A

Project Report Submitted to

UPTU UNIVERSITY

for the award of the degree of

BACHELOR OF PHARMACY

By

Mr. Amit Sharma

Under the Guidance of

Mrs. Ruchika Garg

Department of Pharmaceutical Technology,

Noida Institute of Engineering and Technology,

Greater Noida-201306

MAY – 2011.
ACKNOWLEDGEMENTS:

It is great pleasure for me to acknowledge all those who have contributed towards the
conception, origin and nurturing of this project.
With a deep sense of gratitude and the respect, I thank my esteemed research guide
Mrs. Ruchika Garg, lecturer. Department Of Pharmaceutical Technology, Noida Institute of
Technology,Greater Noida for her inestimable guidance, valuable suggestions and constant
encouragement during the course of this study.
I am thankful to Dr A. Mazumder, Director and Dr S.P.Basu, Director General, Dr
R. Mazumder, Dean (R&D) and Dr S.P. Agarwal, Director (R&D) for their constant moral
support, valuable suggestions, directions and selfless support throughout the investigation.
I am also grateful to Mrs Sushma Verma for her guidance during the project work.
At this moment, I thanks with deep gratitude to my classmates and friends for their
moral support, constant encouragement and patience absolutely needed to complete my
entire study. It was the blessing of them that gave me courage to face the challenges and
made my path easier.

I am indebted infinitely to care, support and trust being shown by my parents without
whom it would not be possible to complete this project.

AMIT SHARMA
Roll Number-0713350006
B.Pharm 4th year
2010-2011

Department of Pharmaceutical Technology,

 Noida Institute of Engineering and Technology,

Greater Noida

CERTIFICATE
The work described in this thesis entitled “FORMULATION & EVALUATION OF
MICROENCAPSULATION OF ASPIRIN” has been carried out by AMIT SHARMA
under my supervision. I certify that this is his bonafide work. The work described
is original and has not been submitted for any degree to this or any other
university.

Date: Guide:

Place: Greater Noida. Ruchika Garg,

Lecturer

Department of Pharmaceutical
Technology,

Noida Institute of Engineering and

Technology,

Greater Noida

Forwarded:

Dr A. Mazumder

Professor and Director,

Department of Pharmaceutical Technology,

Noida Institute of Engineering and Technology,

Greater Noida
 Statement by the candidate
As required by university regulation, I wish to state that this work embodied in
this report titled “FORMULATION & EVALUATION OF MICROENCPSULATION
OF ASPIRIN” forms my own contribution to the research work carried out under
the guidance of Dr. A. Mazumder (Prof. and Director, NIET). This work has not
been submitted for any other degree of this or any other university. Whenever
references have been made to previous work of others, it has been clearly
indicated as such and included in the bibliography.

Mr. Amit Sharma

Forwarded Through

Guide

Ruchika Garg

Name of Guide

Lecturer,

Department of Pharmaceutical Technology,

NIET, Greater Noida

 • Name of the Guide: Mrs Ruchika Garg

• Name of the Student: Amit Sharma

• Topic of the project: Formulation & Evaluation of

Microencapsulation Of Aspirin

• Guide - Student Interaction: Satisfactory Good Poor

• Status of the Project: Completed Will complete by May

middle

• Marks of the candidate (out of 20):

Sign of the Guide:

Date:
 CONTENTS

Sr.No. Chapter No. Name of Chapter Page No.

1 Chapter I Introduction 1-18

2 Chapter II Objective 19-20

3 Chapter III Literature review 21-25

5 Chapter IV Experimental Work 26-33

6 Chapter V Results and Discussion 34-36

7 Chapter VII Summary 37-38

8 Chapter VIII Bibliography 39-43.

 (1)

INTRODUCTION

Micro-encapsulation is a process in which tiny particles or droplets are surrounded by a

coating to give small capsules many useful properties. In a relatively simplistic form, a
microcapsule is a small sphere with a uniform wall around it. The material inside the
microcapsule is referred to as the core, internal phase, or fill, whereas the wall is sometimes
called a shell, coating, or membrane. Most microcapsules have diameters between a few
micrometers and a few millimeters.

The definition has been expanded, and includes most foods. Every class of food ingredient
has been encapsulated; flavors are the most common. The technique of microencapsulation
depends on the physical and chemical properties of the material to be encapsulated.

Without citations, this article may be argumentative. It is cautioned that the information
below may not be correct, as the current definitions and processes in this article can allow
most powders mixed with other liquids to be considered microencapsulated, if the liquid
serves to protect it in any way. The data below needs citations to be considered factual. These
citations do not currently exist.

Many microcapsules however bear little resemblance to these simple spheres. The core may
be a crystal, a jagged adsorbent particle, an emulsion, a suspension of solids, or a suspension
of smaller microcapsules. The microcapsule even may have multiple walls.
 (2)

MORPHOLOGY OF MICROCAPSULES:

The morphology of microcapsules depends mainly on the core material and the deposition
process of the shell.

