playing in a sand-box, for instance. Once infected,
an individual is immune to reinfection. The incubation period or period between
infection and the start of the disease ranges from several days to months.

Anyone can be infected by T. gondii, but usually only those individuals with
weakened immune systems (immunocompromised) develop symptoms of the
disease. For them, toxoplasmosis can be severe, debilitating, and fatal.

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Immunocompromised individuals at risk include those with AIDS, cancer, or

other chronic illnesses.

There is no person-to-person transmission, except from an infected mother to her

child in the womb. Approximately six out of 1,000 women contract
toxoplasmosis during pregnancy. Nearly half of these maternal infections are
passed on to the fetus. Known as congenital toxoplasmosis, this form of the
disease is acquired at birth by approximately 3,300 infants in the United States
every year. The risk of fetal infection is estimated to be between one in 1,000 to
one in 10,000. In children born with toxoplasmosis, symptoms may be severe
and quickly fatal, or may not appear until several months or even years after
birth.

Causes and symptoms

Healthy individuals do not usually display symptoms. When symptoms do occur,

they are usually mild, resembling infectious mononucleosis, and include the
following:

 Enlarged lymph nodes

 Muscle pains
 Fever that comes and goes
 General sick feeling
1.8 (iii) Trachoma

Definition
Trachoma is an eye infection caused by Chlamydia trachomatis, which may
result in chronic scarring and blindness if left untreated.
Alternative Names
Granular conjunctivitis; Egyptian ophthalmia
Causes, incidence, and risk factors

Trachoma is caused by infection with the bacteria Chlamydiatrachomatis. It has

an incubation period of 5 to 12 days and begins slowly as conjunctivitis
(irritation near the eye, "pink eye"), which if untreated may become chronic and
lead to scarring.

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If the eyelids are severely irritated, the eyelashes may turn in and rub against the
cornea. This can cause eye ulcers, further scarring, visual loss, and even
blindness.
Trachoma occurs worldwide -- primarily in rural settings in developing
countries. It frequently affects children, although the consequences of scarring
may not be evident until later in life. While trachoma is rare in the United States,
certain populations marked by poverty, crowded living conditions, and/or poor
hygiene are at higher risk for this illness.
Trachoma is acquired via direct contact with eye or nose-throat secretions from
affected individuals or by contact with inanimate objects that are contaminated
with these secretions, such as towels or clothes. In addition, certain flies that
have fed on these secretions can transmit trachoma.
Symptoms
 Conjunctivitis
 Discharge from the eye
 Swollen eyelids
 Turned-in eyelashes
 Swelling of lymph nodes just in front of the ears
 Cloudy cornea
Signs and tests
Trachoma is definitely diagnosed by detection of the organism or antigen in
conjunctival scrapings or by isolation of the bacteria in culture.
Treatment
Systemic therapy with oral antibiotics can prevent long-term complications if
used early in the infection. Active antibiotics include erythromycin and its
derivatives, or doxycycline. In certain cases, eyelid surgery for lid deformities
may be needed to prevent chronic scarring which can lead to blindness if not
corrected

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Expectations (prognosis)
Early treatment before the development of scarring and lid deformities has an
excellent prognosis.
Complications
 Scarring of the conjunctiva and cornea
 Lid deformities
 Turned-in eyelashes
 Visual loss -- if severe, may result in blindness
Calling your health care provider
Call your health care provider if you or your child recently visited an area of the
world where trachoma is common and there are symptoms of conjunctivitis.
Prevention
Trachoma is spread by direct contact with eye, nose, and throat secretions from
affected individuals or by contact with objects that may have been in contact
with these secretions.
Improved sanitation and not sharing toilet articles such as towels are important
measures for limiting the spread/acquisition of trachoma.

1.9. (iv) Mycobacterium Avium Complex (MAC)

Definition
MAC, formerly known as MAI, stands for Mycobacterium Avium Complex.
MAC is a group of mycobacteria (the two most common being M. avium and
M. intracellulare), that cause a serious disease in people with advanced AIDS.
MAC most often causes a disseminated illness (bacteria is spread though the
blood stream) and can cause many symptoms throughout the body.
MAC bacteria are found in air, water, soil, foods, some tobacco products, and in
many animals. It is impossible to avoid contact with MAC bacteria. A recent
study showed that person-to-person transmission of MAC bacteria is unlikely.

Risk factor
Risk factors for developing MAC include having fewer than 50 CD4 cells, a
high viral load (greater than 90,000 copies per/ml), and having had another
opportunistic infection such as CMV (cytomegalovirus).

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Before HAART (Highly Active Antiretroviral Therapy), also known as the

"cocktail," the number of people with AIDS who developed MAC reached as
high as 40 percent. Since HAART, the number of people getting MAC has
greatly declined.
Signs and symptoms
MAC can infect a person's entire body. The signs and symptoms of MAC can be
the same signs of other diseases. They include high fever, drenching sweats,
diarrhea, weight loss, abdominal pain, fatigue, weakness, anemia (low levels of
red blood cells), neutropenia (low levels of white blood cells) or
thrombocytopenia (low levels of platelets), and elevated liver function tests. The
liver or spleen may be enlarged. Blood infections, hepatitis, skin lesions, and
pneumonia may also occur.
Treatment
A doctor will usually give you a blood test to see if you have MAC. Although
the blood test is the best test at this time, sometimes other tests are needed. Other
tests may include stool samples and biopsies of the liver, digestive tract (gut),
bone marrow, or other organs. Biopsies involve taking a sample of an organ
using a big needle. Biopsies can be painful but are more reliable than stool
samples.
Prevention
Yes, there are medications available that can help reduce one's risk of
developing MAC. Preventive medication, also called prophylaxis, is
recommended for anyone who is HIV-positive and has 50 CD4 cells or less.
While rifabutin, clarithromycin, and azithromycin are all approved drugs for
prophylaxis of MAC, clarithromycin and azithromycin are the preferred choices.
You should talk with your doctor to see which one of these medications is best
for you.
Treatment
Treatment for MAC involves taking a combination of antibiotics. MAC
treatment must include at least two drugs, one of which should be either
clarithromycin or Azithromycin. Ethambutol is the recommended second drug.
Rifabutin, ciprofloxacin, or amikacin may be added for people with more severe

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MAC. All of the drugs are pills except amikacin, which is given intravenously
(IV).
In cases where people with MAC either do not respond to treatment at all or
relapse after first responding to treatment, many doctors recommend a type of
drug test that checks to see if the medications will work on the type of MAC a
person has. This is called a drug susceptibility test. Susceptible means that the
drugs will likely work, while resistant means that the drugs probably will not
work. Susceptibility testing is recommended mainly for clarithromycin,
azithromycin, and rifabutin, though other drugs might be tested as well.
MAC and the drugs used for treatment are hard on the body. You might consider
visiting a nutritionist when you are first diagnosed with MAC so you can keep
your weight up and prevent wasting. There are also medications available to help
ease common MAC symptoms such pain, nausea, vomiting, and diarrhea, so do
not be shy in asking for them.

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1.10 Introduction of product Development

Product development usually begins when the active chemical entity has
been shown to process the necessary attributes for a commercial product.
Generally product development activities can be sub divided into formulation
development and process development.
1.10.1 Formulation Development1
Formulation development provides the basic information on the active
chemical, the formula and the impact of raw materials or excipients on the
product. A typical supportive data generated during these activities may include:
1. Preformulation profile, which includes all the basic physical or chemical
information about the chemical entity.
2. Formulation profile, which consist of physical and chemical characteristics
required for the product, drug excipients compatibility studies, and effect of
formulation on in-vitro dissolution.
3. Effect of formulation variable on the bioavailability of the product.
4. Specific test methods.
5. Key product attributes and specification
6. Optimum formulation
Formulation development should not be considered complete until all those
factors which could significantly alter the formulation have been studied.
Subsequent minor changes to the formulation, however, may be acceptable,
provide they are thoroughly tested and as shown to have no adverse effect on
product characteristics. In case of drug development process, compound tested is
only one. A variety of studies must be performed for this single drug, each
designed to characterize its efficacy, safety, selectivity or purity. Much of the
data generation is driven by strict and extensive regulatory control and in this
most of the studies are interdependent.
Objective: - The overall objective of a drug development process is to move
product candidate through development so that a new drug applicant (NDA) or
product license application (PLA) can be submitted as quickly as possible with
best chance of approval.

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1.10.2 Pharmaceutical issues in drug development

A) Role of excipients in drug development: - The bulk of final product in dosage
form such as tablet, capsule etc the speed of disintegration, rate of dissolution/
release of drug, protection against moisture and stability during storage, as well
as compatibility are determined by the excipients. Various excipients used are
adhesives, absorbent excipients, liquid excipients, diluents, fillers, disintegrates,
etc.
► The general characteristics of excipients are: -
 Must not react with drug substance.
 No effect on function of other excipients.
 Not interfere with the bioavailability of active material nor influence dissolution of
the product.
 No pharmaceutical or physiological activity.
 Have consistent and stable chemical and physical characteristics & properties from
batch to batch and ideally between suppliers.
 Colorless and not support microbiological growth in the product.
Performance characteristics of the excipient are
 Functionality: The control of functionality is important because many excipients
have multiple functions or sometimes there is lack of awareness in some situations
that excipients behave differently.
 Rework ability: The reworking potential is defined as the ratio of areas under the
tensile strength compression profiles for re compression and for initial compression.
Often the results show that recompression reduces tablet strength and that this
reduction is more significant when the initial compaction is carried out at high
pressure.
 Response and force loading rate:
 Modes of deformation: Tableting machines, which deform plastically with little
elastic recovery, should produce better quality tablets than more resilient materials.
 Effects on compression rate: Mostly strength of the tablets depend on the speed of
rotary tablet press and hence on rate of tablet compression. In virtually all the cases,
increase in tablet press speed led to a decrease in tablet strength.

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B) Dosage form design

A rational approach to dosage form design for any drug requires a complete
understanding of its physiochemical and biopharmaceutical properties which can
have a tremendous impact on its bioavailability and thereby on its efficacy and
toxicity profile. Properties that dictate the selection and formulation of dosage
forms include:
 Solubility and dissolution rate.
 Partition coefficient.
 Stability and/or degradation in physiologic fluids.
 Susceptibility to metabolic inactivation.
 Transport mechanism across biological membranes.
C) In vitro correlation
In vitro dissolution tests seem to be the most sensitive and reliable predictors of
in vivo availability. Invitro in vivo correlations are classified as pharmacological
correlations, semi quantitative correlations and quantitative correlations.
Drug development also includes phase 1, 2 and 3 trials carried out on a particular
group of people after analogue development and screening process.
2.10.3 Process Development
Process development activities begin after the formulation has been developed.
The process development should meet the following objectives:
1.Develop a suitable process to produce a product which meets all:
a. Product specifications
b. Economic constrains
c. cGMP
2.Identify the key process parameters that affect the product attributes
3.Identify in-process specification and test method
4.Identify generic and specific equipment that may required.

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PRODUCT DEVELOPMENT FLOWCHART

Solid, Dosage Forms
STAGE 1
LITERATURE
SEARCH

STAGE 2
ACTIVE SOURCING

STAGE 3
ACTIVE EVALUATION

Do not evaluate material
While still in a R & D stage STAGE 4
Use only production activity ACTIVE PURCHASING
PREFORMULATION  STAGE
STAGE 5
ACTIVE TESTING

STAGE 6
INNOVATOR PRODUCT PURCHASING
Purchase a new lot 
Lot number every 3 mth
From the smallest to the STAGE 7
Largest pack size INNOVATOR PRODUCT TESTING
(in each dosage strength ) 
STAGE 8
BULK ACTIVE TESTING

STAGE 9
Excipient Evaluation

Residual solvent Check 

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STAGE 10
Container Closure
System Choices

STAGE 11 DEVELOPMENT BATCHES
Manufacturing Process Evaluation

STAGE 12
Bulk Active Purchase

STAGE 13
Analytical Evaluation

STAGE 14
Prepared full written protocol Process Optimization
For PO scale up & PQ batches PO Batch

STAGE 15
Analytical development PROCESS OPTIMIZATION

STAGE 16.
SCALE – UP


STAGE 17
PROCESS
QUALIFICATION

STAGE 18 PIVOTAL BATCHES
PIVOTAL BATCH
PRODUCTION


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STAGE 19
BIO-EQUIVALENTS
BIO STUDY EVALUATION STUDY

Review all raw data development STAGE 20
& lab note book. Evaluate all interim ANDA PRE-SUBMISSION
Report that from part of the AUDIT

Product Development Report 

SCOPE OF PRODUCT
STAGE 21 Development
ANDA SUBMISSION

STAGE 21 B
PRODUCT DEVELOPMENT REPORT

Process validation STAGE 22
Signify the first THREE Process Validation &
Consecutive production Statistics Process Validation
Lots (same batches size and (3 commercial lots)
Active lot no ) 
STAGE 23
Process Revalidation
After a major change
(Check SUPAC)

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1.11. Process development can be divided into several stages

a) Design
b) Ranging
c) Characterization
d) Verification
a) Design
This is the initial planning stage of process development. During this stage,
technical operation in both the manufacturing and quality-control departments
should be consulted. The practically and the reality of the manufacturing
operation should be kept in perspective.
Key documents for the technical definition of the process are the flow diagram,
the cause and effect diagram and the influence matrix.
The flow diagram provides a convenient basic on which to develop a detailed list
of variables and responses. Preliminary working documents are critical, but they
should never be ―cast in stone‖, since new experimental data may drastically
alter them. The final version will eventually be an essential part of the process
characterization and technical transfer documents. Regardless of the stage of
formulation/process development being considered, a detail identification of
variables and response is necessary for early program planning.
As the development program progresses, new discoveries will provide an update
of the variable and responses. It is important that current knowledge be
adequately summarized for the particular process being considered. It should be
pointed out, however that common sense and experience must be used in
evaluating the variable during process design and development.
An early transfer of the preliminary documentation to the manufacturing and
quality control department is essential, so that they can being to prepare for any
new equipment or facilities that may required.

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b) Ranging
Process-ranging studies will test whether identified parameter are critical to the
product and process being developed. These studies determined the:
a. Feasibility of the design process
b. Criticality of the parameter
c. Failure limits for each of the critical variable
d. Validity of the test methods
This is usually a transition stage between the laboratory and the projected final
process.
c) Characterization
Process characterization provides a systematic examination of critical variables
found during process ranging. The objectives of these studies are:
a) Confirm key process control variables and quality their effect on product
attributes.
b) Establish product conditions for each unit operation.
c) Determine in process operating limits to guarantee acceptable finished product
and yield.
d) A carefully planned and coordinate experimental program is essential in order to
achieve this objective.
d) Verification
Prior to a process being scale-up and transferred to production, verification is
required. This ensures that it behave as designed under simulated production
conditions and Determines its reproducibility. Key elements of the process-
verification runs should be evaluated using well-designed in-process sampling
procedure. These should be focused on potentially critical unit operations.
Validated in-process and final product analytical procedures should always be
used. Sufficient replicate batches should be produced to determine between and
within-batch variations.

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The typical process verification analysis of a tableted product include

Table NO: 2.1
Unit Operation Analysis
Blend uniformity, Dry-mix, Water content by KF
Pre-blending
apparatus
Granulation None required
Granules size distribution, Milled Granules-Water
Sizing
content by KF apparatus.
Blend uniformity, Flow properties
Blending
Potency/assay
Average weight
Hardness
Thickness
Tableting
Disintegration
Dissolution
Friability

The transfer procedure that is followed in order to pass the documented

knowledge and experience gained during development and commercialization to
an appropriate, responsible and authorized party. Technology transfer embodies
both the transfer of documented and demonstrated technology, to the satisfaction
of all parties and any and all applicable regulatory bodies.

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1.12 Technology transfer subdivided into two units6:

o Sending unit
o Receiving unit
● Advantages:
 The transfer of technology from R & D (sending unit) to manufacturing
(Receiving unit) is the first key steps to getting a high quality product to the
market place.
 The transfers of the process technology from the R & D bench to large scale
manufacturing present some unique challenges.
 It also useful to make a timeframe of the process for that particular product.
 Hold time studies is useful for the planning of the product with other batches.
● Objectives:
 To describe the appropriate information set that needs to be complied to
support the transfer of the information and provide regulatory filing
documents.
 To provide guidance on effective approaches for ensuring this information is
available at ―print of use‖ where guidance on specific topic already exists
this will be referred.
 The technology transfer guide is planning in such a way that technology
transfer performed in accordance with the recommendations in this guide
will be the regulatory authorities.

