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

CERTIFICATEThe 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 candidateAs 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.

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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.

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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:

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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.

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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.

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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.

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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

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Microencapsulation processes with their relative particle size ranges:

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Physico-Chemical Processes:

1- Coacervation:

Two methods for coacervation are available, namely simple and complex processes.

Physico – Chemical Processes

Physico – mechanical Processes

Coacervation (2 – 1200 um)

Spray-drying (5 – 5000 um)

Polymer-polymer incompatibility(0.5 – 1000 um)

Fluidized- bed technology(20 – 1500 um)

Solvent evaporation(0.5 – 1000 um)

Pan coating (600 – 5000 um)

Encapsulation by supercritical fluid

Spinning disc (5 – 1500 um)

Encapsulation by Polyelectrolyte multilayer (0.02 – 20 um)

Co-extrusion(250 – 2500 um)

Hydrogel microsphere Interfacial polymerization(0.5 – 1000 um)

Phase Inversion (0.5—5.0 um)

In situ polymerization(0.5 – 1100 um)

Hot Melt (1—1000 um)

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.

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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.

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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.

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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.

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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.

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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

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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.

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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:

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Co-extrusion Process:

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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.

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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.

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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.

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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?

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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.

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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.

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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.

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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)]

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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

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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.

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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%.

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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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