1- Mononuclear (core-shell) microcapsules contain the shell around the core.

2- Polynuclear capsules have many cores enclosed within the shell.

3- Matrix encapsulation in which the core material is distribute homogeneously into the shell
material.

- In addition to these three basic morphologies, microcapsules can also be mononuclear with
multiple shells, or they may form clusters of microcapsules.

Morphology of Microcapsules:
 (3)

Coating material properties:

• Stabilization of core material.

• Inert toward active ingredients.

• Controlled release under specific conditions.

• Film-forming, pliable, tasteless, stable.

• Non-hygroscopic, no high viscosity, economical.

• Soluble in an aqueous media or solvent, or melting.

• The coating can be flexible, brittle, hard, thin etc.

Coating materials:
 • Gums: Gum arabic, sodium alginate, carageenan.

• Carbohydrates:sucrose,dextrose,dextron

• Celluloses: Carboxymethylcellulose, methycellulose.

• Lipids: Bees wax, stearic acid, phospholipids.

• Proteins: Gelatin, albumin.

(4)

Benefits of Microencapsulation:
1- Microorganism and enzyme immobilization.Enzymes have been encapsulated in cheeses to
accelerate ripening and flavor development.

The encapsulated enzymes are protected from low pH and high ionic strength in the cheese.
The encapsulation of microorganisms has been used to improve stability of starter cultures.

2-Protection against UV, heat, oxidation, acids, bases (e.g.colorants and vitamins). e.g.
Vitamin A / monosodium glutamate appearance (white) protection (water, T, ligth).
3- Improved shelf life due to preventing degradative reactions (dehydration, oxidation).

4- Masking of taste or odours.

5- Improved processing, texture and less wastage of ingredients. Control of hygroscopy

enhance flowability and dispersibilitydust free powder enhance solubility.

6- Handling liquids as solids.

7-There is a growing demand for nutritious foods for children which provides them with
much needed vitamins and minerals during the growing age.Microencapsulation could
deliver the much needed ingredients in children friendly and tasty way.

8- Enhance visual aspect and marketing concept.

(5)

9- Carbonless copy paper was the first marketable product to employmicrocapsules. A

coating of microencapsulated colorless ink isapplied to the top sheet of paper, and a
developer is applied to the subsequent sheet. When pressure is applied by writing,
thecapsules break and the ink reacts with the developer to produce the dark color of the
copy.

10-Today's textile industry makes use of microencapsulated materialsto enhance the

properties of finished goods. One applicationincreasingly utilized is the incorporation of
microencapsulated phase change materials (PCMs).

Phase change materials absorb and release heat in response tochanges in environmental
temperatures. When temperatures rise, the phase change material melts, absorbing excess
heat, and feels cool. Conversely, as temperatures fall, the PCM releases heat as it solidifies,
and feels warm.

This property of microencapsulated phase change materials can be harnessed to increase the
com for users of sports equipment, clothing, building materials, etc.

11- Pesticides are encapsulated to be released over time, allowing farmers to apply the
pesticides less amounts than requiring very highly concentrated and toxic initial applications
followed by repeated applications to combat the loss of efficacy due to leaching, evaporation,
and degradation.

12- Ingredients in foods are encapsulated for several reasons.

 Most flavorings are volatile; therefore encapsulation of these components extends the shelf-
life of these products. Some ingredients are encapsulated to mask taste, such as nutrients
added to fortify a product without compromising the product’s intended taste. Alternatively,
flavors are sometimes encapsulated to last longer, as in chewing gum.

13- Controlled and targetted release of active ingredients. Many varieties of both oral and
injected pharmaceutical formulations are microencapsulated to release over longer
periodsof time or at certain locations in the body.Aspirin, for example, can cause peptic
ulcers and bleeding if doses are introduced all at once. Therefore aspirin tablets are often
produced by compressing quantities of microcapsules that will gradually release the aspirin
through their shells, decreasing risk of stomach damage.

14- Microencapsulation allows mixing of incompatible compounds.