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1.12.1 Process Optimization5:

In the environment of increasing international competition where counters
with lower production cost luckily catch up technologically, new thinking is
required in order to meeting the competition is to focus on maximizing the
utilization of exiting technology. This means much more than just investing in
new equipment.
The ability to optimize or improve a process is dependent upon the ability
to control the process. The ability to control the process is dependent upon the
access to reliable and valid management.
The ability to control the processor. The ability to optimize the process is depend
upon the access to reliable and valid managements. A successful industrial
organization thus entails a strategic approach encompassing the whole chain.
A) Need for Optimization
In an environment of increasing competition where countries with lower
production cost, quickly catch up technologically, new thinking is required in
order to meet the competition. Efficient organization and leadership is more
difficult to copy than technology. A successful way of meeting the increasing
competition can thus be to focus the effort on adapting the organization for
maximal utilization of existing technology and faster than competitors, being
able to continuously introduce and make use of new technology.
B) Optimization Technology
There are two type optimization problems. They are:
1. Constrained Optimization:
Constrains are those restricted placed on the system due to physical
limitation.
(Ex: Economic consideration)
2. Unconstrained Optimization:
In unconstrained optimization problems there are no restriction (such as tablet
hardness and disintegration).
An additional complication in pharmacy is that formulations are not usually
simple system. They often contain many ingredients and variables, which may
interact with one another to produce unexpected.
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1.12.3 Scale Up & Technology Transfer Consideration7

 Scale up means increase the batch size; it acts a link between the formulation
research development and production.
The pilot plant and its staff play a critical role in technology evolution scale-up
and transfer activity of new products.
 These activities being early in the development cycle and include technical aspects
of process development and scale-up, organization and responsibility of technology
transfer team, documentation of transfer process, and obtain preparation for an FDA
pre-approval inspection. A properly design and operated pilot plant enhance the
collection of scientific data necessary to support internal transfer activities as well as
regulatory submission and FDA pre-approval inspection.
 Four key technical aspects must be addressed during scale-up in the pilot plant.
Identification and control of critical component and formulation variables early
in the development.
Pilot plant equipment that simulates as closely as possible equipment used at
The manufacturing site.
Identification of critical process parameter and operating ranges with pilot plant
equipment through the use of engineering and regret ion models.
Collection of product and process data to adequately characterized each unit
operation.
The success of any program is highly dependant on the effectiveness of the
communication presiding its implementation. Therefore, the preparation and
distribution of a complete document summarizing the raw material and
equipment requirements, manufacturing and packing process, process validation
protocol, QC processor, safe handling processor as well as a detail plan of action
out limiting expected result and time framer must be distributes prior to scale-up
experiences.
 The three main considerations to be address during an effective technology transfer
of plan. The person involved and process steps. Once prepared, the plan must be
communicated to the involved part in research, at the corporate level and at the
production site.

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 The facility design plan a critical role in addressing each of their technical aspects,
however scientific and pilot plant staff involved in manufacturing operations with in
the pilot facility also play a key role in ensuring smooth and timely transfer of
process technology to the manufacturing site.
 In the part, the transfer of formulation and, manufacturing technology was some
times discretely processed from development staff with little interaction. Today,
however, it is commonly recognize the interaction of these groups at an early
development stage is critical in obtaining an efficient and successful transfer.
 Scientific and pilot plants staff a key role in demonstrating new product
manufacturing techniques to produce personal in the pilot plant environment.
 A team orientation approach to the manufacture of pilot or large scale batches in the
pilot plant will allow key production site personnel to view and comment on the
process and make a specific recommendation for improvement based on the
knowledge of the manufacturing site.

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1.12.4 Introduction of Immediate Release Dosage Form:

Oral route of drug administration is perhaps the most appealing route for the delivery of
drugs.8 Of the various dosage forms administered orally, the tablet is one of the most
preferred dosage forms because of its ease of manufacturing, convenience in
administration, accurate dosing, stability compared with oral liquids, and because it is
more tamperproof than capsules.9, 10 The bioavailability of drug is dependent on in vivo
disintegration, dissolution, and various physiological factors. In recent years, scientists
have focused their attention on the formulation of quickly disintegrating tablets. The
task of developing rapidly disintegrating tablets is accomplished by using a suitable
diluent and superdisintegrant.
The gastrointestinal tract provides sufficient fluid to facilitate disintegration of the
dosage form and dissolution of the drug. The large surface area of gastric mucosa favors
the drug absorption. Therefore, the oral route has continued to be the most appealing
route for drug delivery despite the advancements made in the new drug delivery
systems. Banker and Anderson stated that at least 90% of all drugs used to produce
systemic effect are administered orally.11 Rapidly disintegrating tablets have received
much attention in recent years, as they are preferred by pediatric and geriatric patients.
Moreover, the drug dissolution is facilitated by the tablets quick disintegration.
Bioavailability of a drug depends in absorption of the drug, which is affected by
solubility of the drug in gastrointestinal fluid and permeability of the drug across
gastrointestinal membrane. The drugs solubility mainly depends on physical – chemical
characteristics of the drug. However, the rate of drug dissolution is greatly influenced by
disintegration of the tablet.
The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure
of limited surface area to the fluid. The disintegration test is an official test and hence a
batch of tablet must meet the stated requirements of disintegration.
Disintegrants, an important excipient of the tablet formulation, are always added to
tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this
process of desegregation of constituent particles before the drug dissolution occurs, is
known as disintegration process and excipients which induce this process are known as
disintegrants.
The objectives behind addition of disintegrants are to increase surface area of the tablet
fragments and to overcome cohesive forces that keep particles together in a tablet.

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1.13. Mechanism of tablet Disintegrant 12

The tablet breaks to primary particles by one or more of the mechanisms listed
below:-
1) By capillary action
2) By swelling
3) Because of heat of wetting
4) Due to disintegrating particle/particle repulsive forces
5) Due to deformation
6) Due to release of gases
7) By enzymatic action
1) By capillary action
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
hydrophilic 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.
2) By 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.

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 Chapter 1 Introduction

Figure.1 disintegration of tablet by wicking and swelling

3) Because of heat of wetting (air expansion)
When disintegrants with exothermic properties gets wetted, localized stress is
generated due to capillary air expansion, which helps in disintegration of tablet.
This explanation, however, is limited to only a few types of disintegrants and can
not describe the action of most modern disintegrating agents.
4) Due to disintegrating particle/particle repulsive forces
Another mechanism of disintegration attempts to explain the swelling of tablet
made with ‗non-swellable‘ disintegrants. Guyot-Hermann has proposed a
particle repulsion theory based on the observation that no swelling 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.
5) Due to deformation.
Hess had proved that 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
break up of the tablet. This may be a mechanism of starch and has only recently
begun to be studied.

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 Chapter 1 Introduction

Figure.2. disintegration by deformation and repulsion:

6) Due to release of gases
Carbon dioxide released within tablets on wetting due to interaction between
bicarbonate and carbonate with citric acid or tartaric acid. The tablet
disintegrates due to generation of pressure within the tablet. This effervescent
mixture is used when pharmacist needs to formulate very rapidly dissolving
tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to
small changes in humidity level and temperature, strict control of environment is
required during manufacturing of the tablets. The effervescent blend is either
added immediately prior to compression or can be added in to two separate
fraction of formulation.
7) By enzymatic reaction
Here, enzymes presents in the body act as disintegrants. These enzymes destroy
the binding action of binder and helps in disintegration.
Table.2.2.1. Disintegrating enzymes
Enzymes Binder
Amylase Starch
Protease Gelatin
Cellulose Cellulose and its derivatives
Invertase Sucrose

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 Chapter 1 Introduction

Methods of addition of Disintegrants

The method of addition of disintegrants is also a crucial part. Disintegrating agent can
be added either prior to granulation (intragranular) or prior to compression (after
granulation i.e. extragranular) or at the both processing steps. Extragranular fraction of
disintegrant (usually, 50% of total disintegrant requires) facilitates breakup of tablets to
granules and the intragranular addition of disintegrants produces further erosion of the
granules to fine particles.
1.13.1 Types of Disintegrants
1) Starch
Starch was the first disintegrating agent widely used in tablet manufacturing. Before
1906 potato starch and corn starch were used as disintegrants in tablet formulation.
However, native starches have certain limitations and have been replaced by certain
modified starches with specialized characteristics.
The mechanism of action of starch is wicking and restoration of deformed starch
particles on contact with aqueous fluid and in doing so release of certain amount of
stress which is responsible for disruption of hydrogen bonding formed during
compression.
Lowenthal & Wood proved that the rupture of the surface of a tablet employing starch
as disintegrant occurs where starch agglomerates were found. The conditions best suited
for rapid tablet disintegration are sufficient number of starch agglomerates, low
compressive pressure and the presence of water.
The concentration of starch used is also very crucial part. If it is below the optimum
concentration then there are insufficient channels for capillary action and if it is above
optimum concentration then it will be difficult to compress the tablet.
2) Pregelatinized starch
Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch grain. It
is a directly compressible disintegrants and its optimum concentration is 5-10%. The
main mechanism of action of Pregelatinized starch is through swelling.
3) Modified starch
To have a high swelling properties and faster disintegration, starch is modified by
carboxy methylation followed by cross linking, which is available in market as cross
linked starch. One of them is sodium starch glycolate. Even low andsubstituted
carboxymethyl starches are also marketed as Explotab Primojel®.
Mechanism of action of this modified starches are rapid and extensive swelling with
minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its limit,

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 Chapter 1 Introduction

then it produces viscous and gelatinous mass which increases the disintegration time by
resisting the breakup of tablet. They are highly efficient at low concentration because of
their greater swelling capacity.
Table.2.2.2 List of disintegrants
Concentration in
Special comments
Disintegrations granules
(%w/w)
Higher amount is required,
Starch USP 5-20
poorly compressible
Direct compression 5-15 --
Lubricant properties and
Avicel®(PH 101, PH 102) 10-20
directly compressible
Solka floc® 5-15 Purified wood cellulose
Alginic acid 1-5 Acts by swelling
Na alginate 2.5-10 Acts by swelling
Sodium starch glycolate,
Explotab® 2-8
superdisintegrant
Polyplasdone®(XL) 0.5-5 Crosslinked PVP
Amberlite® (IPR 88) 0.5-5 Ion exchange resin
Methyl cellulose, Na CMC,
5-10 --
HPMC
AC-Di-Sol® 1-3 Direct compression
4) Cellulose and its derivatives
Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly
hydrophilic structure and is soluble in water. But when it is modified by internally
crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is
nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original
volume when it comes in contact with water.
5) Microcrystalline cellulose (MCC)
MCC exhibit very good disintegrating properties because MCC is insoluble and act by
wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of
MCC. It also serves as an excellent binder and has a tendency to develop static charges
in the presence of excessive moisture content. Therefore, sometimes it causes separation
in granulation. This can be partially overcome by drying the cellulose to remove the
moisture.
6) Alginates
Alginates are hydrophilic colloidal substances which has high sorption capacity.
Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in
water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral

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 Chapter 1 Introduction

granulation. Unlike starch and MCC, alginates do not retard flow and can be
successfully used with ascorbic acid, multivitamin formulations and acid salts of
organic bases.
7) Ion-exchange resin
Ion exchange resin (Ambrelite®IPR-88) has highest water uptake capacity than other
disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain
drugs.
8) Miscellaneous
This miscellaneous category includes disintegrants like surfactants, gas producing
disintegrants and hydrous aluminium silicate. gas producing disintegrating agents is
used in soluble tablet, dispersible tablet and effervescent tablet.
Polyplasdone®XL and Polyplasdone®XL10 act by wicking, swelling and possibly
some deformation recovery. Polyplasdone®XL do not reduce tablet hardness, provide
rapid disintegration and improved dissolution. Polyplasdone® as disintegrating agent
has small
Particle size distributions that impart a smooth mouth feel to dissolve quickly. Chewable
tablet does not require addition of disintegrant.
9) Superdisintegrants
As day‘s passes, demand for faster disintegrating formulation is increased. So,
pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective
at low concentration and have greater disintegrating efficiency and they are more
effective intragranularly. But have one drawback that it is hygroscopic therefore not
used with moisture sensitive drugs.
And this superdisintegrants act by swelling and due to swelling pressure exerted in the
outer direction or radial direction, it causes tablet to burst or the accelerated absorption
of water leading to an enormous increase in the volume of granules to promote
disintegration.

Figure.2.2.3 mechanism of superdisintegrants by swelling

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 Chapter 1 Introduction

1.14 Factors affecting disintegration

1) Effect of fillers
The solubility and compression characteristics of fillers affect both rate and
mechanism of disintegration of tablet. If soluble fillers are used then it may
cause increase in viscosity of the penetrating fluid which tends to reduce
effectiveness of strongly swelling disintegrating agents and as they are water
soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents
produce rapid disintegration with adequate amount of disintegrants. Chebli and
cartilier proved that tablets made with spray dried lactose (water soluble filler)
disintegrate more slowly due to its amorphous character and has no solid planes
on which the disintegrating forces can be exerted than the tablet made with
crystalline lactose monohydrate.
2) Effect of binder
As binding capacity of the binder increases, disintegrating time of tablet
increases and this counteracts the rapid disintegration. Even the concentration of
the binder can also affect the disintegration time of tablet.
3) Effect of lubricants
Mostly lubricants are hydrophobic and they are usually used in smaller size than
any other ingredient in the tablet formulation. When the mixture is mixed,
lubricant particles may adhere to the surface of the other particles. This
hydrophobic coating inhibits the wetting and consequently tablet disintegration.
Lubricant has a strong negative effect on the water uptake if tablet contains no
disintegrants or even high concentration of slightly swelling disintegrants. On
the contrary, the disintegration time is hardly affected if there is some strongly
swelling disintegrants are present in the tablet. But there is one exception like
sodium starch glycolate whose effect remains unaffected in the presence of
hydrophobic lubricant unlike other disintegrants.

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4) Effect of surfactant
Table.2.2.3 the effects of various surfactants
Surfactant Remarks
Sodium lauryl sulfate
Good-various drugs Poor - various drugs

Polysorbate 20 Good
Polysorbate 40 & 60 Poor
Polysorbate 80 Good
Tweens Poor
Poly ethylene glycol Poor

(Good – decrease in disintegration time, Poor – increase in disintegration time)

Sodium lauryl Sulphate increased absorption of water by starch or had a variable
effect on water penetration in tablets. Surfactants are only effective within
certain concentration ranges. Surfactants are recommended to decrease the
hydrophobicity of the drugs because the more hydrophobic the tablet the greater
the disintegration time. Aoki and fukuda claimed that disintegration time of
granules of water-soluble drugs did not seem to be greatly improved by the
addition of nonionic surfactant during granulation , but the desired effect of a
surfactant appeared when granule were made of slightly soluble drugs.

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 Chapter 1 Introduction

1.15 Antibacterial agent42

Definition: These are agents which are used for the to kill or inhibit the bacteria.

1.15.1Classification of antibacterial agent:

The antibacterial agents are classified according to its mode of action.

