CHURCHILL LIVINGSTONE
`
`Medical Division of Longman Group UK Limited
`Distributed in the United States of America by
`Churchill Livingstone Inc., 650 Avenue of the Americas,
`New York, 10011, and associated companies, branches
`and representatives throughout the world.
`
`© Wchael Aulton 1988
`
`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,
`mechanical, photocopying, recording, or otherwise,
`without the prior permission of the publishers
`(Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter's Place, Leith Walk, Edinburgh EH1 3AF), or
`a Licence permitting restricted copying in the United
`Kingdom issued by the Copyright Licensing Agency Ltd,
`90 Tottenham Court Road, London, WIP 9HE.
`
`First published 19 88
`Reprinted 1989
`Reprinted 1990
`Reprinted 1991
`Reprinted 1992
`
`ISBN D-LH3-DE|l=LI3-E
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. Aulton, Michael E.
`6l5’.l9
`RS403
`
`2. Drugs
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gunn’s tutorial pharmacy.
`6th ed. 1972.
`Includes bibliographies and index.
`1. Drugs — Design of delivery systems.
`—— Dosage forms. 3. Biopharmaceutics.
`4. Pharmaceutical technology.
`5. Chemistry,
`Pharmaceutical.
`6. Microbiology, Pharmaceutical.
`1. Aulton, Michael E.
`2. Chemistry,
`[DNLM: 1. Biopharmaceutics.
`Pharmaceutical.
`3. Dosage Forms.
`4. Technology,
`Pharmaceutical.
`5. Microbiology, Pharmaceutical.
`QV 785 P5366]
`RS420.P48
`1987
`
`6l5.5’8
`
`86-25888
`
`Printed in Hong Kong
`CPP/05
`
`The
`publisher's
`policy Is to use
`paper manufactured
`tram sustainable forests
`
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`

`
`Contents
`
`
`
`Preface
`Contributors
`
`Acknowledgements
`About this book
`
`1 The design of dosage forms
`
`PART ONE Physicochemical
`principles of pharmaceutics
`2 Rheology and the flow of fluids
`3 Solutions and their properties
`4 Surface and interfacial phenomena
`5 Solubility and dissolution rate
`6 Disperse systems
`7 Kinetics and stability testing
`
`PART TWO Biopharmaceutics
`8 Introduction to biopharmaceutics
`9 Factors influencing bioavailability
`10 Assessment of bioavailabilit
`
`ll Dosage regimens
`
`"
`
`PART THREE Drug delivery -systems
`12 Packs for pharmaceutical products
`13 Preformulation
`
`14 Solutions
`
`15 Suspensions
`16 Emulsions
`
`17 Powders and granules
`18 Tablets
`
`19 Capsules
`20 Therapeutic aerosols
`21 Parenteral products
`22 Topical preparations
`23 Suppositories and pessaries
`
`vii A
`ix
`Xi
`xiii
`
`15
`17
`38
`
`50
`62
`81
`119
`
`129
`131
`135
`174
`191
`
`213
`215
`223
`254
`269
`282
`
`. 300
`304
`322
`341
`359 ’
`381
`412
`
`PART FOUR Pharmaceutical
`
`microbiology
`24 Fundamentals of microbiology
`25 The action of physical and chemical
`agents on micro-organisms
`26 Principles of sterilization
`27 Microbiological contamination and
`preservation of pharmaceutical
`preparations
`28 Pharmaceutical applications of
`microbiological techniques
`
`PART FIVE Pharmaceutical
`
`technology
`29 Materials of fabrication and corrosion
`
`30 Heat transfer and the properties of
`steam
`
`31 Filtration
`
`32 Mixing
`33 Particle size analysis
`34 Particle size reduction
`
`35 Particle size separation
`36 Powder flow
`37 Granulation
`
`38 Drying
`39 Tableting
`40 Tablet coating
`41 Encapsulation
`
`42 Design and operation of clean rooms
`43 Sterilization practice
`44 Packaging technology
`
`Index
`
`423
`425
`
`452
`472
`
`479
`
`491
`
`509
`511
`
`525
`538
`550
`564
`581
`
`591
`600
`616
`629
`647
`
`669
`678
`686
`700
`
`712
`
`725
`