(6)

MICROENCAPSULATION TECHNOLOGIES:

1- PHYSICAL METHODS : -
2- CHEMICAL METHODS :-

1.1 PAN COATING

2.1 INTERFACIAL POLYMERIZATION

1.2 AIR-SUSPENSION COATING

2.2 IN-SITU POLYMERIZATION

1.3 CENTRIFUGAL EXTRUSION

2.3 MATRIX POLYMERIZATION

1.4 VIBRATIONAL NOZZLE

 1.5 SPRAY–DRYING

(7)

Microencapsulation processes with their

relative particle size ranges:
 Physico – Physico –
Chemical mechanical
Processes Processes
Coacervation Spray-drying
(2 – 1200 um) (5 – 5000 um)
Polymer-polymer Fluidized- bed
incompatibility technology
(0.5 – 1000 um) (20 – 1500 um)
Solvent evaporation Pan coating
(0.5 – 1000 um) (600 – 5000 um)
Encapsulation by Spinning disc
supercritical fluid (5 – 1500 um)
Encapsulation by Co-extrusion
(8)
Polyelectrolyte (250 – 2500 um)
multilayer
(0.02 – 20 um)
Hydrogel Interfacial
microsphere polymerization
(0.5 – 1000 um)
Phase Inversion In situ polymerization
Physico- (0.5—5.0 um) (0.5 – 1100 um)
Hot Melt
(1—1000 um)
Chemical Processes:

1- Coacervation:
Two methods for coacervation are available, namely simple and complex processes.

In simple coacervation, a desolvation agent is added for phase separation.

Whereas complex coacervation involves complexation between two oppositely charged

polymers.Coacervation.

1- First the core material (usually an oil) is dispersed intoa polymer solution (e.g., a cationic
aqueous polymer, gelatin).

2- The second polymer (anionic, water soluble, gumarabic) solution is then added to the
prepared dispersion.

3- Deposition of the shell material onto the core particles occurs when the two polymers
form a complex.

4-This process is triggered by the addition of salt or by changing the pH, temperature or by
dilution of the medium.
5- Finally, the prepared microcapsules are stabilized by crosslinking (with formaldehyde),
desolvation or thermal treatment.

-Complex coacervation is used to produce microcapsules containing fragrant oils, liquid

crystals, flavors, dyes or inks as the core material.

(9)
 (10)

2- Polymer-polymer incompatibility (phase separation):-

1- This method utilizes two polymers that are soluble in a common solvent, yet do not mix
with one another in the solution.

2- The polymers form two separate phases, one rich in the polymer intended to form the
capsule walls, the other rich in the incompatible polymer meant toinduce the separation of
the two phases. The second polymer is not intended to be part of the finished microcapsule
wall.
 (11)

3- Solvent Evaporation:-
- It is the most extensively used method of microencapsulation.

1-Prepare an aqueous solution of the drug (may contain a viscosity building or stabilizing
agent)

2- Then added to an organic phase consisting of the polymer solution in solvents like
dichloromethane or chloroform with vigorous stirring to form the primary water in oil
emulsion.
3- This emulsion is then added to a large volume of water containing an emulsifier like PVA
or PVP to form the multiple emulsion (w/o/w).

4- The double emulsion is then subjected to stirring until most of the organic solvent
evaporates, leaving solid microspheres.

5- The microspheres can then be washed and dried.

(12)

II-Physical process

1- Spray-Drying & spray-congealing:

Microencapsulation by spray-drying is a low-cost commercial process which is mostly used
for the encapsulation of fragrances, oils and flavors.

Steps:

1- Core particles are dispersed in a polymer solution and sprayed into a hot chamber.

2- The shell material solidifies onto the core particles as the solvent evaporates.
The microcapsules obtained are of polynuclear or matrix type. Microencapsulation by spray-
drying.

(13)
Spray-congealing:

- This technique can be accomplished with spray drying equipment when the protective
coating is applied as a melt.

1- The core material is dispersed in a coating material melt.

2- Coating solidification (and microencapsulation) is accomplished by spraying the hot

mixture into a cool air stream.

- e.g. microencapsulation of vitamins with digestable waxes for taste masking.

(14)

2- Fluidized-Bed Technology:
Different types of fluid-bed coaters include top spray, bottom spray, and tangential spray.

Used for encapsulating solid or liquids absorbed into porous particles Steps:

1-Solid particles to be encapsulated are suspended on a jet of air and then covered by a
spray of liquid coating material.

2- The rapid evaporation of the solvent helps in the formation of an outer layer on the
particles.

3- This process is continued until the desired thickness and weight is obtained.

Schematics of a fluid-bed coater.

(A)Top spray (B) bottom spray (C) tangential spray

(15)

3- Pan coating:
1- Solid particles are mixed with a dry coating material.
2- The temperature is raised so that the coating material melts and encloses the core
particles, and then is solidified by cooling. Or, the coating material can be gradually applied
to core particles tumbling in a vessel rather than being wholly mixed with the core particles
from the start of encapsulation.

(16)

4- Co-Extrusion:
1- A dual fluid stream of liquid core and shell materials is pumped through concentric tubes
and forms droplets under the influence of vibration.

2-The shell is then hardened by chemical cross linkings, cooling, or solvent evaporation.

- Different types of extrusion nozzles have been developed in order to optimize the process
Schematic presentation of the Co-extrusion process:

(17)

Co-extrusion Process:
(18)
 (19)

Objective:-
To preparation and evaluation of the microencapsulation of aspirin drug
capsule. Microencapsulation drug delivery is the most preferable
route of drug delivery due to the ease of administration, patient
compliance and flexibility in formulation.