(A) Antibacterial agents which interfere with the synthesis or action of folate.
1. Sulphonamide
2. Trimethoprim
(B) Beta-lactam antibiotics
1. Penicillin
2. Cephalosporins and Cephamycin
3. Other β – lactam antibiotics
(C) Antibacterial agents affecting bacterial protein synthesis.
1. Tetracyclines
2. Chloramphenicol
3. Aminoglycosides
4. Macrolides
i. Azithomycin
ii. Erythromycin
iii. Clarithomycin
(D) Antibacterial agents affecting topoisomerase-2
1. Fluoroquinolones
(E) Miscellaneous antibacterial agents
1. Glocopeptide
2. Polymixin antibiotics
3. Bacitracin
4. Metronidazole
5. Nitrofurantion
(F) Antimycobacterial agents for treat to tuberculosis.
1. Streptomycin
2. Isoniazide
3. Rifampicin
4. Ethambutal
5. Pyrazinamide
6. Capreomycin
7. Cycloserine
(G) Antimycobacterial agents for treat to leprosy
1. Dapsone
2. Rifampicin
3. Cloazimine

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 Chapter 1 Introduction

1.15.2 Macrolides antibiotics

The macrolides are a large group of antibacterial mainly derived from
Streptomycess spp.and having a common macrocyclic lactone ring to which one
or more sugar is attached. They are all weak base and only slightly soluble in
water .Their properties are very similar and in general they have low toxicity
and a similar spectrum of antimicrobial activity with cross-resistance b/w
individual members of the group. The macrolides are bacteriostatic or
bactericidal depending on the concentration and the type of micro-organism
and are thought to interfere with bacterial protein synthesis. Their antimicrobial
spectrum is similar to that of benzyl penicillin but they are also active against
such organisum as legionella pneumophila, mycoplasm pneumoniae and some
rickettsias, chlamydias and chlamydophilas.
Macrolides and related drug have a postantibiotic effect;
that is antibacterial activity persists after concentration have dropped below the
minimum inhibitory concentration.

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 Chapter 1 Introduction

1.15.3 Biochemical reaction as potential target

Class -1 reaction:
Class-1 reaction are not promising targets, for two reason.
1st – there is no very marked difference b/w bacteria and human cells in the
mechanism for obtaining energy from glucose since both use the embden-
meyerh of pathway and the citric acid cycle.
2nd – even if the glucose pathways were to be blocked a large verity of other
compounds (amino acids lactate etc).
Class-2 reaction
Class-2 reactions are better targets since some pathways involved in class-3
reaction exust in parasitic but not in human cells. For instance human cells have
in the course of evolution lost the ability possessed by bacteria to synthesis lost
the ability passed by bacteria to synthesis some amino acids the so called
essential amino acids and also the growth factors or vitamins any such difference
represents apotential target. Another type of target occur when a pathways is
identical in both bacteria and man but has differential sensitivity to drug.

Class-3 reaction
Class-3 reaction are particularly good targets for selective toxicity because
every cell has to make its own macromolecules. These cannot be picked up from
the environment and there are very distinct differences b/w mammalian cells in
the pathways involved in class-3 reaction. In the class-3 reaction protein are
synthesized.

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 Chapter 1 Introduction

1.15.4 Protein synthesis

The ribosome are cytoplasmic nucleoprotein structures that are the basic
units of machinery for the synthesis of protein on messenger RNA templates.
They are different in eukaryotes and prokaryotes and this provides the basis for
the selective antimicrobial action of some antibiotics. The bacterial ribosome
consists of a 50s subunit and a 30s subunit. In this respect it differs from the
mammalian ribosome which has a 60s and 40s subunit. A simplified version of
protein synthesis in bacteria is as follows. Messenger RNA which is transcribed
from DNA becomes attached to the 30s subunit of the ribosome which moves
along the mRNA so that successive condones of the messenger pass along the
ribosome from the right the ―A‖ position to the left the ―P‖ position as show in
,The ―P‖ site contains the graving peptide chain attached to a molecule of
transfer RNA.The next amino acid residue to be added linked to its specific
tRNA with its distinctive anticodon-moves into the A site being bound to the site
by a codan,anticodon recognition, which occur by complementary base-pairing.
A transpeptidation reaction occurs which links the incoming tRNA at the ‗A‘
site. The tRNA from which the peptide chain has removed is now ejected from
the ―P‖ site. The tRNA at the A site is Tran located to the P site and the
ribosome moves on one codon relative to the messenger. A new tRNA with
amino acid attached and with the relevant anticodon now moves into the ―A‖ site
and the whole process is repeated.

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 Chapter 2 Drug Profile

CHAPTER - 2

1.0 AZITHROMYCIN DRUG PROFILE

2.1 DRUG-PROFILE 13, 14, 15, 16, 17 & 18

Azithromycin is a newer macrolide that was developed to overcome some of the

shortcoming of erythromycin such as intolerance, pharmacokinetics, and limited
antimicrobial pectrum.Azithromycin (technically an azalide) has a 15-
membered ring, which is derived from the insertion of an amino group into the
erythromycin ring.Azithromycin has unique pharmacokinetics that give rise to
prolonged tissue levels, which allow briefer duration of therapy(3to5 days) for
most infections and a single-dose regimen of treatment of chlamydial STDs.It
contain two molecules of water.

Chemical abstracts registry no

(i) For anhydrous- [83905-01-5]

(ii) For dehydrate- 117772-70-0

Chemical abstracts name:

(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl-3-
O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-
3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-
hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one

Structure:

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 Chapter 2 Drug Profile

2.1.1 Physical and chemical properties

Mol. Formula
Anhydrous C38H72N2O12
Dihydrate C38H72N2O12. 2H2O

Mol. Wt
Anhydrous 748.98
Dihydrate 785.0

% Composition C- 60.94%
H- 9.69%
N-3.74%
O- 25.63%

State solid (crystalline power)

Odor Odorless
Taste not available
M.P 113- 115 ºC (for anhydrous)
126 ºC (for dihydrate)

Color white

pH 9.0 to 11.0

Solubility Practically insoluble in water, freely soluble in

anhydrous ethanol and in methylene chloride.

Specific optical rotation -45 to -49 (anhydrous substance)

Water contain 1.8% to 6.5% determined on 0.200g
Sulphate ash maximum 0.2%, determined on 1.0gm
Heavy metals maximum 25 ppm

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 Chapter 2 Drug Profile

Azithromycin Tablet:-

Azithromycin Tablet contain not less than 90.0% and not more than 110.0% of
the labeled amount of Azithromycin

Description:

White tablet or film coated tablets with White or almost white coar.

Identification

Dissolve quantity of the powder tablets in ethanol to produce a solution

of 10mg of Azithromycin/ml and filter, using successive filtrate as a test
solution. Dissolve a quantity of Azithromycin LRS in ethanol to produce a
reference solution of 10mg of Azithromycin/ml, the solution comply with test
(1) for identification describe under Azithromycin.

Dissolution:

Carryout the dissolution test (method-2) using a phosphate BS (to 6000ml of

0.1mol/L disodium hydrogen phosphate solution add 40ml of hydrochloric acid,
adjust the ph value to 6.0) 900ml as the dissolution medium ,adjust the rotation
speed of the paddle to 100 rpm.Withdraw the solution after exact 45 minute and
filter. Dilute an accurately measured quantity of the successive filtrate with the
same solvent to produce a solution of 55µg per ml ,as test solution .Triturate 10
tablets to an accurately weight quantity equivalent to about the average wt of one
tab add aquantity of ethanol(using 1ml of ethanol for 2mg of the labeled amount
of Azithromycin) and the dissolution medium, shake for 30 minutes or ultrasonic
ate for 10 minutes to dissolve Azithromycin.Dilute an accurately measured
quantity of the successive filtrate with the dissolution medium to produce a
solution of 55µg per ml and filter, using the successive filtrate as the reference
solution. Measure accurately 5ml each of the two solution separately to two
tubes with stoppers respectively and accurately 5ml of sulfuric acid solution
(75→100) mix well, allow to stand for 30 minutes ,cool measure the absorbance
of the resulting solution at 482nm.Calculate the dissolution of Azithromycin
form each tablet not less than 75% is dissolve.

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 Chapter 2 Drug Profile

Assay:

Weigh accurately and triturates 10 tablets dissolve accurately weighed quantity

equivalent to 0.25gm Azithromycin in 125ml of ethanol, dilute with sterile water
to produce a solution of 1000unit per ml, mix well, carry out the assy describe
under Azithromycin using the supernatant liquid.

Storage:

Preserve in tightly closed container stored in dry place.

References:

1) Pharmacopoeia of people’s republic of china Vol-II ,(2005)

2. 2 Pharmacokinetics

Absorption

Azithromycin given orally is about 40% bioavailability absorption from capsule,

but not tablet is reduced by food. Peak plasma concentration are achieved 2-3
hours after a dose but Azithromycin extensively distributed to the tissue and
tissue concentration subsequently remain much higher than these in the blend. In
contrast to other antibacterial plasma concentration is therefore, a little value as a
guide to efficacy. High concentrations are taken of in to add blood cell.
Azithromycin is more stable than erythromycin at gastric ph. The
Pharmacokinetic profile of Azithromycin reflects a rapid and extensive uptake
from the circulation into intracellular compartment, followed by slow release.
Azithromycin has been show to penetrate tissues rapidly and extensively,steady-
state levels were 0.64µg/ml at 2 to 4hr,0.1µg/ml at 10 to 12hr,and 0.012µg/ml at
72 to 96hr.Azithromycin remains in human polymorph nuclear leukocytes in
vitro for several hr even after extra cellular drug has been removed ,and its
release can be stimulated by phagocytosis. Azithromycin level in pulmonary
macrophages, polymorphonuclear leukocyte, tonsillar tissue and genital or pelvic
tissue remain increased for extended periods, with a mean tissue half –life of 2to
4 days.

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 Chapter 2 Drug Profile

Distribution

Azithromycin is distributes widely throughout the body, except to the brain and
CSF. Azithromycin has unique pharmacokinetic properties include extensive
tissue distribution and high drug concentration within cells(including
phagocytes)resulting in much greater concentration of drug in tissue or secretion
compared to simultaneous serum concentration. Tissue fibroblast acts as the
natural reservoir for the drug in vivo. Protein binding is 50% at very low plasma
concentration and less at higher concentration..

Metabolism and Excretion

A small amount of Azithromycin are demethylated in the liver and it is excreted

in bile as unchanged drug and metabolites. About 6.0% of oral dose(representing
about 20% of the amount in the systemic circulation) is excreted in urine. The
terminal elimination half life 40 to 68hr is prolonged because of extensive tissue
sequestration and dinding.

2. 2.1 Resistance:

Resistance to macrolides usually results from one of four mechanisms

(i) Drug efflux by an active pump mechanism (en coded by mrsA, mefA, or mefE in
staphylococci,group A. streptococci ,or S.pneumoniae, respectively.

(ii) Ribosomal protection by inducible or constitutive production of methylase

enzyme, mediated by expression of ermA,ermB AND ermC, which modify the
ribosomal target and decrease drug binding.

(iii) Macrolides hydrolysis by esterases produced by enterobacteriaceae.

(iv) Chromosomal mutation that alter a 50s ribosomal protein (found in B.sub ilis,
complyobacter spp, mycobacteria and gram-positive cocci.

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 Chapter 2 Drug Profile

2.3 Mode of action

Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by

binding reversibly to the 50s ribosomal subunit of sensitive
organisum.Azithromycin appears to inhibit the translocation step where in the
nascent peptide chain temporarily residing at the a site of the transferase reaction
fails to move to the P or donar site alternatively macrolides may bind and cause a
conformational change that terminates proteins synthesis by indirectly
interfering with transpeptidation and translocation. Fig no.1

Fig no- 1

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 Chapter 2 Drug Profile

2.4 Side Effects

Minor: Abdominal pain, diarrhea, dizziness, headache, nausea, or vomiting.
These effects should disappear as your body adjusts to Azithromycin.
Azithromycin can cause increased sensitivity to sunlight. It is important to avoid
prolonged exposure to sunlight and sunlamps. Wear protective clothing, and use
an effective sunscreen.
If you feel dizzy or light-headed, sit or lie down for a while; get up slowly from
a sitting or reclining position; and be careful on stairs.
Major, palpitations, rash, rectal or vaginal itching, shortness of breath, swelling
of the face or neck, sore throat, unusual bruising or bleeding, or yellowing of the
eyes or skin. If your symptoms of infection seem to be getting worse rather than
improving, you should contact your doctor.

2.5 Drug- Interactions

Azithromycin interacts with several medications:

 Azithromycin may increase blood levels of aminophylline, theophylline,

carbamazepine, cyclosporine, tacrolimus, disopyramide, phenytoin, digoxin,
triazolam, phenobarbital, ergotamine, dihydroergotamine, or oral anticoagulants
(blood thinners, such as warfarin) when they are used concurrently; this may lead to
serious side effects.

 Antacids containing aluminum or magnesium will decrease the efficacy of

Azithromycin. Take antacids one hour before or two hours after your dose of
Azithromycin.

 Do not take Azithromycin if you are taking pimozide; increased adverse effects on
the heart may result.

Adverse reactions

In clinical trials, most of the reported side effects were mild to moderate in severity
and were reversible upon discontinuation of the drug. Approximately 0.7% of the
patients from the multiple-dose clinical trials discontinued azithromycin therapy
because of treatment-related side effects. Most of the side effects leading to
discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting,

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 Chapter 2 Drug Profile

diarrhea, or abdominal pain. Rarely but potentially serious side effects were
angioedema and cholestatic jaundice

Storage :

to store this medicine:

 Keep out of the reach of children.

 Store away from heat and direct light.

 Store the pediatric suspension form of azithromycin in the refrigerator.

 Do not store in the bathroom, near the kitchen sink, or in other damp places. Heat
or moisture may cause the medicine to break down.

 Do not keep outdated medicine or medicine no longer needed. Be sure that any
discarded medicine is out of the reach of children

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 Chapter 3 Aim and Plan of Work

CHAPTER - 3

1.0 3.1 AIM AND OBJECTIVE

To develop formulation of pharmaceutical equivalent of formulation and product

development of azithromycin tablets.

Selection criteria of immediate release dosage form

1.) longer half life

2.) Poor solubility
3.) To need the immediate action of the drug.
4.) Absorption from mainly stomach.
5.) Long elimination half life
Azithromycin:

 Azithromycin is Anti-bacterial agents. It is used for mainly MAC infection,

community acquired pneumonia and trachoma disorders. Very low solubility in
aqueous media & oral bioavailability is 37%.its half life is 68 hrs & clearance is 630
ml/min.

 As per literature it is observed that Azithromycin the newest generation of

macrolides is as effective and better tolerated, and associated with a lower risk of
adverse effects.

 It is more stable in the gastric pH.

 Azithromycin prevents bacteria from growing by interfering with their ability to

make protein.

 The macrolides antibiotics do not interfere with humans’ ability to make protein.

 Azithromycin is effective against a wide variety of bacterial organisms.

 Azithromycin has the advantage of shorter treatment regimens and improved

tolerance.

 For better bioavailability drug should release fast from formulation to media.
This can be performing with a disintegrant agent.

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 Chapter 3 Aim and Plan of Work

 Physical properties show that poor flow properties so we can conclude about the
key ingredients of our formulation to make a fast release tablet.

In the development of Azithromycin tablet we using, Microcrystalline cellulose,

Croscarmellose sodium, Pregelatinized starch, Sodium lauryl Sulphate, Syloid
244 FP, Magnesium Stearate, Hypromelose, PEG-6000, Titanium di oxide. Pre-
formulation testing is the first step in rational development of dosage form of
drug substance, in this study characterization of drug API is most important
study, solubility study, practical size analysis of API, Bulk density, Tapped
density, and compressibility of the API was done. For development of
Azithromycin formulation known about the details of innovator product. To
develop a non – infringing formulation of Azithromycin, which is stable and bio-
equivalent to Zithromax of Pfizer. We select the dissolution media as per the
U.S.P, phosphate buffer pH 6.0 with tripsin in 900 ml at 100 rpm, NLT 75 %
dissolved in 45 minutes. Accelerated stability testing was done as per the ICH
guidelines and successful formulation was found highly stable in all respects.

Keeping above factor in view it is aimed to develop formulation of

pharmaceutical equivalent Azithromycin as an immediate release dosage form.