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`

`
`19
`
`Capsules
`
`
`
`HISTORICAL DEVELOPMENT OF GELATIN
`CAPSULES
`
`RAW MATERIALS FOR GELATIN CAPSULES
`Gelatin
`Plasticizers
`Colorants
`Preservatives
`
`HARD GELATIN CAPSULES
`
`Sizes of hard gelatin capsule shells
`Determination of capsule fill weight
`Filling
`Formulation of powders for filling
`Formulation of non-powders for filling
`Granules and pellets
`Tablets
`
`Semisolids
`Bioavailability aspects of hard gelatin capsules
`Disintegration and dissolution
`Formulation factors affecting release from hard
`gelatin capsules
`Active ingredient
`Diluent
`Glidants and lubricants
`Wetting: effects of porosity and addition
`of surfactants
`
`SOFT GELATIN CAPSULES
`
`Description
`Advantages of soft gelatin capsules as a
`dosage form
`Compression
`Mixing and powder flow
`Stalgility
`Bioavailability
`Formulation of soft gelatin capsules
`
`* Introduction and hard gelatin capsules
`** Soft gelatin capsules
`
`04‘!
`
`Formulation of the gelatin shell
`Gelatin
`Plasticizers
`
`Water
`Preservatives
`Colours
`
`Opacifiers
`Enteric treatment
`
`Formulation of the capsule contents
`Limitations for fill materials
`Liquid vehicles
`Water-immiscible oils
`
`Water-miscible liquids
`
`Suspensions
`Bioavailability aspects of soft gelatin capsules
`
`HISTORICAL DEVELOPMENT OF
`GELATIN CAPSULES
`
`The word capsule is derived from the latin
`‘capsula’ meaning a small box. In current English
`usage it
`is applied to many different articles
`ranging from flowers to space craft. In pharmacy
`the word capsule is used to describe an edible
`package made from gelatin which is filled with
`medicines to produce a unit dose, mainly for oral
`use. There are two types of capsule, differentiated
`by the adjectives
`‘hard’ and ‘soft’. The hard
`gelatin capsule consists of two pieces, a cap and
`a body, that fit one inside the other. They are
`produced empty and are filled in a separate oper-
`ation. The soft gelatin capsule is a capsule which
`is manufactured and filled in one operation.
`The gelatin capsule originated in the first half
`of the nineteenth century as a means of masking
`the flavours of the many obnoxious medicines then
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`
`in vogue. It was devised by a French pharmacy
`student, F A B Mothes, who made bubbles of
`gelatin which could be filled with the drug and
`sealed with a drop of gelatin solution. These one-
`piece capsules were prepared by dipping small
`mercury-filled leather sacs into gelatin solutions,
`emptying out
`the mercury to collapse the bag,
`removing the gelatin films and then air drying
`them. ‘The first patent was filed in Paris in 1834
`by Mothes in association with a registered phar-
`macist, Dublanc. The capsule became immedi-
`ately popular because it perfectly fulfilled a need.
`Within 2 years, capsules werebeing manufactured
`as far apart as Berlin and New York. Mothes was
`an astute businessman in that he allowed the
`
`market to develop freely and then in 1836 he used
`his patent and litigation to restrict the manufac-
`ture of capsules to himself. Following on from this
`there were many attempts to get around the patent
`by using alternative materials or manufacturing
`methods. Two products emerged from this work:
`the gelatin—coated pill and the hard two-piece
`capsule.
`In France the one-piece capsule remained the
`most popular form. Developments were made in
`the manufacturing process. The moulds were
`changed to pear-shaped metal ones mounted on
`disc which simplified the production process.