(20)
 (21)

LITERATURE SURVEY:-
The first research leading to the development of microencapsulation procedures for
pharmaceuticals was published by Bungenburg de Jong and Kass in 1931 and dealt with the
preparation of gelatin spheres and the use of gelatin coacervation process for coating.

On July 5, 1955, Dayton, Ohio, resident and National Cash Register Company employee
Barrett K. Green received a patent for the process of microencapsulation. Microencapsulation
involves filling capsules with liquid. Over a period of time and under certain conditions, the
capsules break open, dispensing the liquid.

Green first applied his new invention to typing paper. He used microencapsulation to
manufacture the first carbon-free carbon paper in the world. When placed between two sheets
of paper, carbon paper would create a duplicate copy of words written or typed on one sheet
onto the other sheet of paper. With microencapsulation, by placing two sheets of paper
together, a writer or typist only had to apply pressure to the paper to duplicate what was
written or typed onto the other sheet of paper. No carbon paper was necessary.

Green and the National Cash Register Company eventually applied microencapsulation to
other products. Microencapsulation allowed for the creation of scratch-and-sniff
advertisements. The first company to utilize scratch-and-sniff technology was the Dayton
Power & Light Company. This firm sent cards with scratch-and-sniff technology to allow its
customers to distinguish the smell of natural gas.

Microencapsulation by solvent evaporation technique is widely used in pharmaceutical

industries. It facilitates a controlled release of a drug, which has many clinical benefits. Water
insoluble polymers are used as encapsulation matrix using this technique. Biodegradable
polymer PLGA (poly (lactic-co-glycolic acid)) is frequently used as encapsulation material.
Different kinds of drugs have been successfully encapsulation: for example hydrophobic
drugs such as cisplatin, lidocaine, naltrexone and progesterone; and hydrophilic drugs such as
insulin, proteins, peptide and vaccine. The choice of encapsulation materials and the testing
of the release of drug have been intensively investigated. However process-engineering
aspects of this technique remain poorly reported. To succeed in the controlled manufacturing
of microspheres, it is important to investigate the latter. This article reviews the current state
of the art concerning this technique by focusing on the influence of the physical properties of
materials and operating conditions on the microspheres obtained. Based on the existing
results and authors’ reflection, it gives rise to reasoning and suggested choices of materials
and process conditions. A part of this paper is also dedicated to numerical models on the
solvent evaporation and the solidification of microspheres. This review reveals also the
surprising lack of knowledge on certain aspects, such as the mechanism of formation of pores
in the microspheres and the experimental study on the solidification of microspheres.

(22)

Microencapsulation is one of the quality preservation techniques of sensitive substances and a

method for production of materials with new valuable properties. Microencapsulation is a
process of enclosing micron-sized particles in a polymeric shell. There are different
techniques available for the encapsulation of drug entities. The encapsulation efficiency of
the microparticle or microsphere or microcapsule depends upon different factors like
concentration of the polymer, solubility of polymer in solvent, rate of solvent removal,
solubility of organic solvent in water, etc. The present article provides a literature review of
different microencapsulation techniques and different factors influencing the encapsulation
efficiency of the microencapsulation technique.

• • 'Safapryn' and benorylate — a comparative trial of two new preparations of aspirin

and paracetamol in the treatment of rheumatoid arthritis and osteoarthritis.

• • Preparation and Evaluation of High Drug Content Particles.

• • Biopharmaceutical evaluation of a tablet dosage form made from ethyl cellulose

encapsulated aspirin particles

• • Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid

Paracetamol Tablets in Fed and Fasted Volunteers.

• • Sucralfate as a Bioadhesive Gastric Intestinal Retention system: Preliminary

Evaluation.

• • The pharmacokinetics of the individual constituents of an aspirin-metoclopramide

combination (‘Migravess’).

• • Cinnamedrine: Potential for Abuse.

• • Lubricants as a Formulation Factor Affecting In Vitro Properties of Double

Compressed Tablets.

• • Plasma Salicylate Levels In Rheumatoid Arthritis: A Comparison Between Micro-

Encapsulated And Conventional Aspirin.

• • ‘Buscopan’ in spasmodic dysmenorrhoea.

• • A High Performance Liquid Chromatographic Method for the Simultaneous Assay

of aspirin, Caffeine, Dihydrocodeine Bitartrate and Promethazine Hydrochloride in
a Capsule Formulation.

(23)

• Evaluation of Dika Fat as a Suppository Base.

• • Preparation and performance evaluation of plain proliposomal systems for

cytoprotection.

• • Suppository Dissolution Testing: Apparatus Design and Release of Aspirin.

• • Segregation of Active Constituents from Tablet Formulations during Grinding:
Effects on Coated Tablet Formulations.