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Chapter 4 Literature Review

CHAPTER - 4

LITERATURE REVIEW

KM Olsen et al (2005)19 Intrapulmonary pharmacokinetics of Azithromycin in healthy

volunteers given five oral doses. The intrapulmonary pharmacokinetics of oral
Azithromycin were studied in 25 healthy volunteers, each of whom received an initial
dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy,
bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340,
and 508 h after the first dose was administered. Azithromycin concentrations in
epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and
serum were measured by high-performance liquid chromatography. Azithromycin was
extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/-
standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h
(21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28
micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin
concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were
detectable up to 172 h (7 days), when they were 20 times the concurrent serum
concentrations. Although the clinical significance of antibiotic concentrations in these
compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic
accumulation demonstrated in this study support the proven efficacy of azithromycin
administered on a 5-day dosage schedule in the treatment of extra cellular or
intracellular pulmonary infections.
R Mason ET AL (2012)20 Spectrum and mode of action of Azithromycin (CP-62,993), a
new 15-membered-ring macrolide with improved potency against gram-negative
organisms The macrolide antibiotic azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-
aza-9a-homoerythromycin A; also designated XZ-450 [Pliva Pharmaceuticals, Zagreb,
Yugoslavia]) showed a significant improvement in potency against gram-negative
organisms compared with erythromycin while retaining the classic erythromycin
spectrum. It was up to four times more potent than erythromycin against Haemophilus
influenzae and Neisseria gonorrhoeae and twofold more potent against Branhamella
catarrhalis, Campylobacter species, and Legionella species. It had activity similar to that
of erythromycin against Chlamydia spp. Azithromycin was significantly more potent
versus many genera of the family Enterobacteriaceae; its MIC for 90% of strains of
Escherichia, Salmonella, Shigella, and Yersinia was less than or equal to 4
micrograms/ml, compared with 16 to 128 micrograms/ml for erythromycin.
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Chapter 4 Literature Review

Azithromycin inhibited the majority of gram-positive organisms at less than or equal to

1 micrograms/ml. It displayed cross-resistance to erythromycin-resistant
Staphylococcus and Streptococcus isolates. It had moderate activity against Bacteroides
fragilis and was comparable to erythromycin against other anaerobic species.
Azithromycin also demonstrated improved bactericidal activity in comparison with
erythromycin. The mechanism of action of azithromycin was similar to that of
erythromycin since azithromycin competed effectively for [14C] erythromycin
ribosome binding sites.

21
Suhagia BN ET AL Determination of Azithromycin in pharmaceutical dosage forms
by spectrophotometric methodA simple and sensitive spectrophotometric method has
been developed for determination of Azithromycin in its pharmaceutical dosage forms.
In the proposed method, azithromycin is oxidized with potassium permanganate to
liberate formaldehyde, which is determined in situ using acetyl acetone, in the presence
of ammonium acetate. A yellow coloured chromogen was obtained, having absorption
maxima at 412 nanometer. The method is found to be linear in the concentration range
of 10-75 microgram per milliliter, with regression coefficient of 0.9978. Various
parameters such as concentration of potassium permanganate and reagent, time required
for oxidation, and maximum colour intensity were optimized. The method was
validated, and can be used successfully to assay azithromycin in its pharmaceutical
dosage forms viz. tablets, capsules and injections.

22
Hooda AK ETAL Azithromycin in the treatment of gingival hyperplasia in renal
allograft recipients of cyclosporineBackground: Gingival hyperplasia is a known
complication of Cyclosporine therapy. We studied the efficacy of Azithromycin in the
treatment of gum hyperplasia in renal transplant patients on follow-up in our center.
Methods: All renal transplant recipients with symptomatic gum hyperplasia were given
Azithromycin for a period of 5 days in a dose of 500 mg on day 1 followed by 250 mg
OD on days 2-5. The ratio of crown height and width in each of the 8 incisors was
measured before starting therapy, at 4 weeks and at 8 weeks after therapy. Results:
There were 122 renal transplant recipients on our follow-up. Of these, 115 were on
Cyclosporine. Out of these, 11 patients (Males 9, Females 2) had symptomatic gum
hyperplasia (9.56 percent). The symptoms in patients with gum hyperplasia were pain
and bleeding from the gums. The average duration on Cyclosporine therapy in these
patients was 25.8 months (3 to 36 months). Symptomatic relief was seen in all patients
after Azithromycin therapy. The average value of ratio of crown height and width
increased from pre-treatment baseline of 1.06 plus 0.11 to 1.18 plus 0.11 (at 4 weeks)
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Chapter 4 Literature Review

and to 1.24 plus 0.09 at 8 weeks after therapy (p less than 0.001). The drug was well
tolerated and none of the patients reported any side effects. There was no significant
change in the creatinine level at 1 month after Azithromycin therapy. Cyclosporine C2
assays done in 3 patients before and 4 weeks after therapy also showed no significant
change. Conclusion: We conclude that Azithromycin is a safe and effective therapy for
Cyclosporine induced gum hyperplasia.

23
Singhi MK et all Comparison of oral Azithromycin pulse with daily Doxycycline in
the treatment of acne vulgarisIntroduction: Oral Azithromycin has been advocated by
some in the treatment of acne. However, its efficacy has not been established. Material
and Methods: This non-randomized controlled trial was conducted on 70 outpatients
with acne vulgaris to compare the efficacy and safety of Azithromycin and doxycycline
in the treatment of inflammatory acne. In the first group, azithromycin was administered
500 mg daily before meals for 3 consecutive days in a 10-day cycle, with the remaining
seven days in each cycle being drug-free days. The second group was given doxycycline
100 mg daily after meals. Topical erythromycin was prescribed to all patients. Clinical
assessment was done at 10-day intervals for both the groups up to three months. We
followed the severity index described by Michaelsson for assessment of outcome
measures. Results: There was 77.26 percent improvement in Aazithromycin treated
group in comparison to 63.74 percent in the doxycycline treated group. There was a
statistically significant reduction in severity in the azithromycin treated group.
Conclusion: The study showed that a combination of Azithromycin with topical
erythromycin was significantly better than doxycycline with topical erythromycin in the
treatment of acne vulgaris. The incidence and severity of side effects were also lower
with Aazithromycin.

Ogale SB et al 24 Comparative evaluation of the efficacy and safety of Azithromycin

and Roxithromycin in children suffering from otitis media An open, randomized,
comparative study was undertaken to compare the efficacy and safety of Azithromycin
(Kid tablets) with Roxithromycin (Kid tablets) in the treatment of otitis media in
children. 51 patients of either sex, under 12 years and presenting with signs and
symptoms of otitis media were included in the study. The patients were randomly
assigned to two groups and received either Azithromycin tablet 10 mg/kg once daily for
3 days or Roxithromycin tablet 2.5-5 mg/kg twice daily for 7 days. The daily mean
severity scores measuring the ear discharge suggested that there was a statistically
significant fall in the severity scores in the Azithromycin group from day 1 onwards,
whereas of the other signs and symptoms showed a statistically significant fall from day

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Chapter 4 Literature Review

2 onwards in the Azithromycin group as compared to day 4 in the Roxithromycin group.

Both Azithromycin and Roxithromycin were equally well tolerated by the children with
only one incidence of rash in the Roxithromycin group. 77 percent of the patients in the
Azithromycin group were assessed as being cured as compared to only 36 percent of
patients in the Roxithromycin group. 23 percent of patients in the Azithromycin group
had improved as compared to 64 percent of patients in the Roxithromycin groups. The
advantages of Azithromycin in the treatment of otitis media include broad spectrum of
activity, pharmacokinetic properties that allow once daily dosing and short course
therapy. Azithromycin is an appropriate choice for the treatment of otitis media in
children.

25
H. Rautelin1 et al Azithromycin resistance in Campylobacter jejuni and
Campylobacter coliAbstract The MICs of erythromycin, Azithromycin and
ciprofloxacin were determined for 60 human fecal isolates ofCampylobacter. Of these,
30 strains selected on the basis of their resistance to erythromycin by disk diffusion
were highly resistant to both erythromycin and Azithromycin. Nine of these selected
isolates were resistant to ciprofloxacin. The remaining 30 strains were non-selected,
consecutive isolates ofCampylobacter susceptible to erythromycin by disk diffusion and
were shown to be two- to five-fold more susceptible to Azithromycin than to
erythromycin as determined by MIC testing.

R. Haye1 et al 26 Azithromycin versus placebo in acute infectious rhinitis with clinical

symptoms but without radiological signs of maxillary sinusitis Abstract In this double-
blind, parallel-group, multicenter study, 169 patients with symptoms of maxillary
sinusitis but without radiographically confirmed empyema (pus) were randomly
assigned to receive either 500 mg Azithromycin once daily for 3 days (87 patients) or
placebo daily for 3 days (82 patients). Nasal secretion, maxillary tenderness and pain,
nasal obstruction, general malaise, and hyposmia were assessed at the start of the study
and on days 4, 11, and 25 of treatment. After 11 days 58% of the patients in the
Azithromycin group were cured versus 31% in the placebo group; after 25 days the cure
rate was 79% versus 67%, respectively. When both cure and improvement were
considered, the corresponding figures after day 25 were 90% and 88%, respectively.
Adverse events, predominantly gastrointestinal, occurred in 24 (27%) of the
Azithromycin-treated patients and in 15 (18%) of those treated with placebo, but the
difference was not statistically significant. There was a difference in efficacy in favor of
Azithromycin in the treatment of rhinitis with symptoms of maxillary sinusitis but

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Chapter 4 Literature Review

without radiological signs of empyema (pus). Antibiotics should only be used to

alleviate symptoms in patients with moderate to severe symptoms, as the results after 25
days for both improvement and cure are equal. In the treatment of acute rhinitis with
symptoms and signs of maxillary sinusitis but without empyema, treatment with
Azithromycin seems to result in a better cure rate after 10–12 days when compared with
placebo.

27
J Retsema, et al Spectrum and mode of action of Azithromycin (CP-62,993), a new
15-membered-ring macrolide with improved potency against gram-negative
organisms.The macrolide antibiotic Azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-
aza-9a-homoerythromycin A; also designated XZ-450 [Pliva Pharmaceuticals, Zagreb,
Yugoslavia]) showed a significant improvement in potency against gram-negative
organisms compared with erythromycin while retaining the classic erythromycin
spectrum. It was up to four times more potent than erythromycin against Haemophilus
influenzae and Neisseria gonorrhoeae and twofold more potent against Branhamella
catarrhalis, Campylobacter species, and Legionella species. It had activity similar to that
of erythromycin against Chlamydia spp. Azithromycin was significantly more potent
versus many genera of the family Enterobacteriaceae; its MIC for 90% of strains of
Escherichia, Salmonella, Shigella, and Yersinia was less than or equal to 4
micrograms/ml, compared with 16 to 128 micrograms/ml for erythromycin.
Azithromycin inhibited the majority of gram-positive organisms at less than or equal to
1 micrograms/ml. It displayed cross-resistance to erythromycin-resistant
Staphylococcus and Streptococcus isolates. It had moderate activity against Bactericides
fragilis and was comparable to erythromycin against other anaerobic species.
Azithromycin also demonstrated improved bactericidal activity in comparison with
erythromycin. The mechanism of action of azithromycin was similar to that of
erythromycin since Azithromycin competed effectively for [14C] erythromycin
ribosome binding sites.

Sivasubramanian L et al 28 Visible spectrophotometric methods for the determination

of Azithromycin in tabletsTwo visible spectrophotometric methods have been
developed for the estimation of Azithromycin in pure and in pharmaceutical
formulations. The first method (A), a visible spectrophotometric method was based on
the formation of a red colored chromogen with ferric chloride and 1,10-phenanthroline,
which showed absorbance maximum at 490 nm and Beer's law was obeyed in the
concentration range of 2.5-15 micro-g/ml. The second method (B) was based on the
formation of a blue colored chromogen with Folin-Ciocalteau reagent, which showed
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Chapter 4 Literature Review

maximum absorbance at 720 nm and Beer's law was obeyed in the concentration range
of 25-150 micro-g/ml. Results of analysis for both the methods were validated
statistically and by recovery studies. ottom of Form

3. 2 Review of work done of Immediate Release dosage form

Becker C, Dressman JB, et al 29 Biowaiver monographs for immediate release solid oral
dosage forms: IsoniazideBecker C et al Literature data relevant to the decision to allow
a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release
(IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical
ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics
according to the Biopharmaceutics Classification System (BCS), as well as its
therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the
possibility of excipient interactions and reported BE/bioavailability (BA) problems were
taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and
permeability are inconclusive, suggesting this API to be on the borderline of BCS Class
I and III. For a number of excipients, an interaction with the permeability is extreme
unlikely, but lactose and other deoxidizing saccharides can form condensation products
with isoniazid, which may be less permeable than the free API. A biowaiver is
recommended for IR solid oral drug products containing isoniazid as the sole API,
provided that the test product meets the WHO requirements for "very rapidly
dissolving" and contains only the excipients commonly used in isoniazid products, as
listed in this article. Lactose and/or other deoxidizing saccharides containing
formulations should be subjected to an in vivo BE study.

30
Dumont ML et al Probability of passing dissolution acceptance criteria for an
immediate release tablets Dumont ML et al During development of solid dosage
products, a pharmaceutical manufacturer is typically required to propose dissolution
acceptance criteria unless the product falls into Biopharmaceutics Classification System
(BCS) class I, in which case a disintegration test may be used. At the time of filing the
new drug application (NDA) or common technical document (CTD), the manufacturer
has already met with regulatory agencies to discuss and refine dissolution strategy. The
dissolution acceptance criteria are based on stability and batch history data and are often
arrived at by considering the percentage of batches that pass United States
Pharmacopeia (USP) criteria at Stage 1 (S(1)), when in fact, the product is deemed
unacceptable only when a batch fails USP criteria at Stage 3 (S(3)) [H. Saranadasa,
Disso. Technol. 7 (2000) 6-7, 18 [1]]. Calculating the probability of passing (or failing)

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Chapter 4 Literature Review

dissolution criteria at S(1), S(2), or S(3) can assist a manufacturer in determining

appropriate acceptance criteria. This article discusses a general statistical method that
was developed to assess the probability of passing the multistage USP test for
dissolution and how it was applied to an immediate release tablet formulation. In this
case, acceptance criteria were set and the analysis was conducted to assess the
probabilities of passing or failing based on this acceptance criterion. Whether the
acceptance criteria were relevant to the product was also considered. This mathematical
approach uses a Monte Carlo simulation and considers a range of values for standard
deviation and mean of historical data.

31
Qureshi SA et al Applications of a new device (spindle) for improved
characterization of drug release (dissolution) of pharmaceutical products Qureshi SA et
al a crescent spindle (patent pending) is described which may be used in place of the
USP paddle component in USP dissolution apparatus 2. The new spindle is curve
shaped, corresponding to the bottom of a dissolution vessel, with attached bristles to fill
in the gap between the spindle and the surface of the vessel. The geometry of the new
spindle provides more efficient mixing than the USP paddle and prevents accumulation
of disintegrated material (no cone formation). Using the new spindle, in comparison
with the USP paddle, dissolution characteristics of three drug products: 250 mg
amoxicillin capsules, 15.6 g acetylsalicylic acid (ASA) boluses and 200 mg
carbamzepine tablets were evaluated. The experimental conditions for dissolution
testing with the two stirring devices included; 900 ml of 0.05 M phosphate buffer, pH
6.8 with 50 rpm, 900 ml of 0.05 M acetate buffer, pH 4.5-ethanol (7:3) with 50 rpm, and
water containing 1% sodium lauryl sulphate with 75 rpm for amoxicillin capsules, ASA
boluses and carbamazepine tablets, respectively. Uncharacteristic of the test products,
which are fast release, the USP paddle provides significantly slower drug release. For
example, 90 min for <80% drug release vs. 10 min for >90% for amoxicillin capsules
and 6 h for 80% vs. 30 min for >90% for ASA boluses with USP paddle vs. the new
spindle. In case of the carbamazepine tablets, three products which are bioequivalent
and prescribed interchangeably, the USP paddle method shows significantly different
dissolution characteristics. However, with the new device, all these products show
similar drug release characteristics, a better reflection of product release characteristics
and in vivo drug release behaviour. Compared with the USP paddle, the suggested
device (spindle) provides improved stirring and mixing which appears to provide more
appropriate (biorelevant) characterization of pharmaceutical products.

