Tài liệu Pharmaceutical Coating Technology (Part 1) ppt

Film coat quality Michael E.Aulton and Andrew M.Twitchell 13.1 Desirable and adverse properties of film coats 363 13.3 The influence of formulation, atomization and other process condit

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Pharmaceutical Coating Technology

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Pharmaceutical Coating Technology

edited by Graham Cole

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UK Taylor & Francis Ltd, 4 John Street, London WC1N 2ET USA Taylor & Francis Inc., 1900 Frost Road, Suite 101, Bristol, PA 19007

This edition published in the Taylor & Francis e-Library, 2002.

Copyright © Taylor & Francis Ltd 1995

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or

transmitted, in any form or by any means, electronic, electrostatic, magnetic tape, mechanical,

photocopying, recording or otherwise, without the prior permission of the copyright owner.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN 0-203-01435-9 Master e-book ISBN

ISBN 0-203-33272-5 (OEB Format) ISBN 0-13-662-891-5 (Print Edition)

Library of Congress Cataloging Publication data are available

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4.4 The influence of formulation and atomization conditions on spray droplet size and size

Page vii

7.6 Flow through a tablet bed in a side-vented coating pan 189

11.11 Summary of main components of any validation programme 283

12 Mechanical properties of film coats Michael E.Aulton

13 Film coat quality Michael E.Aulton and Andrew M.Twitchell

13.1 Desirable and adverse properties of film coats 363

13.3 The influence of formulation, atomization and other process conditions on the quality

13.5 Summary of the influence of the atomization and film formation processes on the

14 Modified release coatings John E.Hogan

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14.3 The structure and formulation of modified release films and the mechanism of drug

15 Some common practical questions and suggested answers 439

16 Bibliography Michael E.Aulton

A pharmaceutical film coating publications bibliography 447

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Page 1

1 Introduction and overview of pharmaceutical

coatingGraham C.Cole

This would appear to be a very good reason for painting anything (film coating is a painting process) and while the penalty for coating tablets the wrong colour is unlikely to be so extreme, the Queen (FDA, MCA, etc.) is likely to extract very costly and damaging retribution No doubt ‘heads would roll’

metaphorically So why are tablets coated? After all, it is a messy, complicated and expensive process

‘Look out now, Five! Don’t go splashing paint over me like that!’

‘I couldn’t help it,’ said Five, in a sulky tone ‘Seven jogged my elbow.’

It adds a degree of risk to the production process that could result in the whole batch being rejected The costs in terms of space, personnel, equipment, Quality Control and Validation are considerable The modern coating technique has developed over the years from the use of sugar to provide a

pleasant taste and attractive appearance to tablets which were unpleasant to swallow due to their

bitterness There are, of course, many forms of coating which have a special function (such as enteric coating to delay the release of

‘Would you tell me, please,’ said Alice, a little timidly, ‘why you are painting those roses?’

Five and Seven said nothing, but looked at Two Two began, in a low voice, ‘Why, the

fact is, you see Miss, this here ought to have been a red rose-tree, and we put a white one in

by mistake; and if the Queen was to find it out, we should all have our heads cut off, you

know?’

Lewis Carroll, Alice in Wonderland

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the drug until it reaches the intestine), but here the simple case will be examined First of all to answer the question ‘Why are tablets coated?’ A number of reasons can be suggested, some not quite so

obvious as others:

This is not an exhaustive list but suggests several good reasons for coating tablets

This book contains sections on modern pharmaceutical coating materials and processes and these can

be broken down into three main groups and one minor section:

These processes and the selection and evaluation of equipment will be discussed in detail Some chemical engineering unit operations will also be used to illustrate the differences between types of equipment

There are several other historical coating processes such as pearl coating and pill coating which will not be discussed here

In addition, some of the more fundamental aspects of film coating are covered, for example, an examination of the properties of coating solutions and suspensions, a detailed examination of the

atomization stage, an explanation of surface interactions occurring between the coating liquid and the substrate (essential for an understanding of wetting and film adhesion), and a discussion on the

mechanical properties and overall quality (with respect to roughness and defects, particularly) of the resulting coats