• • Effect of Storage Conditions on the Physical Properties and In Vitro Dissolution of

Directly Compressed Tablets.

• • Gastric Mucosal Damage by Aspirin

• • Studies on the Microencapsulation of Dextropropoxyphene Hydrochloride. Part 1.

Preparation by Coacervation and the in Vitro Evaluation.

• • Release kinetic study of RHPC coated aspirin microcapsules.

• • Chemopreventive Effects of Nonsteroidal Anti-Inflammatory Drugs on 1, 2-

Dimethylhydrazine-Induced Colon Carcinogenesis in Rats.

• • Gastrointestinal Decontamination for Enteric-Coated Aspirin Overdose: What to

Do Depends on Who You Ask.

• • Evaluation of compressibility of pentaestergum coated aspirin microcapsules.

• • Swelling and Aspirin Release Study: Cross-Linked pH-Sensitive Vinyl Acetate-

co-Acrylic Acid (VAC-co-AA) Hydrogels.

• • A Realistic Approach to the Prevention of Childhood Poisoning, with Special

Emphasis on Aspirin.

• • Aspirin, a Silent Risk Factor in Urology.

• • Therapeutic effects of nitric oxide-aspirin hybrid drugs.

• • Patterns of Aspirin Use among American Youth.

• • Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?

• (24)

•
 • Effects of salicylic acid on post-ischaemic ventricular function and purine efflux in
isolated mouse hearts.

• • Aspirin Degradation in Mixed Polar Solvents.

• • Desensitization of Aspirin-Sensitive Asthmatics: A Therapeutic Alternative?

• • The impact of intravenous aspirin administration on platelet aspirin resistance after

on-pump coronary artery bypass surgery.

• • Comparative bioavailability of aspirin and paracetamol following single dose

administration of soluble and plain tablets.

• • Investigation of the release of aspirin from spray-congealed micro-pellets

• • Effects of copper-aspirin complex on plasma 6-keto-prostaglandin F1α level and

platelet cytosolic calcium in rabbits.

• • Update on COX-2 inhibitor patents with a focus on optimised formulation and

therapeutic scope of drug combinations making use of COX-2 inhibitors.

• • Aspirin differentially regulates endotoxin-induced IL-12 and TNF-α production in

human dendritic cells.

• • The Use and Misuse of Aspirin: A Contemporary Problem.

(25)
(26)
DRUG CANDIDATE

Chemical Name : - ACETYLESALICYLIC ACID

IUPAC Name : - 2-Acetyloxybenzoic acid

Molecular weight : - 180.160

Formula : - C9H8O4

Melting point : - 138–140 °C (280–284 °F)

Description : - White crystel

Solubility : - freely soluble in ethanol, soluble in chloroform & in ether,

Slightly soluble in water.

Structure:-

Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is
responsible for most of the actions. It is one of the oldest analgesic-antiinflammtory drugs
and is still widely used.

PHARMACOLOGICAL ACTION:-

The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention
of PG-mediated sensitization of nerve endings. Aspirin reset the hypothalamic thermostat and
rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation).but does
not decrease heat production.

Antiinflammatory action is exerted at high doses (3-6/day or 100mg/kg/day).signs of

inflammation like pain, tenderness, swelling, vasodilation and leucocyte infiltration are
suppressed.In addition to COX (cyclo oxygenase) inhibition, quenching of free redicals may
contribute to its antiinflammtory action.

(27)
PHARMACOKINETICS PARAMETERS:-

• Bioavailability:-Rapidly and completely absorbed

• Protein binding:-99.6%

• Metabolism:-Hepatic

• Half life:- 300–650 mg dose: 3.1–3.2hrs

1 g dose: 5 hours
2 g dose: 9 hours

USES:-

• As analgesic,

• As antipyretic,

• In acute rheumatic fever,

• Rheumatoid arthritis,

• Osteoarthritis,

• Postmayocardial infarction and Post stroke patients.

DOSES:-

For adults doses of 300 to 1000 mg are generally taken four times a day for fever or arthritis,
with a maximum dose of 8000 mg (8 grams) a day. Regular low dose (75 to 81 mg) aspirin
users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of
death from any cause. Low dose aspirin use was also associated with a trend toward lower
risk of cardiovascular events, and lower aspirin doses (75 to 81 mg/day) may optimize
efficacy and safety for patients requiring aspirin for long-term prevention. In children
with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times
a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks.
 (28)

ADVERSE EFFECT:-

• Side effect-Nausea, Vomiting, Epigastric Distress, Peptic ulceration, Gastric Mucosal

Damage.

• Hypersenstivity and idiosyncrasy.

• Acute salicylate poisoning.

INTERACTION:-

Aspirin displaces WARFARIN, NAPROXEN, SULFONYLUREASE, PHENYTOIN and

METHOTREXATE from binding sites on plasma proteins: toxicity of these drugs may occur.