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Chapter 4 Literature Review

Yu LX et al 32 we sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can

be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release
(IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble
drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles
of both innovator and generic IR products were determined using USP apparatus 2 at 50
rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles
from USP apparatus 3 were compared to those from USP apparatus 2 using the f(2)
similarity test. The dissolution profile from USP apparatus 3 generally depends on the
agitation rate, with a faster agitation rate producing a faster dissolution rate. It was
found that USP apparatus 3 at the extreme low end of the possible agitation range, such
as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With
appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to
USP apparatus 2 or distinguish dissolution characteristics for the IR products of
metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the
furosemide tablets using USP apparatus 3. Although it is primarily designed for the
release testing of extended-release products, USP apparatus 3 may be used for the
dissolution testing of IR products of highly soluble drugs, such as metoprolol and
ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP
apparatus 3 offers the advantages of avoiding cone formation and mimicking the
changes in physiochemical conditions and mechanical forces experienced by products in
the gastrointestinal tract.

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Chapter 4 Literature Review

Influence of higher rates of agitation on release patterns of immediate-release drug

products

33
Shah VP et al The dissolution procedure serves as a quality control test to assure
batch-to-batch uniformity and bioequivalence of a product once the bioavailability of
the product has been established. It can also be used to detect manufacturing and/or
process variations that could reduce product bioavailability. Dissolution testing must be
conducted at an appropriate agitation rate. Tests conducted at high agitation rates may
lose the ability to differentiate between good and bad products. Although the effect of
high agitation rates has been known for some time, several immediate-release drug
products still have United States Pharmacopeia (USP) monograph dissolution
procedures that require very high agitation rates. A systematic survey was conducted on
marketed tablets of chloroquine phosphate, griseofulvin, hydroxychloroquine sulfate,
isocarboxazide, primaquine phosphate, and sulfadiazine. Each of these products has a
USP monograph requiring a dissolution test at a paddle speed of 100 rpm. To study the
influence of agitation rate on the dissolution rate of these products, dissolution studies
were conducted at paddle speeds of 50, 75, and 100 rpm with the USP apparatus 2
(paddle method). The dissolution rate increased with an increase in the agitation rate
from 50 to 75 rpm. However, no significant increase in the dissolution rate was noted
with an increase in the agitation rate from 75 to 100 rpm. The data support the position
that the higher agitation rate of 100 rpm is not necessary for a quality control procedure
or a compendia standard for the products tested.

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 Chapter 4 Literature Review

3 Patent Survey:

(i) Drug substance

Patent no Assignee/applicant Clues from the invention

US6268489 Pfizer Monohydrate Azithromycin is hygroscopic. It is most difficult to
prepare and maintain this monohydrate in a from having a
contant,reproducible water content. it is particularly difficult to
handle during formulation ,since at higher RH levels, the
monohydrates readily picks up varying amount of water. Such
problems have been over come by the present invention of stable
dihydrate.

US7056893 Insite vision Azithromycin antibiotic have a maximum stability over a ph

interval of about 5.0 to 7.0 preferably with at a ph of about 6.3

WO03/053399 Pfizer Azithromycin can be produced in many different forms. For

example, the current commercial from of Azithromycin is a
stable, crystalline, non-hygroscopic dihydrate, also referred to as
from A. The commercial tablet is then formulated by using water
as the granulating liquid. Several crystalline non-dihydrate forms
of Azithromycin are also known. From B is hygroscopic crystalline
hydrate. This form of Azithromycin is difficult to handle during
formulation due to its propensity for readily absorbing varying
amount of water.

EP01127580 Pfizer The bioavailability of Azithromycin can be increased by co-

administering Azithromycin with a p- glycoprotein inhibitor.

WO03063838 Pfizer Dry granulated formulations of Azithromycin (using non-dihydrate

form of Azithromycin )

WO03053416 Pfizer Directly compressible formulation of Azithromycin (using non

dihydrate from of Azithromycin)

WO2004087096 Pliva Pharmaceutical composition having reduced bitter taste.

Pfizer The invention provides the use of Azithromycin in the manufacture

of a rapidly disintegrating oral dosage form with high
EP00679400 bioavailability for the treatment of a microbial infection in a
mammal that has eaten or will eat in the period commencing 1
hour prior to dosing and terminating 2 hour after dosing.

Abraxis
A stable, sterile liquid formulation comprising lyophilized
WO200611549
Azithromycin, ethanol, citric acid &/or NaoH.
4

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 Chapter 5 Formulation development

CHAPTER – 5

Formulation development

5.1 Objective:

To develop a non-infringing formulation of Azithromycin, which is stable and

bioequivalent to Zithromax of Pfizer and being marketed in domestic.

The strength to be developed is 250 mg.

Qualitative composition of the formulation with respect to the Excipients

would be same as that of the innovator.

Quantitative composition would be derived by trials, to ensure a drug product

having similar physico-chemical properties as that of the innovator.

Manufacturing Process:

The same manufacturing process and the equipments used during development
would be similar to the intended commercial scale equipments.

5.2 Selection of Excipients

Sourcing

The excipients used during development were procured from qualified

vendors.

5.2.1 Function and Justification41

Diluents: In view of drug dose it is essential to add bulking agents or diluents to

increase the weight of the tablet. Microcrystalline cellulose was selected as the
main diluent.

Disintegrant: Cross carmellose sodium we selected as superdisintegrant. The

strong correlation of disintegration time to bioavailability. Thus, it is important
to optimize the disintegration time in order to enhance in vivo dissolution of the
drug. In order to release the active ingredient from a solid dosage form matrix as
efficiently as possible, disintegrate is often used in the formulation, especially

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 Chapter 5 Formulation development

when the dosage forms are compressed with binder. Disintegrates help rupturing
the dosage form matrix by swelling or capillary action when moisture is
absorbed into the dosage form.

Binder: Pregelatinized starch was used as a tablet binder in the concentration of

0.5 – 5 %.Formulators skilled in art can determine the binder level for the
formulations, but binder usage level of 2-25% in tablet formulations is common.

Lubricants: Magnesium Stearate is a widely used as Tablet and Capsule

lubricant. It is generally used in the concentrations between 0.25 – 5.0 %.

Glidant: Colloidal Anhydrous Silica is widely used as Tablet and Capsule

Glidant. It is generally used in the concentrations between 0.25 – 3.0 %.

Lubricants: Magnesium Stearate is a widely used in Tablet and Capsule as a

lubricant. It is generally used in the concentrations between 0.25 – 5.0 %.

Film former: Hypromellose is widely used in oral and topical pharmaceutical

formulation. It is generally used in coating suspension in the concentrations
between 50- 30.0 %.

Coating agent: titanium dioxide is widely used in oral pharmaceutical

formulations as white pigment and as opacifier in film coating. it is generally
used in the concentrations b/w 10.0 – 30.0 %.

Plasticizer: polyethylene glycol 6000 is widely used as plasticizer in film coating

of tablet. It is generally used in the concentrations b/w 5.0 – 20.0 %.

Granulation vehicle: Water is widely used for granulating Agent because of no

any toxic effect and for non- aqueous solvent we widely use Isopropyl alcohol.

Wetting agent: Sodium lauryl sulfate is mainly used as wetting agent. It is

generally used in the concentrations b/w 1.0 – 2.0 %.

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 Chapter 5 Formulation development

5.3 Selection of Dissolution Medium

Initially dissolution was done with reference product Aazithral in phosphate

buffer, pH 7.5 in 900 ml with type -2 apparatus at 100 rpm.

Later on, it was decided to comply with I.P draft monograph dissolution test

Dissolution media: sodium phosphate buffer pH 6.0 with trypsin

Apparatus: USP II (Paddle)

RPM: 100
Time points: 5, 10, 15, 20, 30, 45 minutes
Identification: HPLC
Limit: NLT 75 % labeled amount should release in 45 minutes
Table no- 6.1 comparative dissolution profile of Azithromycin 250 mg tablets in
different batches.

Fig – no 2

Batch no Time (min)

Dissolution media
10 15 30 45

Sodium phosphate buffer

250/015 59.2 73.7 82.6 95.2%
pH 6.0 with trypsin

250/018 ,, 57.3 74.4 81.7 97.2%

250/020 ,, 58.5 75.7 82.9 98.1%

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 Chapter 5 Formulation development

120

100
% drug release
80
B.NO 250/015
60 B.NO 250/018
B.NO 250/020
40

20

0
0 10 20 30 40 50
Time(min)

Fig –no 2: comparative dissolution profile of Azithromycin 250 mg tablets in

different batches.

5.6 Development Trial

Trial no:-1 prototype formula

In the 1st trial we take the excipent as per the innovator.

IFF qualitative formulation

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Calcium phosphate dibasic Dilunt
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Hypromelose Film former
6 Lactose Diluent
7 PEG-6000 Plasticizer
8 Titanium di oxide Opacifier
Observation: Capping is occur

Remark: API is crystalline, milling required so API is milled by 0.3 mm screen

and passed in 80 #.

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 Chapter 5 Formulation development

Trial no:-2

In this trial API is milled through the 0.3 mm screen and passed through
mesh # 80

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Calcium phosphate dibasic Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Hypromelose Film former
6 PEG-6000 Plasticizer
7 Titanium di oxide Opacifier

Observation: Sticking is occurs

Remark: Replacement of Dibasic calcium Phosphate with Microcrystalline

cellulose to improve compressibility

Trial no: - 3

In this trial we use microcrystalline cellulose as a diluent and to decrease the

stickiness

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Microcrystalline cellulose Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Hypromelose Film former
6 PEG-6000 Plasticizer
7 Titanium di oxide Opacifier

Observation: Again we found sticking

Remark: Add aerosol to reduce the stickiness

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 Chapter 5 Formulation development

Trial no: -4

In this trial we used Aerosil to reduce the stickiness

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Microcrystalline cellulose Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Aerosil Glidant
6 Hypromelose Film former
7 PEG-6000 Plasticizer
8 Titanium di oxide Opacifier

Observation: Improve but DT increased & abrasiveness in blend

Remark: To solve this problem we Add Sodium lauryl Sulphate to improve

wettability of API

Trial no: - 5

In this to solve the problem of stickiness we adding Sodium lauryl Sulphate

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Microcrystalline cellulose Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Sodium lauryl Sulphate Wetting agent
6 Aerosil Glidant
7 Hypromelose Film former
8 PEG-6000 Plasticizer
9 Titanium di oxide Opacifier

Observation: Again slightly sticking occur but DT ok

Remark: To solve again this problem we adding of Syloid in place of Aerosil.

Dept. of Pharmaceutics 71 JKK Nattraja College of Pharmacy

 Chapter 5 Formulation development

Trial no: - 6

In this trial we used Syloid in place of Aerosil.

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Microcrystalline cellulose Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Sodium lauryl Sulphate Wetting agent
6 Syloid Glidant
7 Hypromelose Film former
8 PEG-6000 Plasticizer
9 Titanium di oxide Opacifier
Observation: Slightly sticking is occur but at later stage

Remark: We increased binder addition & kneading time and sizing with 1.2 mm
in place of 1.00 mm

Trial no: - 7

In this trial we increased binder addition time kneading time and sizing
through 1.2 mm screen

Sr.No Ingredients Function

1 Pregelatinized starch Binder
2 Microcrystalline cellulose Diluent
3 Croscarmellose sodium Disintegration
4 Magnesium Stearate Lubricants
5 Sodium lauryl Sulphate Wetting agent
6 Syloid Glidant
7 Hypromelose Film former
8 PEG-6000 Plasticizer
9 Titanium di oxide Opacifier
Observation: No sticking is occurring

Remark: Finalization of formulation

Dept. of Pharmaceutics 72 JKK Nattraja College of Pharmacy

 Chapter 5 Formulation development

Componenents and composition of the final Formula

Strength: 250 mg

Sr.No Ingredients Function Qty/tablet(m % w/w

g)

1 Azithromycin (as Active 262.00* 81.88

dehydrate)

2 Microcrystalline Diluent 19.06 5.96

cellulose

3 Croscarmellose Disintegrant 2.90 0.91

sodium

4 Pregelatinized starch Binder 12.00 3.75

5 Sodium lauryl Wetting agent 0.64 0.20

Sulphate

6 Purified water Granulating Qs Qs

fluid

7 Syloid 244 FP Glidant 4.80 1.81

8 Magnesium Stearate Lubricant 4.80 1.50

9 Hypromelose Film former 6.05 1.89

10 PEG-6000 Plasticizer 0.85 0.27

11 Titanium di oxide Opacifier 0.50 0.16

12 Quinoline yellow Colorant 0.10 0.03

* 785 mg Azithromycin dehydrate ~ 749 mg Azithromycin anhydrous.

Dept. of Pharmaceutics 73 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.0 PRODUCT OPTIMIZATION

Following parameter were studied with for the optimization of
manufacturing process and check robustness of formula.
6.1 Dispensing:
Dispense the all the materials as per robust formula. All material dispense
under control room temp.
6.2 Shifting:
Shift the material API through 80 # and other material through 40 # and 60 #
There is no residue found on their surface.
6.3 Dry mixing:
Using rapid mixing granulator (capacity – 6 lit.) for dry mixing and
granulation
Dry mixing time optimize with trial of mixing at different time interval.

Sample no. 3 min. 5 min. 8 min.

S-1 92.6 99.6 100.5
S-2 96.3 101.1 98.9
S-3 95.6 100.4 99.5
S-4 95.8 98.9 99.35
S-5 94.2 99.35 99.3
S-6 91.5 97.8 100.3
S-7 98.3 99.7 98.9
S-8 95.4 100.6 100.5
S-9 96.8 99.8 98.9
S-10 99.6 99.5 99.3
Avg. 95.61 99.68 99.55
SD 2.30 0.88 0.62
Composite assay (%) 96.5 100.2 99.4
Conclusion:
From the above result, 5 minutes BUA RSD is very less, so 5 to 8 minutes
mixing is efficient during dry mixing. Dry mixing at 5 min. gives satisfactory
result.

Dept. of Pharmaceutics 74 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.4 Granulation:

Optimization of binder addition time

Impeller slow Impeller fast

1-2 min. 2-3 min. 3-4 min. 5-7 min. 1 min. 2 min 3 min 5 min

Not good
Not good wetted Good granules Uniform
wetted and Dusting problem during granulation.
and no granules are not addition and
no granules Granules become hard in nature.
forms found. good granule
forms

The dry mix powder is not bulky, so impeller slow is good for granulation. Binder
addition with 5 to 7 minutes gives satisfactory result. Chopper will off during
binder addition to prevent dusting of powder.

Conclusion:

Binder addition time was optimized as 5 to 7 mint with impeller slow and
chopper off... This gives satisfactory result.

6.5 Kneading:

Kneading time – High kneading retard the dissolution due to hard granules
formed.
Low kneading produce better result but it is unable to break the lumps and
produce less uniformity of granulation process.
Kneading time High (5-6 mints) Optimum(2-4 Low (1-3 mints)
mints)
Dissolution time in % drug released
minutes
5 35 45.8 60.8
10 42.6 56.5 65.8
15 48.6 60.5 70.4
20 55.9 65.3 75.3
30 75.5 78.9 80.5
45 82.5 88.4 88.5

Dept. of Pharmaceutics 75 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

Conclusion:

Kneading time was optimized as 2 to 4 mints with impeller fast and

chopper fast.

6.6 Drying time

In granulation process the granulating agent is used purified water. So dry is

required for remove the amount of water.

Set the temp as 60° C for 20 mints and drying up to us got the LOD
becomes 3 to 4 %.

6.7 Sizing

screen size 0.8 mm 1.0 mm 1.2 mm

Granule Passed particle Low residue Fine and coarse
characteristic are fine and quantity both particles,
high quantity negligible
of residue residue
Conclusion:
Sizing through 1.2 mm screen produce optimum ratio of fine and coarse thus
sizing through 1.2 mm screen gives satisfactory result.

6.8 Blending
Blending time is optimized with trial at different period of blending.
Sample no. 5 min. 8 min. 10 min. 12 min.
S-1 90.30 92.40 95.13 97.32
S-2 91.33 97.72 94.50 98.52
S-3 88.91 94.45 96.17 94.65
S-4 87.92 97.58 96.48 97.57
S-5 78.36 96.26 96.76 97.41
S-6 89.04 95.54 96.00 96.98
S-7 92.33 95.14 96.34 96.00
S-8 97.62 96.15 96.42 94.53
S-9 92.58 95.31 96.79 96.35
S-10 95.71 97.34 96.40 96.80
Avg 90.41 95.79 96.10 96.71
SD 5.22 1.69 0.76 0.80
Composite 94.80 97.00 95.62 96.05
assay
Conclusion: 10 minutes gives low SD value and good assay result.