HISTORICAL PERSPECTIVE

Sugar coating was largely borrowed from the confectionery industry which had developed this

technique over the ages and is still widely used today The pharmaceutical industry concentrated on using the open, copper, bowl-shaped pan, which has been largely replaced by stainless steel It was not uncommon for as many as

• The core contains a substance which imparts a bitter taste in the mouth or has an unpleasant

odour

• The core contains a substance which is unstable in the presence of light and subject to

atmospheric oxidation, i.e a coating is added to improve stability

• The core is pharmaceutically inelegant

• The active substance is coloured and migrates easily to stain patient’s clothes and hands

• The coated tablet is packed on a high-speed packaging unit The coating reduces friction and increases the production rate

• To modify the drug release profile, e.g enteric coating, sustained release coating, osmotic pumps, etc

• To separate incompatible substances by using the coat to contain one of them or to coat a pellet which was previously compressed into a core

• Sugar coating

• Film coating

• Particulate/pellet coating

• Compression coating

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one hundred of these pans to be installed in a coating department The sugar-coating process was a skilled manipulative operation and could last five days The operator was highly skilled and jealously guarded his knowledge In one operation the installation of temperature gauges on the inlet air duct almost caused a strike This was only averted by some modification to the bonus scheme to increase payments for improved productivity!

This type of pan was used for batches of up to 150–200 kg and there was pressure to increase the batch sizes Some pans were developed subsequently which improved handling, particularly in the way the drying air was introduced and extracted

The Pelligrini pan, which was a large cylinder mounted on rollers with dished ends, was widely used

in Europe, as was the doughnut-shaped pan in the United States This enabled batches of 500–600 kg to

be coated It should be remembered that these sugar-coating processes double the weight of the core and, therefore, batch sizes have to be calculated on the finished tablet weight (i.e after coating) Also, material was applied from ladles by hand and the operator ‘worked’ the batch The air flow and

temperature were very critical in achieving an elegant finish

Generally, today, the pharmaceutical industry does not develop new sugar-coated tablets due to the lengthy process, the high degree of operator skill required and the fact that identification of the product

is difficult Printing of individual tablets with the house logo and product name and identification is another messy, slow and expensive process, and produces additional reject material It is a process to be avoided if at all possible The last major sugar-coated tablet to be developed was Brufen (Boots)

Film coating has the advantage that logo, identification numbers and names can be engraved on the tablet core, and these intagliations, as they are known in some companies, are clearly legible after coating

The pressure to develop alternative methods was considerable In the last twenty-five years tablet coating has undergone several fundamental changes Although the sugar-coating process produced a very elegant product, its main disadvantage was the processing time, which could last up to five days Many modifications were advocated to improve the basic process, such as air suspension techniques in a fluidized bed, the use of atomizing systems to spray on the sugar coating, the use of aluminium lakes of dyes to improve the evenness of colour, and more efficient drying systems However, the process

remained complicated Generally the sugar-coating process resulted in the weight of the tablet being doubled but the use of modern spraying systems enabled this increase to be dramatically reduced Compression coating was one of these alternative techniques Two methods enjoyed some popularity

in the 1950s and 1960s The process was designed to replace the long lead time of sugar coating by, in one case, compressing the core and then compressing the core-coating material around the core This technique was favoured by Manesty Machines in the design of their Drycota machine Two rotary machines were combined on a common base The core was compressed on the first machine and then transferred to the second machine where coating was applied However, the process relies on a number

of very important effects

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The disadvantages of this process are:

One of the main advantages of the Drycota process is that incompatible drugs can be separated into core and coat However, layered tablets achieve the same result and can be produced at a faster rate Killian, on the other hand, favoured feeding precompressed cores into a Prescota machine which applied the coat This process, it was reasoned, enabled the core to expand overnight (or longer) and did not result in splitting of the coated tablet, the main disadvantage of both of these processes