BRANDS:-

CLOPIGREL-A cap® [USV]

CLOPITAB-A cap® [Lupin (Pinnacle)]

ASPIN 100 enteric-coated tab® [Cipla]

ASPENT tab® [Ranbaxy]

ASOGREL-A tab® [AS Pharma]

ASICOM tab® [Comed]

ASPITRATE tab® [Aristo (Otsira)]

ASPISOL tab® [Shreya]

A1A cap® [Grandix]

ARRENO cap® [Intas]

ATCHOL ASP cap® [Aristo]

ATOPLUS cap® [Triton (Calyx)]

ATOSA cap® [Skymax]

AZTOR ASP 150 cap® [Sun]

AZTOR ASP cap® [Sun (Aztec)]

CERUVIN-A tab® [Ranbaxy]

CLASPRIN cap® [Biocon]

CLOPISA cap® [Skymax]

AZTOR ASP cap® [Sun (Aztec)]

(29)

FORMULATION POCEDURE:-

Materials
Aspirin, Acetone, Cyclohexane, Ethanol, Heavy liquid paraffin, ethyl cellulose, and water.
All chemicals used in the experiments were of analytical grade.
Method
Microcapsules of ethyl cellulose containing aspirin were prepared by an emulsion-solvent
evaporation method as reported by Nokhodchi and Farid, 2002. Aspirin microcapsules were
prepared by dissolving polymers in an organic solvent to form a homogeneous polymer
solution. The core material, aspirin was added in a thin stream of heavy liquid paraffin. The
mixture was agitated using a propeller mixer with the rotation speed 600rpm.The dispersed
phase consisting of drug and polymer EC was immediately transformed into fine droplets,
which subsequently solidified into rigid microcapsules due to solvent evaporation. The liquid
paraffin was decanted, and the microcapsules were collected, washed twice in cyclohexane to
remove any adhering oily phase (liquid paraffin), and was air dried for at least 12 h to obtain
discrete microcapsules. The quantity of polymer, drug and the solvent used is given in Table.

Formulation Drug:Polymer Liquid Paraffin(ml) Ethanol (ml) EC (gm)

Aspirin: EC 2:1 60 10 1

(30)

OBJECT: - To formulate 200mg hard gelatin capsules of

microencapsulated aspirin.

REQUIREMENTS:-

• MATERIALS- Microencapsulated Aspirn, lactose, talc, Magnesium

Stearate.

• APPARATUS- Digital balance; Spatula; Capsule filling machine;

Hard gelatin Capsules.

WORKING FORMULA:-

Microcapsules of Aspirin 2 gms

Lactose 2.6 gm

Magnesium Stearate 400 mg

 Talc 200 mg

PROCEDURE:

1. Take about 2 gms of Microcapsules of Aspirin & Calculated amounts of Lactose talc
& magnesium stearate, Mix them thoroughly.

2. Filling of granules in hard gelatin capsules size 0 is done by capsule filling machine
batch scale or if it is not working properly filling done manually by Hand & take
weight of individual capsules to reduce the weight variation .

3. Sealing & Locking done by moistening the edges of capsules by standing them up
right on a piece of wet filter paper before fixing.

4. Evaluation done for checking the various parameters.

(31)

EVALUATION

1. Shape and size:-

A sample of ten capsules were selected and shown shape and size of the capsule.

2. Colour:-

A sample or ten capsules were taken and their colour in sun light by necked eye.
 3. Thickness of capsule size:-

For the measurement of the thickness of the capsule shell 10 empty capsule shells was
taken and measure by vernier calipers (0.01mm capacity)

4. Disintegration test:-

For performing disintegration test on capsule the tablet disintegration test apparatus is
used but the guiding disc may not be used except that the capsule float on the top of
the water. One capsule is placed in each tube which is then suspended in the beakers
to move up and down for 30 minutes, unless otherwise stated in the monograph. The
capsule pass the test if no residue of the drug or other than fragment of shell remain
on No. 10 mesh screen of the tubes.

5. Weight variation test:-

10 Capsule are taken at random and weighed. Their average weight is calculated.
Then each capsule is weighed individually and their weight noted. The capsule pass
the test if the weight of individual capsule falls with in 90-110% of the average
weight. If this requirement is not met then weight of the contents for each individual
capsule is determined and compared with the average weight of contents. The
contents form the shells can be removed just by emptying or with the help of small
brush. From soft gelatin capsules the contents are removed by squeezing the shells
which has been carefully cut.the remainder contents are removed by washing with a
suitable solvent. After drying the shells, they ere weighed and the content weights of
the individual are calculated. The requirement are met if

a-not more than two of the differences are greater than 10% of the average net content

b-in no case the differences is greater than 25%.