Dept. of Pharmaceutics 76 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.9 Lubrication:
Lubrication time is optimizing with trial at different period of mixing.
RPM was set as 10 to 20.
Sample no. 3 mints 5 mints 7mints
L–1 95.2 99.2 98.6
L–2 91.1 99.4 94.6
L–3 95.5 97.5 97.5
L–4 96.2 98.8 99.8
L–5 98.7 100.2 99.4
L–6 99.4 99.1 100.1
L–7 94.3 98.3 99.7
L–8 95.3 98.9 96.4
L–9 98.3 99.7 99.2
L – 10 99.5 99.9 98.7
Avg 96.35 99.1 98.4
SD 2.52 0.75 1.66
Composite Assay 96.4 100.1 98.6
Conclusion: ok

6.10 Tablet compression:

Selection of punch and die
Compress the granules into tablets on rotary compression machine using 12/32"
SC, Plain/Plain (D tooling) punches plain on both the sides.
Parameters set up:
1. Set up of tablet weight and marketing requirements we are selecting punch
and die. This tablet weight is 312.00 mg ± 3 %.
2. Set up of hardness
Effect of hardness on friability:

Sample Hardness range Friability Dissolution (%) in 45

(N) minutes
1 50 – 90 0.39 88.6
2 90 – 130 0.15 89.7
3 130 – 170 0.09 78.5
Conclusion:
We set various hardness 50 to 200 N

Dept. of Pharmaceutics 77 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

Product Composition:

6.11 Demo Batch:

6.11.1 Product Composition:

Strength: 250 mg

Lot A: Granulation

S. Qty Tab. Qty./

Ingredients Spec. Function %w/w
No. (In mg) Batch (g)
Dry mix:
Azithromycin
1 USP Active 81.88 262.00 1572.00$
(as dihydrate)
Microcrystallin
2 IP Diluent 5.96 19.06 114.36$
e cellulose
Croscarmellose USP/
3 Disintegrant 0.91 2.90 17.40
Sodium NF
Pregelatinized
4 USP Binder 3.75 12.00 72.00
Starch
Granulation :
Sodium Lauryl Wetting
5 IP 0.20 0.64 3.84
Sulphate agent
USP/EP
Granulating
6 Purified water /BP/IP/ Qs Qs 600.00
IH fluid
Dried sized granules weight 296.60 1779.60
Lot B: Granulation

S. Qty Tab. Qty./

Ingredients Spec. Function %w/w
No (In mg) Batch (g)
Dry mix:
Azithromycin
1 USP Active 81.88 262.00 1572.00$
(as dihydrate)
Microcrystalline
2 IP Diluent 5.96 19.06 114.36$
cellulose
Croscarmellose USP/
3 NF
Disintegrant 0.91 2.90 17.40
Sodium
Pregelatinized
4 USP Binder 3.75 12.00 72.00
Starch
Granulation :
Sodium Lauryl
5 IP Wetting agent 0.20 0.64 3.84
Sulphate
USP/EP Granulating
6 Purified water BP/IP/ Qs Qs 600.00
IH fluid
Dried sized granules weight 296.60 1779.60

Dept. of Pharmaceutics 78 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

Blending of Lot A and Lot B : 296.60 3559.20

Lubrication :
USP
7 Croscarmellose Sodium 1.50 5.80 69.60
/NF
Silicon Dioxide USP
8 1.81 4.80 57.60
(Syloid 244 FP) -NF
9 Magnesium Stearate IP 1.50 4.80 57.60
Core tablet weight 97.50 312.00 3744.00
Coating Ingredients@ :
10 Hydroxyl Propyl Methyl
IP 1.89 6.05 116.16
Cellulose (6cps)
11 PEG -6000 IP 0.27 0.85 16.32
12 Talc IP 0.16 0.50 9.60
13 Titanium dioxide IP 0.16 0.50 9.60
14 Quinoline yellow IH 0.03 0.10 1.92

USP
/EP
15 Purified water BP/I Qs Qs 1382.0
P/
IH

Coated tablet weight 100.00 320.00 3840.00

Note:

$
Quantity of Azithromycin (as dihydrate) USP taken considering 100% assay
on as such basis, its quantity to be adjusted with Microcrystalline cellulose IP.
@ 60 % extra coating solution to be prepared to compensate loss during coating
262.00 mg of Azithromycin USP (as dihydrate) equivalent to 250.00 mg
Azithromycin anhydrous.

Dept. of Pharmaceutics 79 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.11.2 Formula Calculation:

For each Lot:

Qty of Azithromycin dihydrate USP

Required (Q) = 1500.00 x 100 x 100 gm

A x (100 – W)

Where A= Assay of Azithromycin dihydrate on anhydrous basis in %.

W= water by K.F. in % w/w

Quantity of Microcrystalline cellulose IP required:

= 114.36gm – (Q – 1572.00) gm

Remark: Record B. No., Assay (anhydrous basis) & water by K.F. of API used.

Dept. of Pharmaceutics 80 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.11.3 Process Flow Diagram-Schematic:

Ingredients Process step / equipment In-process Tests
Azithromycin Milling
Dihydrate (Comminuting Mill, 0.3mm impact
forward, fast speed)
Sifting

Mechanical Sifter
Microcrystalline Cellulose (80#)
Croscarmellose Sodium Co-sifting
Pre gelatinized starch
Mechanical Sifter
(40#)
Dry Mixing (RMG)
Dry mix B.D: 0.40 gm/cc
Time: 5 minute, Impeller: slow,
LOD: 3-4% at 105°C
chopper: off

Purified Water + SLS Granulation (RMG)

Through Peristaltic pump Binder addition time: 7 to 8 minute. Impeller: slow,
Chopper: off. Kneading time: 5 to 7 minute
Impeller: fast, chopper: fast

Wet milling (8 # mesh)

Drying (FBD)
Temp: 60°C ± 5°C LOD@105°C: 3-4%

Sizing (1.2 mm OG) LOD@105°C

Croscarmellose Sodium, Blending

Silicon dioxide Conta Blender 10 min. 17 rpm

Co-sifting 40 # Description, Assay, BUA,

Lubrication
B.D, T.D., C.I, AOR, Flow rate
Magnesium Stearate Conta Blender 6 lit, 5 min. 17 rpm (gm/min) Sieve analysis
60 #
Description, Wt of 20
Compression tabs Uniformity Wt,
Assay, Hardness,
HPMC E6 Thickness, Friability, and
PEG 6000 DT
Coating (Autocoater) Description, % Wt gain,
Talc
Titanium Dioxide Thickness, Avg. wt, DT,
Lake of Quinoline Yellow Water content (by K.F.)
Purified Water Packing
(Transparent yellow PVC/Alu Blister)
As per Finished Product
Filter through 100 #
Release Specifications

Dept. of Pharmaceutics 81 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.11.13 complete analysis of core tablets:

250 mg
Sr.No Test Limit

1 Description White,round,biconvex tablet, plain on both side

2 Average weight 312.0±3% 312.00

Assay

3 Optimum Hardness 115 N ± 20 N

100.0 %

Related Substances

(Optimum Hardness)
4 To be monitored
Single Max impurity 0.74%

Total impurities 1.78%

Dissolution (45 min) pH 6.0,phosphate buffer,600 mg trypsin added,900

5.
ml/paddle/100 rpm/time point:45 min

Optimum Hardness
98.4 (2.68)
Low Hardness NLT 75%(D)
92.3 (1.5)
High Hardness
99.5 (1.49)

Dept. of Pharmaceutics 82 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.11.14 complete analysis of coated tablets:

Sr.N Test Limit 250 mg

o
1 Description yellow,round,biconvex tablet, plain on both
side
2 Average weight 320.0±3% 320.00
3 Assay ----
optimum hardness 98.7 %

4 Related Substances
(optimum hardness) To be
Single Max impurity monitored 0.94%
Total impurities 1.89%
5. Dissolution pH 6.0,phosphate buffer,600 mg trypsin
added,900 ml/paddle/100 rpm/time point:45
min
6 % Drug Release
(45 min)
optimum hardness NLT 75%(D) 99.8 (1.43)
(RSD)

Dept. of Pharmaceutics 83 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

6.11.15 Conclusion/Recommendation
1. Water addition rate should be control with peristaltic pump with in binder
addition time period as Mentioned.
2. Granulation should be perform with slow addition of binder solution and
kneading with impeller slow & chopper off to get desired granule characteristics.
2. Wet milling should be performed after granulation.
3. Drying should not perform at more than 55±5°C temp.
4. During coating product temp should not be more than 40°C± 5°C
6.11.16 Stability study

Demo Batch

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet
40 °C, 75 % RH
Sr. Tests Specification Initial 1 month 2 month
No

1 Description Yellow colored, round complies Complies complies

shaped, biconvex,
coated tablet, plain on
both side.

2 Assay (%) 90 % to 110 % of 99.7 99.2 100.1

label claim

3 Water To record 5.12 5.32 5.40

content (%)
4 Disintegrati Not more than 30 1.56 1.30 2.45
on time minutes

5 Dissolution Not less than 75 % (D) 95.2 99.4 9 100.6

at pH 6.0 in 45 minutes (0.58) (0.85) (2.08)
phosphate
buffer
Observation: Stability data show that drug product is stable upto 2 month in
accelerated condition

Dept. of Pharmaceutics 84 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet

30 °C, 75 % RH

S. Tests Specification Initial 1 month 2 month

No

1 Description Yellow colored, round complies Complies complies

shaped, biconvex,
coated tablet, plain on
both side.

2 Assay (%) 90 % to 110 % of 99.7 99.5 98.8

label claim

3 Water To record 5.12 5.42 5.6

content (%)

4 Disintegratio Not more than 30 1.56 2.00 2.00

n time minutes

5 Dissolution Not less than 75 % 95.2(0.58 97.6 97.5

at pH 6.0 (D) in 45 minutes )
phosphate
buffer

Observation: Stability data show that drug product is stable upto 2 month in
intermediate condition.

Dept. of Pharmaceutics 85 JKK Nattraja College of Pharmacy

 Chapter 6 PRODUCT OPTIMIZATION

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet
25°C, 60 % RH
S. Tests Specification Initial 1 month 2 month
No
1 Description Yellow colored, round complie Complie complies
shaped, biconvex, s s
coated tablet, plain on
both side.
2 Assay (%) 90 % to 110 % of 99.7 99.9 100.0
label claim
3 Water content To record 5.12 5.28 5.30
(%)
4 Disintegration Not more than 30 1.56 2.00 2.10
time minutes
5 Dissolution at Not less than 75 % 95.2(0.5 96 97.23
pH 6.0 (D) in 45 minutes 8)
phosphate
buffer

Observation: Stability data show that drug product is stable upto 2 month in
normal condition

Dept. of Pharmaceutics 86 JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

6.11.4 Processing steps:

Critical Process Expected Observed
Process Stage Remarks Proposed Specifications
Parameter Response Response
Lot A granulation
0.3 mm screen, impact 0.3 mm screen, impact 0.3 mm screen, impact
0.3 mm screen, impact forward,
API milling forward, fast speed in forward, fast speed in forward, fast speed in Satisfactory
fast speed in cad mill
cad mill cad mill cad mill
1.Binder Addition Satisfactory
6-8 Minutes 4 min 30 sec 6-8 Minutes
Granulation Time(Peristaltic pump (Kneading parameter have
5 to 7 Minutes 7 min (impeller slow, 5 to 7 min (impeller slow,
rate) to changed to get desire
(fast-fast) chopper off) chopper off)
2.Kneading Time granules consistency)
Wet milling 8 # sieve 8 # sieve 8 # sieve Satisfactory 12.7 mm Co- mill
Drying LOD@105°C 3.0% to 4.0% 4.56% Dry mix LOD was 5.0% 3.5% to 5.0%
1.2 mm screen on 1.2 mm screen on 1.2 mm screen on
Sizing Satisfactory 1.2 mm screen on horizontal O.G.
horizontal O.G. horizontal O.G. horizontal O.G.,
Lot B granulation
1.Binder Addition
6-8 Minutes 7 min 6-8 Minutes
Granulation Time(Peristaltic pump
(30 ml/min) Satisfactory 5 to 7 min (impeller slow,
rate)
5 to 7 Minutes 7 min chopper off)
2.Kneading Time
Wet milling 8 # sieve 8 # sieve 8 # sieve Satisfactory 12.7 mm Co- mill
Drying LOD@105°C 3.0% to 4.0% 4.62 % Dry mix LOD was 4.68 % 3.5% to 5.0%
1.2 mm screen on 1.2 mm screen on 1.2 mm screen on
Sizing Satisfactory 1.2 mm screen on horizontal O.G.
horizontal O.G. horizontal O.G. horizontal O.G.
Blending of Lot A & B 10 min. 10 minutes 10 minutes Satisfactory 10 minutes

Blending 10 min. 10 minutes 10 minutes Satisfactory 10 minutes

Lubrication 5 min. 5 min. 5 min. Satisfactory 5 min.
Bulk Density To be recorded 0.47 Satisfactory To be recorded
Granulometry Tapped Density To be recorded 0.58 Satisfactory To be recorded
Sieve Analysis To be recorded Satisfactory To be recorded

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

Compression : For 250 mg strength:

Avg weight 312.00 ± 3% 312.16 mg Satisfactory 312.00 ± 3%

Thickness 5.00 ± 0.3 mm 5.10 mm Satisfactory 5.00 ± 0.3 mm
Hardness (115±20 N ) 125 N Satisfactory (115±20 N )
Friability NMT 1.0% 0.1 % Satisfactory NMT 1.0%
D.T. NMT 15 min 1 min 23 sec Satisfactory NMT 15 min
Coating : For 250 mg strength:

Inlet temp 60 ± 5° C 60 ± 5° C Satisfactory 55 ± 5 °C

Product temp 45 ± 5 °C 40 ± 5 °C Satisfactory 40 ± 5 °C

Pan RPM 2-4 2-4 Satisfactory 2-4

6.11.5 Ingredients and sieve used:

Sr. No. Ingredients Code Screen Size Remarks

1 Azithromycin dehydrate 1000494 80# Satisfactory

Microcrystalline
2 2000185 40# Satisfactory
cellulose

3 Pregelatinized starch 2000227 40# Satisfactory

4 Croscarmellose sodium 2000054 40# Satisfactory

5 Silicon dioxide 2000446 40# Satisfactory

6 Magnesium Stearate 2000156 60# Satisfactory

The above API was co-sifted with dry mix excipients sifted on vibratory sifter.

Description: White to off-white granular powder.