Many of the products developed for this equipment used drugs that were moisture sensitive, e.g aspirin, but other methods of protecting these materials eliminated even this advantage Some machines are still in use around the world but the development of the film-coating process sealed their fate as a viable coating option Currently renewed interest has been shown in this technique as a means of

blinding Clinical Trials

MODERN PROCESSES

The first reference to tablet film coating appeared in 1930 but it was not until 1954 that Abbott

Laboratories produced the first commercially available film-coated tablet This was made possible by the development of a wide variety of materials—for example, the cellulose derivatives One of the most important of these is hydroxypropyl methylcellulose which is prepared by the reaction of methyl

chloride and propylene oxide with alkali cellulose (Remington Pharmaceutical Sciences, 1990) It was

generally applied in solution in organic solvents at a concentration of between 2 and 4%w/v: the

molecular weight fraction chosen gives a solution viscosity of 5×10−2 Pas at these concentrations When Abbott introduced this process into production they used a fluidized bed-coating column based

on the Wurster principle (Wurster, 1953) and this process was developed a stage further by Merck in their plants in the US and the UK The plant in the UK had a design capacity of 1000 million coated tablets per annum However, the advent of aqueous film coating and the development of side-vented pans heralded the demise of the coating column for tablets It is still probably the system of choice for coating particulates and pellets

1 The drug to be coated can be incorporated into a core of probably no more than 12 mm in

diameter and no greater weight than 150 mg

2 The coat bonds onto the substrate

3 The total tablet size is not greater than 15 mm in diameter

4 The total tablet weight is not greater than 900 mg

1 It is difficult to bond the coat and core satisfactorily

2 The core expansion causes the coat to split

3 It is impossible to recover cores coated with this method

4 The process is relatively slow, i.e 1000 tablets per minute maximum, compared to compressing outputs of up to 10 000 tablets per minute

Page 5During the period 1954–1975 the lower molecular weight polymers of hydroxypropyl methylcellulose with a solution viscosity of 3–15×10−3 Pas did not receive much attention because of the cheapness of organic solvents and the ease with which the coating could be applied There was also a belief that the lower viscosity grades produced weaker films which would not meet the formulation requirement for stability and patient acceptability However, there is now a very significant move towards aqueous film coating for the following reasons:

Most of the early development work for aqueous film coating concentrated on the use of existing conventional coating pans and tapered cylindrical pans such as the Pellegrini, largely because models already existed in production departments This pan is open at the front and rear, and the spray guns are mounted on an arm positioned through the front opening The drying air and exhaust air are both fed in and extracted from the rear The drying air is blown onto the surface of the tablets, but because of the power of the extraction fan most of the heat is lost with the exhaust air Very poor thermal contact results and a poor coating finish is obtained The perforated rotary coating pan, which permits the drying air to be drawn co-current with the spray through the tablet bed and pan wall during film coating, offers better heat and mass transfer and results in a more efficient coating process and a more elegantly

finished product

There are several companies which offer equipment of this type; the Manesty Accelacota, the Driam Driacoater and the Glatt Coater are three well-known models There are significant differences between them

In this book the authors will show how materials can be controlled, selected and used in the current available equipment to produce a pharmaceutically elegant product so that we do not have to resort to the solutions used by Two, Five and Seven

REFERENCES

Remington Pharmaceutical Sciences, 18th edn, 1990

Wurster, D.E (1953) Winsconsin (Alumini Research Foundation), US Patent 2,648,609

1 The cost of organic solvents has escalated

2 A number of regulatory authorities have banned chlorinated hydrocarbons altogether because of environmental pollution

3 The development of improved coating pans and spraying systems has enabled these more

difficult coating materials to be applied

4 Flameproof equipment is not required This reduces capital outlay and a less hazardous working environment is provided for the operator

5 Solvent recovery systems are not required resulting in less capital outlay