(32)

6. Dissolution:-
 Composition- 0.1M acetic acid, 0.1M sodium acetate (tri-hydrate) (13.6g / l)

Release of aspirin from the microcapsules was studied at 1.2 pH (900 ml) for the first
2 hr sand followed by in acetate buffer at F pH 6.0 (900 ml) upto 5 hrs using an USP
XXIV single stage Dissolution Test Apparatus with a paddle stirrer at 50 rpm. Tab the
granules from a capsule and 100 mg of microcapsules was properly weighed and
taken in a pouch tied to a glass slide and was placed in 900 ml of dissolution fluid
(pH-1.2) and maintained at 37 ± 0.2 ºC. At appropriate intervals (15, 30, 60, 90, 120
mins), 5 ml of the sample was taken and filtered through 0.45 μm Millipore. The
dissolution media was then replaced by 5 ml of fresh dissolution fluid to maintain a
constant volume. After two hours, the pouch containing microcapsules was removed
and placed in 900 ml of dissolution fluid containing acetate buffer (pH-6.0) and then
samples were collected at an appropriate intervals (15, 30, 60, 120, 180 minutes). The
samples were then analyzed at 278.5 and 239.5 nm by Elico UVVisible Double beam
Spectrophotometer at pH-1.2 and 6.0, respectively.

7. Microscopy studies:-
The microcapsules as well as aspirin crystals (standard drug) were observed under
projection microscope. For microscopy the microcapsules and aspirin drug were
mounted directly on projection microscope. Photomicrographs of prepared for

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RESULTS AND DISCUSSION

1. The shape of capsule was found to be oval and size was 0 no. capsules.

2. The colour of the capsule was found to be white and transparent.

3. Thickness of the capsule shall was to be found 0.5mm.

4. By performing disintegration test on micrencapsules, disintegration time was to be

taken 1.5 minute.

5. Weight of empty capsule shell was 48 mg.

No. of capsule Wt of capsules

1 282
2 280
3 287
4 281
5 286
6 272
7 284
8 285
9 282
10 279
Total 2828

Average weight of one capsule was 282mg.

So wt individual capsule was fall within 90- 110% of the average wt.

6. Drug release was found to be maximum in 5hrs.

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7. From microscopy it was clear that the crystals of aspirin was microencapsulated to
great extent.

Pure Aspirin Crystal Microencapsulated Aspirin Crystal

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SUMMARY

Encapsulation is a useful method for prolonging the drug release from dosage forms and
reducing adverse effects. Microcapsules are composed of a polymer wall enclosing a liquid
core or other body of material. Microencapsulation can be achieved by a myriad of
techniques. The emulsion solvent evaporation (ESE) method can be used to prepare
microcapsules of water insoluble drug. Moreover, addition of non-solvent also markedly
affects the morphological and release kinetics of resultant particles. Sustained release
formulation of aspirin would reduce the undesired side effects, reduce frequency of
administration and improves patient compliance. In this present study, Aspirin microcapsules
were prepared by emulsion solvent evaporation technique using EC. Ethanol and acetone
were used for the preparation of microcapsules.

Acetylsalicylic acid (Aspirin) is a non-steroidal anti-inflammatory and antipyretic drug. It

inhibits platelet aggregation and prolongs bleeding time. It is widely used for the relief of
pain. It is a Cyclo-oxygenase-2 inhibitor and is amply used as analgesic and anti-
inflammatory. Drug having a half-life of 15–20 minutes. Aspirin has a direct irritant effect on
gastric mucosa due to inhibition of prostaglandins and prostacyclins and thus causes
ulceration, epigastric distress, and/or hemorrhage.
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References

1. Arshady, R.: Microspheres, microcapsules and liposomes. General concepts and criteria,
Arshady, R., Eds., Citrus Books, London, United Kingdom, 1999, 11-45.

2. Thies, C.: A survey of microencapsulation processes, Benita, S., Eds., Marcel Dekker, Inc.,
New York, N.Y., 1996, 1-19.

3. Benoit, J. -P., Marchais, H., Rolland, H., and Velde, V. V.: Biodegradable microspheres:
Advances in production technology, Benita, S., Eds., Marcel Dekker, Inc., New York, N.Y.,
1996, 35-72.

4. Allemann, E., Gurny, R., and Doelker, E.: Drug-loaded nanoparticles-preparation methods
and drug targeting issues, Eur. J. Pharm. Biopharm. 39: 173-191, 1993.

5. Okada, H., and Toguchi, H.: Biodegradable microspheres in drug delivery, Critical Review
in Therapeutic Drug Carrier Systems 12: 1-99, 1995.

6. Li, J. K., Wang, N., and Wu, X. S.: A novel biodegradable system based on gelatin
nanoparticles and poly (lactic-co-glycolic acid) microspheres for protein and peptide drug
delivery, J. Pharm. Sci. 86: 891-895, 1997.