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

6.11.6 Dry mix blends analysis:

Sr. Parameter Results

No.
1 Dry mix : Time 5 minutes
2 B.D. 0.41 gm/cc
3 LOD AT 105°C 4.68%

6.11.7 Details of the blend characteristics after sizing:

Sr. No Parameter Lot A Lot B

White to off-white White to off-white granular
1 Description
granular powder powder
2 B.D 0.47 gm/cc 0.46 gm/cc
3 T.D 0.57 gm/cc 0.55 gm/cc
4 C.I 17.39 14.66
5 H.R. 1.23 1.19
6 AOR 24.3° 23.7°
Flow rate (Erveka flow meter,
7 10.6 sec/100 gm 9.8 sec/100 gm
15.0 mm funnel)
8 Particle size distribution % wt retain % wt retain
#20 retain 1.44 3.52
#20-#30 7.9 5.34
#30-#40 8.32 12.06
#40-#60 18.56 16.42
#60-#80 19.58 19.68
#80-#100 16.34 16.20
Pass through # 100 27.32 24.20
9 Assay 96.7 % 98.2 %
Related Impurities
10 Single Max Impurity 0.83 % 0.72 %
Total Impurities 1.88 % 1.95 %

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

6.11.8 Details of the lubrication:

Blending with Croscarmellose sodium & Silicon Dioxide: 10 minutes
Lubrication with Magnesium stearate: 5 minutes in conta blender at 17 rpm
Inference: 10 min with Croscarmellose sodium & Silicon Dioxide then 5 min
with Magnesium stearate is sufficient.
6.11.9 Final blend characteristics:

Sr. Parameter Results

No.
1 Description White to off-white coloured
granular powder
2 LOD@105°C 4.78%
3 Bulk density 0.49 gm/cc
4 Tapped density 0.62 gm/cc
5 Hausner’s ratio 1.27
6 Compressibility Index 21.37%
7 Angle of repose 24.8°
8 Flow rate (Erveka flow 8.5 sec/100 gm
meter, 15.0 mm funnel)
9 Particle size distribution % Retain
#20 retain 2.6
#20-#40 18.1
#40-#60 17.45
#60-#80 17.10
#80-#100 11.70
Pass through # 100 33.00
10 Blend uniformity
S-1 98.4
S-2 97.5
S-3 98.9
S-4 97.2
S-5 99.4
S-6 98.8
S-7 97.8
MEAN 98.3
11 Composite 101.8
12 Related Impurities
Single Max Impurity 0.52%
Total Impurities 0.52%
Inference: Lubricated blend is found satisfactory in terms of flow and particle size
distribution

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

6.11.10 compressions:
S.No. Parameters Observation
250 mg
Machine Name Cad mach rotary compression machine 20
01
station
02 Machine rpm 25
Punch description 12/32" Circular Biconvex, Plain/Plain (D
03
tooling) punches plain on both the sides.
04 No. of punch sets 2 sets
05 Machine run time 3 hr
6.11.11 Compression parameters:
Batch no. Demo
Dimension 12/32"
U/P plain
L/P plain
Tooling D
311.39mg
Low hardness
(308.0 mg to 314.0 mg)
Average weight (mg)
312.16mg
Optimum hardness 312.0 ± 3 %
(311.6 mg to 313.0 mg)
(302.64 to 321.36 mg)
308.2mg
High hardness
(306.8 mg to 309.5mg)
63.70N
Low hardness
(61 N to 75 N)
Hardness
125.10N
Optimum hardness 115 N ± 20 N
(113 N to 140 N)
(95 N to 135 N)
165.60N
High hardness
(138 N to 182 N)
5.29mm
Low hardness
(5.21 mm to 5.39 mm)
Thickness
5.10mm
Optimum hardness0 5.00 ± 0.3 mm
(4.96 mm to 5.31 mm)
(4.70 to 5.30 mm)
4.82mm
High hardness
(4.78 mm to 4.87 mm)
Low hardness 54 sec
DT
Optimum hardness 1.0 min 40 sec
NMT 15 mins.
High hardness 3.0 min 10 sec
100R-0.28 200R–0.39%
Low hardness
300 R - 0.46 %
Friability %w/w 100R-0.1% 200R-0.27%
Optimum hardness
NMT 1.0 % w/w 300 R - 0.37 %
100R-0.20% 200R-0.26%
High hardness
300 R - 0.41 %

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 6 Product optimization

6.11.12 Coating parameters: 250 mg

Time Inlet Temp Product temp Pan rpm Spray rpm Spray rate
12:05 56 40 1 - -

12:15 57 40 1 - -

12:17 57 38 2 2 3

12:25 62 39 3 3 5

12:30 60 39 3 3 6

12:40 67 39 3 4 6

12:45 66 40 3 5 6

12:55 66 38 3 3 6

13:05 63 37 3 3 5

13:15 64 37 3 3 5

13:25 45 35 2 - -

Dept. of Pharmaceutics JKK Nattraja College of Pharmacy

 Chapter 7 Materials and Methods

Product Composition:

Granulation lot A & Lot B

Qty
Qty./ba
S. Spec. Functi %w/ /Tab.
Item code Ingredients tch
No * on w (In
(In kg)
mg)
Dry mix:
Azithromycin 81.8 262.0
1 1000494 USP Active 19.65$
(as dihydrate) 8 0
Azithromycin
2 1000494 USP Active -- -- 0.20#
(as dihydrate)
Microcrystalline Diluen
3 2000185 IP 5.96 19.06 1.43$
cellulose t
Croscarmellose USP/ Disint
4 2000054 0.91 2.90 0.218
Sodium NF egrant
Pregelatinized
5 2000227 USP Binder 3.75 12.00 0.900
Starch
Granulation :
Wettin
Sodium Lauryl
6 2000329 IP g 0.20 0.64 0.048
Sulphate
agent
USP/P
Granul
h.Eur/ 7.500*
7 1822352 Purified water ating Qs Qs
BP/ *
fluid
IP/IH
Dried sized granules weight 296.60 22.246

Dept. of Pharmaceutics 87 JKK Nattraja College of Pharmacy

 Chapter 7 Materials and Methods

Qty
S. Item Spec %w/ Qty./batch
Ingredients /Tab.
No code .* w (In kg)
(In mg)
Blending of Lot A and Lot B : 296.60 44.492
Lubrication :
Croscarmellose USP
8 2000054 1.81 5.80 0.870
Sodium /NF
Silicon Dioxide
USP
9 2000446 (Syloid 244 1.50 4.80 0.720
-NF
FP)
Magnesium
10 2000156 IP 1.50 4.80 0.720
Stearate
Core tablet 97.5
312.00 46.802
weight 0
Coating Ingredients@ :
11 Hydroxyl
2000115 Propyl Methyl IP 1.89 6.05 1.452
Cellulose (6cps)
12 2000198 PEG -6000 IP 0.27 0.85 0.204
13 2000352 Talc IP 0.16 0.50 0.120
14 Titanium
2000358 IP 0.120
dioxide 0.16 0.50
15 Quinoline
2000241 IH 0.024
yellow 0.03 0.10
USP/P
h.
16 1822352 Purified water Eur/B Qs Qs 17.280**
P/IP/
IH
Coated tablet weight 100.00 320.00 48.000
Note:

* Always current version of specification should be followed

$
Quantity of Azithromycin (as dihydrate) USP taken considering 100% assay on
As such basis, its quantity to be adjusted with microcrystalline cellulose IP

# 1.0% w/w extra API to be dispensed to compensate for milling loss and 19.65 kg
milled API with assay compensation is to be used for the further processing. The
excess API, if Any, is to be discarded after milling.

@ 60 % extra coating solution to be prepared to compensate loss during coating

** Removed during process, does not remain in the finished product

262.00 mg of Azithromycin USP (as dihydrate) equivalent to 250.00 mg

Azithromycin Anhydrous.

Dept. of Pharmaceutics 88 JKK Nattraja College of Pharmacy

 Chapter 7 Materials and Methods

Formula Calculation:
7.1 Calculation for actual quantity of Azithromycin dihydrate USP:

For each Lot:

Actual Quantity of
Azithromycin Assay on anhydrous basis Assay on as is basis
=
dihydrate USP
18.75 x 100 x 100 or 18.75 x 100
Required in kg (Q) A x (100 – W) B
per batch

Where:

A = Assay of Azithromycin USP on anhydrous basis in % w/w

B = Assay of Azithromycin USP on as is basis in %w/w

W= water by KF in % w/w

7.2 Calculation for actual quantity of microcrystalline cellulose IP

(Depending upon 3.1.1 and Theoretical Quantity of Microcrystalline cellulose IP)

Actual Quantity of Microcrystalline

= 1.43 – ( Q – 19.65)
cellulose IP required per batch in kg (P)

Note:

API of multiple A.R. No’s may be used for which assay calculation has to be
done accordingly

Process Flow Diagram-Schematic:

Dept. of Pharmaceutics 89 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

Dry Mixing Wet

Milling Sifting
Granulation

Blending II Blending I Sizing Drying

Lubrication Compression Coating

Packaging

Dept. of Pharmaceutics 90 JKK Nattraja College of Pharmacy

 Chapter 7 Materials and Methods

7.3 Manufacturing conditions and Precautions:

Ensure that all the area is cleaned and free from previous product material before taking
any batch

Ensure that all the input materials used in a batch bear QA approved labels.

Ensure that all the personals in the manufacturing area wear protective clothing.

Ensure that the Room Temperature is NMT 27°C and Relative humidity is below 60 %
RH.

Ensure that all the activities are carried out as per MFC and recorded in the BMR.

7.3.1 Manufacturing Process:

7.3.2 Milling of API: Mill the Azithromycin dihydrate USP through 0.3mm screen impact
Forward at fast speed in Cadmill.

7.3.3 Dispensing:

Check all the dispensed ingredients as per the material requisition note and record in
BMR.

7.3.4 Sifting

1 Sift the calculated quantity of milled API through 80 # mesh on Vibratory sifter.

2 Co-sift the calculated quantity of Microcrystalline cellulose IP, Croscarmellose sodium

USP-NF 0.218 kg and Pregelatinized starch USP 0.900 kg with API of step 7.3.1 through
40# on vibratory sifter

7.3.5 Dry Mixing

Dept. of Pharmaceutics 91 JKK Nattraja College of Pharmacy
Chapter 7 Materials and Methods

Load the sifted materials from step 9.4.3 into a clean and dry Rapid Mixer
Granulator fitted with co-mill having 8.0 mm SS Screen and mix for 5 minutes
with Chopper off and impeller at slow speed.

Sampling locations in Rapid mixer Granulator:

X Y Z

Figure No. 8.1: Sampling locations in Rapid mixer Granulator (Not to scale)

X – 1/3 of material height from bottom – Top layer

Y – 1/2 of material height from bottom – Middle layer

Z – 2/3 of material height from bottom – Bottom layer

S1 –Upper –Rear S6 – Middle– Center

S2 - Upper –Left S7-Lower – Rear

S3 – Upper – S8 – Lower – Left

Center

S4 – Upper - Right S9 – Lower – Right

S5 – Upper- Front S10 – Lower – Front

Dept. of Pharmaceutics 92 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

7.3.6 Granulation

1) Binder solution preparation

Dissolve Sodium Lauryl Sulphate IP 0.048 kg in 7.500 kg of purified

water USP/Ph.

Eur/BP/IP/IH to get a clear solution.

2) Binder Solution Additions

Add binder solution prepared at step 7.5.1 to the dry mixed of step 7.4
by using peristaltic

Pump in Rapid Mixer Granulator fitted with co-mill having 8.0 mm SS

Screen with

Impeller at slow speed and Chopper off in 6 to 8 min.

3) Kneading

Carry out kneading for 4 to 7 minutes at impeller slow and chopper off.
If required, add

Extra amount of Purified water USP/Ph.Eur/BP/IP/IH to get the desired

consistency of wet

Mass. Record the extra quantity added in BMR.Unload the wet mass
(Granules) through

Co-mill using 8.0 mm SS Screen.

7.3.7 Drying

Dry the wet mass of Step of 7.5.3 at inlet air temperature 55 ± 5°C
to get LOD 3.5% to

5.0% w/w at 105°C.

7.3.8 Sizing:
Pass the dried granules of step 7.6 through Oscillating granulator fitted
with 1.2 mm SS

Screen. Collect the granules into clean & dry suitable container.

Theoretical Yield = 22.246 kg

Lot B: Granulation

Dept. of Pharmaceutics 93 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

Manufacturing Process: for Lot B: Granulation

Repeat the manufacturing process same as steps 9.1 to 9.7

7.3.9 Blending I of Lot A and Lot B:

Blending the Lot A and Lot B sized granules in Bunker with Conta blender
for 10 min.

7.4 Blending – II:

7.4.1 Sift 0.870 kg of Croscarmellose sodium USP/NF and 0.720 kg Silicon

Dioxide USP-NF (Syloid 244 FP) through 40# sieve on vibratory sifter.

7.4.2 Blend the granules of step 7.8 with Croscarmellose sodium USP/NF and
Silicon Dioxide (Syloid 244 FP) USP-NF for 10 minutes in Bunker with Conta
blender.

7.5 Lubrication:

7.5.1 Sift 0.720 kg of Magnesium Stearate IP through 60# sieves on vibratory

sifter then blend With material of step 7.9.2 for 5 minutes

7.5.2 Send the sample of blend material to Q.C along with sample test request
slip for Analysis.

7.5.3 Weight and record the yield of the blend in BMR.

Theoretical Yield: 46.802 kg

Sampling Instruction:
Dept. of Pharmaceutics 94 JKK Nattraja College of Pharmacy
Chapter 7 Materials and Methods

Insert the unit dose sampler at an angle of 45-600 in closed position, such that the
slot is facing upwards at the nearest locations identified in the figure.

Figure No. 7.2: Sampling locations in Conta Blender (Not to scale)

S
1
S
S
S 3
S 9
7
5
SS S
41 2
0
S
6

S
8

Bunker
X Y Z

X – 2/3 of material height from bottom – Upper layer

Y – 1/2 of material height from bottom – Middle layer

Z -- 1/3 of material height from bottom – Lower layer

7.6 Compression:
Dept. of Pharmaceutics 95 JKK Nattraja College of Pharmacy
Chapter 7 Materials and Methods

7.6.1. Conmpress the granules into tabalets on rotary compression machine

using 12/32” SC, plain /Plain (D tooling ) punches plain on both sides
7.6.2 Check Description, Weight of 20 tablets, Average weight, Uniformity of
weight Hardness, Friability, Thickness, Disintegration time & record these
parameters in BMR.
7.6.3. Send the sample of compressed tablets to QC along with sample test
request slip for analysis Weigh and record the weight of compressed tablets in
BMR.

Theoretical yield = 46.802 kg

Dept. of Pharmaceutics 96 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

7.7 Coating

Preparation of Film coating suspension:

7.7.1 Take 10.00 kg Purified Water USP/Ph.Eur/BP/IP/IH in a SS tank and

slowly add 1.452 kg Hydroxyl Propyl Methyl Cellu. (6cps) IP into it while
stirring. Stir continuously till Clear Solution is obtained.

7.7.2 Take 5.00 kg of Purified Water USP/Ph.Eur/BP/IP/IH. Disperse 0.120 kg

Titanium Dioxide IP and 0.120 kg Talc IP and 0.024 kg of Quinoline yellow IH
mill it in colloidal Mill for 20 min. Rinse the colloid mill with Purified water
USP/Ph.Eur/BP/IP/IH

7.7.3 Add suspension of step 7.12.2 in solution of step 7.12.1 with continuous
stirring.

7.7.4 Dissolve 0.204 kg PEG 6000 IP in purified water USP/Ph.Eur/BP/IP/IH

and add in to Coating suspension of step 7.12.3. Continue the stirring for 10
minutes.

7.7.5 Filter the coating solution through 100#.

7.7.6 Drying/Heating of Tablets

Dept. of Pharmaceutics 97 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

Stage Inlet Temp. Duration Pan RPM

(°C) (min)

Before Coating 55 ± 5 10 Inching

After 100% 40 ± 5 10 Inching

Coating

7.7.5 Coating parameters:

Sr. Parameter Limit

No.

01. Inlet air temperature 55.0 °C ± 5.0°C

02. Exhaust temperature To be established

03. Pan R.P.M. To be established

04. Spray rate To be established

05. Atomization air To be established

pressure

06. Product temperature 40 ± 5°C

07. Spraying gun nozzle 1.2 mm

Diameter

Dept. of Pharmaceutics 98 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

7.8 Coating Process:

7.8.1 Prior to loading the tablets in coating pan, record average mass (A) of 50
tablets.

7.8.2 Spray the coating suspension on the tablets in pan according to conditions
given above till required weight gain is achieved. After completion of coating
process, allow the tablets to dry in the pan in inching mode for 10 minutes in a
stream of air temperature at 40°C ±5°C.

7.8.3 Record the average mass of coated tablets in the BMR. Weight gain should
be 2.5 + 0.5% w/w on the average mass (A).

7.8.4 Unload the coated tablets in to a clean double polypropylene lined

container. Weigh and record the weight of coated tablets in BMR.

7.8.5 Send the sample of coated tablets along with Test Request Form to QC
dept.for analysis as per finish product release specification.