7. Wang, N., and Wu, X. S.: A novel approach to stabilization of protein drugs in plga
microspheres using agarose hydrogel, Int. J. Pharm. 166: 1-14, 1998.

8. Schwendeman, S. P., Tobio, M., Joworowicz, M., Alonso, M. J., and Langer, R.: New
strategies for the microencapsulation of tetanus vaccine, Journal of microencapsulation 15:
299-318, 1998.

9. Zhou, S., Deng, X., and Li, X.: Investigation on a novel core-coated microspheres protein
delivery system, J. Controlled Rel. 75: 27-36, 2001.

10. Park, K., Shalaby, W. S. W., and Park, H.: Biodegradable Hydrogels for Drug Delivery,
Technomic Publishing co., Inc. Lancaster, P., 1993, pp.99-140.
11. Tice, T. R., and Lewis, D. H.: Microencapsulation process, U.S. Pat. No. 4,389,330, 1983

(40)

12. Weert, M., Hennink, W. E., and Jiskoot, W.: Protein instability in plga
microparticles, Pharm. Res. 17: 1159-1167, 2000.

13. Le, H. P.: Progress and trends in ink-jet printing technolog, J. Imaging Sci. Technol., 42:
49-62, 1998.

14. Mumenthaler, M., Hsu, C. C., and Pearlman, R.: Feasibility study on spray-drying protein
pharmaceuticals: Rhgh and t-pa, Pharm. Res. 11: 12-20, 1994.

15. Maa, Y. -F., Nguyen, P. -A. T., and Hsu, S. W.: Spray-drying of air-liquid interface
sensitive recombinant human growth hormone, J. Pharm. Sci. 87: 152-159, 1998.

16. Knutson, B. L., Debenedetti, P. G., and Tom, J. W.: Preparation of microparticulates
using supercritical fluids, Cohen, S., and Bernstein, H., Eds., Marcel Dekker, Inc., New York,
N.Y., 1996, 89-125.

17. Ghaderi, R., Artursson, P., and Carlfors, J.: Preparation of biodegradable microparticles
using solution-enhanced dispersion by supercritical fluids (seds), Pharm. Res. 16: 676-681,
1999.

18. Johnson, O. L., and Tracy, M. A.: Peptide and protein drug delivery, in Encyclopedia of
Controlled Drug Delivery, Mathiowitz, E., Eds., Jone Wiley & Sons, Inc., New York, N.Y.,
1999, 816-833.

19. Sah, H.: Protein instability toward organic solvent/water emulsification: Implications for
protein microencapsulation into microspheres, PDA J. Pharm. Sci. Technol. 53: 3-10, 1999.

20. Morlock, M., Koll, H., Winter, G., and Kissel, T.: Microencapsulation of
rherythropoietin, using biodegradable plga: Protein stability and the effects of stabilizing
excipients, Eur. J. pharmaceutics Biopharm. 43: 29-36, 1997.

21. Bayer HealthCare AG.

Aspirin: History & Structure.

http://www.aspirin-foundation.com
 (41)

22. Reynolds JE, Ed.

Analgesic anti-inflammatory and antipyretic.

In: Martindale: The complete drug reference. 32nd ed. Parfitt K, Massachusetts. 1999: 2–12.

23. Rowland M, Riegelman S.

Pharmacokinetics of acetyl salicylic acid and salicylic acid after intravenous administration in
man.

J Pharm Sci. 1968; 57: 1316–1319.

doi:10.1002/jps.2600570807

24. Raderick PJ, Wilkes HG, Meade TW.

The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.

Br J Clin Pharmacol. 1993; 35: 219–226.

PMid: 8471398

25. Holliday WM, Berdrick M, Bell SA, Kiritsis GC.

Sustained relief analgesic composition

U S Patent 3,488,418. 1970 Jun 01.

26 Powell TC, Steinle ME, Yoncoskie RA.

Process of forming minute capsules en masse.

U S Patent 3,415,758. 1968 Oct 12.

27. Amperiadou A, Georgarakis M.

Controlled release salbutamol sulphate microcapsules prepared by emulsion solvent-

evaporation

Technique and study on the release affected parameters.

 (42)

28. Takada S, Kurokawa T, Iwasa S.

Sustained-release microcapsule of amorphous water-soluble pharmaceutical active agent.

U S Patent 6,117,455.1995 Sep 28.

29. World Book, Inc.

Microencapsulation definition from the World Book Encyclopedia.

http://www.rtdodge.com/worldBook.html

30. Nilkumhang S, Basit AW.

The robustness and flexibility of an emulsion solvent evaporation method to prepare pH-
responsive microparticles.

Int J Pharm. 2009; 377: 135–141.

doi:10.1016/j.ijpharm.2009.03.024

32. Herber A. Leberman & Leon Lachman; Theory & practice of industrial pharmacy; Lea &

febiger, Philadelphia, USA.

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