Theoretical yield = 48.000 kg

7.8.6 On receipt of QA/QC approval, send the tablets for packing.

Dept. of Pharmaceutics 99 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

7.9. In process test parameters:

Stage Test Acceptance Criteria
Drying LOD 3.5 – 5.0 %w/w at 105°C
Description White to off-white granular powder
Water Content NMT 6.0%w/w
Lubrication
Not less than 95.0 % and not more than
Assay
105.0% of labeled amount of Azithromycin.
White to off-white, round biconvex, uncoated
Description
tablets plain on both sides
Average weight 312.0 mg + 3% (302.6 mg to 321.3 mg)
Weight of 20 tablets 6.24 g + 3% (6.05g to 6.43 g)
Uniformity of weight Average weight + 5 %
Hardness 115 N ± 40 N (75 N to 155 N)
Disintegration time Not more than 15 min
Friability Not more than 1% w/w
Compression
Thickness 5.00 ± 0.30 mm (4.70 mm to 5.30 mm)
Not less than 75 % (D) of the labeled
Dissolution amounts of Azithromycin dissolved in 45
minutes.
Not less than 95.0% and not more than
Assay 105.0% of the labeled amounts of
Azithromycin
Water content NMT 6.0%w/w
Yellow colored, round biconvex, film coated
Description
tablets plain on both sides
Thickness 5.10 ± 0.30 mm (4.80 mm to 5.40 mm)
Theoretical weight 320.0 mg
Avg. Weight 320.0 mg ± 3 % (310.4 mg to 329.6 mg)
Coating* % Wt. gain 2.50% ± 0.5%
Disintegration Time Not more than 30 min.
Not more than two of the individual weights
Uniformity of Weight deviates from the average weight by more
than 5% and none deviates by more than 10%

* Remaining tests to comply as per the finished product release

specification.

Dept. of Pharmaceutics 100 JKK Nattraja College of Pharmacy

Chapter 7 Materials and Methods

7.10 Yield Statement:

Sr. Stage Theoretical Yield

No.

1. Lubricated granules 46.802 kg

2. After Compression 46.802 kg

3. After Coating 48.000 kg

Dept. of Pharmaceutics 101 JKK Nattraja College of Pharmacy

 Chapter 8 Results and Discussion

CHAPTER - 8

1.0 RESULTS AND DISCUSSION

2.0 8.1 Evaluation of physical parameters of Azithromycin:

3.0 8.1.1 Organlopetic Properties:

Test Specification/Limits Observations

White or almost white White crystalline

Color
crystalline powder powder

Taste Bitter Bitter

Odour Odourless Odourless

8.2 Flow Properties (Angle of repose):

Table No 11

Material Angle of repose

Azithromycin 32o85”

8.3 Determination of Densities:

Table No 12

Material Bulk Density (gm/ml) Tapped density (gm/Ml)

Gliclazide 0.27 0.35

Dept. of Pharmaceutics 102 JKK Nattraja College of Pharmacy

Chapter 8 Results and Discussion

8.4 Powder compressibility:

Table No 13

Materials Compressibility index Hausner ratio

Azithromycin 22.86% 1.30%

4.0

8.5 Solubility:

It was determined as per procedure given in method section 5.1.6. The

following table illustrated the result

Table No 14

Test Specification Result

Solubility in water, Practically insoluble in water

alcohol. Soluble in methanol, ethanol, Complies
chloroform, and
dimethylchloride

Assay (by AZIT-IMTB-10-IN):

Table No 15
Test Specification Observation

Assay 99.0 - 101.0 99.89

Dept. of Pharmaceutics 103 JKK Nattraja College of Pharmacy

Chapter 8 Results and Discussion

8.6 Formulation Compositions:

Table No 23

INGRIDIENT
F1 F2 F3 F4 F5 F6
NAME (mg)

Azithromycin 262.00 262.00 262.00 262.00 262.00 262.00

dehydrate
Microcrystalline 19.06 19.06 19.06 19.06 19.06 19.06
cellulose
Pregelatinized starch 12.00 12.00 12.00 12.00 12.00 12.00

Croscarmellose sodium 2.90 2.90 2.90 2.90 2.90 2.90

Croscarmellose sodium 5.80 5.80 5.80 5.80 5.80 5.80

Colloidal Silicon 4.80 4.80 4.80 4.80 4.80 4.80

dioxide
Magnesium Stearate 4.80 4.80 4.80 4.80 4.80 4.80

Purified water QS QS QS QS QS QS

Total weight 312.00 312.00 312.00 312.00 312.00 312.00

Coating

Hydroxyl Propyl
6.05 6.05 6.05 6.05 6.05 6.05
Methyl Cellulose
(6cps)

PEG -6000 0.85 0.85 0.85 0.85 0.85 0.85

Talc 0.50 0.50 0.50 0.50 0.50 0.50

Titanium dioxide 0.50 0.50 0.50 0.50 0.50 0.50

Quinoline yellow 0.10 0.10 0.10 0.10 0.10 0.10

Purified water Qs Qs Qs Qs Qs Qs

Total weight 320.00 320.00 320.00 320.00 320.00 320.00

Dept. of Pharmaceutics 104 JKK Nattraja College of Pharmacy

 Chapter 8 Results and Discussion

8.7 Physical Parameters and Drug Content:

Table No 24

Weight
variation Disintegration Drug Thickness
Formul- Friability Hardness
(n=20) Time content (mg ±
ations (%) (Newton)
(mg ± SD) (seconds) (%) SD)

F1 312±0.54 0.36 112±20 85±0.7 99.24 3.2±0.009

F2 311±0.91 0.35 113±20 86±0.8 98.16 3.2±0.008

F3 312±0.63 0.41 110±20 85±0.6 98.74 3.2±0.011

F4 312±0.52 0.42 111±20 84±0.6 98.02 3.1±0.010

F5 313±0.49 0.36 112±20 86±0.7 98.21 3.3±0.008

F6 312±0.83 0.37 113±20 87±0.4 99.46 3.2±0.008

The formulated tablets were then evaluated for various physical

characteristics like weight variation, friability, hardness, disintegration time,
drug content, thickness. The weight variation of tablet was uniform in all
formulations and ranged from 312±0.52 to 313±0.49. Friability values were
ranged from 0.35 to 0.42. The hardness of prepared tablets was ranged from
110±20 to 113±0.20.disintegration time of tablet values ranged from 84±0.6 to
87±6.3. Drug content of tablets ranged from 98.02 to 99.46 And the thickness
values were ranged from 3.1±0.008 to 3.3±0.008.

Dept. of Pharmaceutics 105 JKK Nattraja College of Pharmacy

Chapter 8 Results and Discussion

8.8 Dissolution Data of Tablet Formulation of Azithromycin tablets:

Table No 25

Time
(min) CUMULATIVE PERCENT DRUG RELEASE (%)

F1 F2 F3 F4 F5 F6

0 0 0 0 0 0 0

15 45.19 49.13 41.05 50.04 46.15 46.72

30 75.61 71.91 70.13 71.19 70.89 71.17

45 91.09 96.94 93.61 99.92 93.22 97.61

60 98.71 99.54 98.76 -- 99.07 --

Fig No 13: In-vitro Dissolution Graph of Tablet Formulation of

Azithromycin tablets

Dept. of Pharmaceutics 106 JKK Nattraja College of Pharmacy

Chapter 8 Results and Discussion

Dissolution data of Optimized Formulation and Marketed Brand:

8.9 Comparison with the Marketed Product

Table No 26

Mean Cumulative % Drug

Time Release
(min)
F4 Marketed product

0 0 0

15 50.04 39.63

30 71.19 68.25

45 99.92 93.07

60 -- 99.48

Fig No 14: Comparision with the Marketed Product

Dept. of Pharmaceutics 107 JKK Nattraja College of Pharmacy

 Chapter 8 Results and Discussion

8.10 STABILITY STUDIES:

Optimized formulation (F4) was subjected to stability studies at 40oc±

o
2 c/75% RH ±5 % for 2 months. The product was evaluated for appearance and
hardness. Drug release studies were conducted as per the planned scheduled as
above.

Storage conditions at: 40OC2 OC/ 75 % RH5%.

Stability studies are evaluated for following parameters

 Hardness

 Friability

 Weight variation

 Drug content

 In-vitro dissolution studies

Descriptions:

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet
40 °C, 75 % RH
Sr. Tests Specification Initial 1 month 2 month
No

1 Description Yellow colored, round complies Complies complies

shaped, biconvex,
coated tablet, plain on
both side.

2 Assay (%) 90 % to 110 % of 99.7 99.2 100.1

label claim

3 Water content (%) To record 5.12 5.32 5.40

4 Disintegration Not more than 30 1.56 1.30 2.45
time minutes

5 Dissolution at pH Not less than 75 % (D) 95.2 99.4 9 100.6

6.0 phosphate in 45 minutes (0.58) (0.85) (2.08)
buffer

Observation: Stability data show that drug product is stable upto 2 month in
accelerated condition

Dept. of Pharmaceutics 108 JKK Nattraja College of Pharmacy

 Chapter 8 Results and Discussion

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet
30 °C, 75 % RH

S. Tests Specification Initial 1 month 2 month

No
1 Description Yellow colored, round complies Complies complies
shaped, biconvex,
coated tablet, plain on
both side.
2 Assay (%) 90 % to 110 % of 99.7 99.5 98.8
label claim
3 Water To record 5.12 5.42 5.6
content (%)
4 Disintegratio Not more than 30 1.56 2.00 2.00
n time minutes
5 Dissolution Not less than 75 % 95.2(0.58 97.6 97.5
at pH 6.0 (D) in 45 minutes )
phosphate
buffer

Observation: Stability data show that drug product is stable upto 2 month in
intermediate condition.

Dept. of Pharmaceutics 109 JKK Nattraja College of Pharmacy

 Chapter 8 Results and Discussion

Batch No – Demo batch Packing – Yellow PVC blister Storage condition

B. Size – 12000 tablet
25°C, 60 % RH
S. Tests Specification Initial 1 month 2 month
No

1 Description Yellow colored, round complie Complie complies

shaped, biconvex, s s
coated tablet, plain on
both side.

2 Assay (%) 90 % to 110 % of 99.7 99.9 100.0

label claim

3 Water content To record 5.12 5.28 5.30

(%)

4 Disintegration Not more than 30 1.56 2.00 2.10

time minutes

5 Dissolution at Not less than 75 % 95.2(0.5 96 97.23

pH 6.0 (D) in 45 minutes 8)
phosphate
buffer

Observation: Stability data show that drug product is stable upto 2 month in
normal condition

Dept. of Pharmaceutics 110 JKK Nattraja College of Pharmacy

 Chapter 9 Conclusion

CHAPTER - 9

CONCLUSION

From the present work , it can be concluded that the results suggested
that the prepared formulations were stable and globally acceptable. In the wake
of patentability of immediate release dosage forms

The results of the present research work gives idea about the formulation
of various bacteriostatic drugs as immediate release dosage forms. The research
work was done with economical, commercial and regulatory point of view. The
final products developed in the research may be commercialized after the
establishment of the safety and efficacy in the human volunteers.

In future , with the help of invivo studies reduction is dose is possible,

which reduce adverse effect

Dept. of Pharmaceutics 111 JKK Nattraja College of Pharmacy

Chapter 10 Bibliography

CHAPTER - 10

1.0 BIBLIOGRAPHY

1. Noedl H, Krudsood S, Jongsakul K, Sriwichai S, Rowan J, Bhattacharyya H,

Ohrt C, Azithromycin combination therapy with artesunate or quinine for the
treatment of uncomplicated Plasmodium falciparum malaria in adults: a
randomized, phase 2 clinical trial in Thailand. Clin Infect Dis. 2006 Nov
15;43(10):1264-71. Epub 2006 Oct 12.

2. KM Olsen, G San Pedro, LP Gann, PO Gubbins, DM Halinski and GD

Campbell Jr Department of Pharmacy Practice, College of Pharmacy,
University of Nebraska Medical Center,Omaha 68198-6045,USA

3. J Retsema, A Girard, W Schelkly, M Manousos, Central Research Division,

Pfizer Inc., Groton, Connecticut 06340. Antimicrob Agents Chemother. 1987
December; 31(12): 1939–1947.

4. Suhagia BN; Shah SA; Rathod IS; Departm Indian Journal of Pharmaceutical
Sciences. 2006 Mar-Apr; 68(2): 242-5 ent of Quality Assurance, L.M. College
of Pharmacy, Navrangpura, Ahmadabad

5. Hooda AK; Narula AS, Department of Nephrology, Command Hospital,

Central Command, Lucknow Indian Journal of nephrology 2004 Apr; 14(2):
53-55

6. Singhi MK; Ghiya BC; Dhabhai RK Department of Skin, VD, and Leprosy,
Dr. S.N. Medical College, Jodhpur, India

7. Ogale SB; Oke VG; Bowalekar SK; Karandikar V; Salgaonkas U; Sawant N;

Hegde R; Nair A Department of otolaryngology, G.S. Medical College and
KEM Hospital, Parel Mumbai Indian Practitioner. 2000 Oct; 53(10): 651-7

Dept. of Pharmaceutics 112 JKK Nattraja College of Pharmacy

Chapter 10 Bibliography

8. H. Rautelin1 , O. -V. Renkonen1 and T. U. Kosunen1 Department of

Bacteriology and Immunology, University of Helsinki, Haartmaninkatu 3, PO
Box 21, 00014, Finland

9. R. Haye1 , E. Lingaas2, H. O. HØivik3 and T. Ødegård4 Department of

Otolaryngology, National Hospital, Pilestredet 32, N-0027 Oslo, Norway

10. Department of Microbiology, National Hospital, Pilestredet 32, N-0027 Oslo,

Norway

11. Elverum Medical Clinic, 2400 Elverum, Norway

12. J Retsema, a Girard, W Schelkly, M Manousos, M Anderson, G Bright, R

Borovoy, L Brennan, and R Mason Central Research Division, Department of
Pharmaceutical Chemistry, Vellore Institute of Technology, Deemed
University, Vellore-632014

13. Indian Journal of Pharmaceutical Sciences. 2004 Mar; 66(2): 249-251

14. Becker C, Dressman JB, Amidon GL, Junginger HE “Biowaiver monographs

for immediate release solid oral dosage forms: Isoniazide” J Pharm Sci.2007
Mar; 96(3):522-31

15. Dumont ML, Berry MR, Nickerson B “Probability of passing dissolution

acceptance criteria for an immediate release tablets” J Pharm Biomed Anal.
2007 Feb 3;

16. Qureshi SA, Shabnam J “Applications of a new device (spindle) for improved
characterization of drug release (dissolution) of pharmaceutical products.” Eur
J Pharm Sci. 2003 Jul; 19(4):291-7

17. Yu LX, Wang JT, Hussain AS “Evaluation of USP apparatus 3 for dissolution
testing of immediate release products” AAPS PharmSci. 2002; 4(1):E1

Dept. of Pharmaceutics 113 JKK Nattraja College of Pharmacy

Chapter 10 Bibliography

18. Shah VP, Gurbarg M, Noory an “Influence of higher rates of agitation on

release patterns of immediate-release drug products” J Pharm Sci.1992 Jun;
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19. Lachman L. and Lieberman H.A., Pharmaceutical Dosage Forms: Tablets,

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20. Leon Lachman., The Theory and Practice of Industrial Pharmacy, 3rd Edition,
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22. Aulton M.E., Pharmaceutics - The science of dosage form design, 2nd Edition,
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23. Leon Shargel and Andrew., B.C.Y.U; Applied Biopharmaceutics and

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24. The Merck Index, 13th Edition, 2001; 6909.

25. James Swarbrick and James C. Boylan, Encyclopedia of pharmaceutical

technology, 2nd Edition, Vol 1, 642- 647.

26. Raymond C Rowe, Paul J Sheskey and Siaane Owen, Handbook of

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Dept. of Pharmaceutics 114 JKK Nattraja College of Pharmacy

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33. Leon Lachman, Herbert A. Liberman, Joseph L.Kenig, The theory and practice
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34. European Pharmacopoeia, 1475-1476.

35. British pharmacopoeia, 2000; 585-589.

36. Beckett A.H., Stenlake J.B., Pharmaceutical Chemistry, 4th Edition, Part-I,
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1, 2nd Edition, Revised and Expanded, Ch-4, 195-245.

39. ICH harmonized tripatite guidelines for validation

40. CIMS current index of medical science, IEEE computer society, April –July
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Dept. of Pharmaceutics 115 JKK Nattraja College of Pharmacy