`During the 1840s a completely new process was
`devised; this used a pair of metal plates which had
`matching sets of cavities on their surface. Two
`sheets of gelled gelatin mixture were then laid over
`. each of them. The medicine to be filled was placed
`in the cavities on one sheet,
`the matching plate
`was placed on top and the resulting sandwich
`passed through a pair of pressure rollers which
`stamped out
`the capsules. These capsules were
`much more regular
`in size than those made
`previously and were called ‘perles’.
`The formulation of these shells was a mixture
`
`of gelatin, acacia and honey which produced a
`hard wall. The next significant change in the
`process occurred in 1873 when another French
`pharmacist, Taetz,
`suggested the inclusion of
`glycerol
`into the formulation in order to make
`them soft and elastic and thus easier to swallow.
`
`These capsules were now identical to the modern
`soft gelatin capsule. Finally in 1932, R P Scherer
`perfected the rotary die process which was the
`
`CAPSULES
`
`323
`
`first continuous method of encapsulation to be
`implemented and is still the method of choice.
`The hard two-piece capsule was invented by a
`French pharmicist,
`]—C Lehuby, who took out a
`patent in 1846 for ‘medicinal envelopes’. These
`were pairs of open—ended cylinders of gelatin
`which fitted one inside the other. They were
`produced by dipping silver plated metal moulds
`into a gelatin solution, drying the resulting films,
`cutting them to length and, joining the two halves
`together. The performance of
`these capsules
`depends‘ upon the accuracy with which the two
`pieces were made. The development of
`these
`capsules was held up until a cheaper accurate
`mould system could be developed. The problem
`was solved by an American pharmacist, Mr Hubel
`of Detroit. He had the idea of using standard
`gauged iron rod which was widely used in the
`engineering industry. He cut this into lengths and
`mounted them into wooden blocks. In 1874, he
`commenced the first industrial scale manufacture
`
`of hard gelatin capsules. From then until after the
`second World War, this process was confined to
`the USA.
`
`After Mr Hubel’s success, other companies
`started their manufacture: Eli Lilly & Company
`of Indianapolis in 1896 and Parke Davis Company
`of Detroit in 1901. These two companies remain
`the leading manufacturers in the world. Currently,
`hard gelatin capsule manufacturing plants are
`located in all of the major trading blocs.
`
`RAW MATERIALS FOR GELATIN
`CAPSULES
`
`The raw materials used in manufacture are similar
`for both hard and soft gelatin capsules. The first
`stage of the process is to prepare a gelatin solution
`in demineralized water or a mixture of deminer-
`
`alized water and glycerol. To this are added,
`colorants, preservatives and process
`aids de-
`pending upon the type of capsule required.
`
`Gelatin
`
`Gelatin is the major component of the capsule and
`has been the only material from which they have
`been successfully made. The reason for this is that
`gelatin possesses four essential basic properties:
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`
`324
`
`DRUG DELIVERY SYSTEMS
`
`1 It is non-toxic. It is widely used in foodstuffs
`and is acceptable for use in every country in the
`world.
`
`2 It is readily soluble in biological fluids at body
`temperature.
`
`DJ
`
`It is a good film forming material.
`4 As a solution in water or a water—glycerol blend
`it undergoes a reversible phase change from a
`sol to a gel at temperatures only a few degrees
`above ambient. This is in contrast to other films
`
`other hand are more soft and flexible; it is turgid
`because it is manufactured and filled in one oper-
`ation which results in the pressure of the contents
`maintaining the capsule shape. The capsule is soft
`because it contains a large proportion of a plasti-
`cizer. This can be varied to produce capsules for
`different applications (see Table 19.1). The plas-
`ticizer which is most frequently used is glycerol;
`sorbitol, propylene glycol, sucrose and acacia have
`been used also.
`
`which are produced in pharmacy where either
`volatile organic solvents or large quantities of
`heat are required to effect this change of state.
`This property enables films of gelatin to be
`prepared easily.
`
`Gelatin is a substance of natural origin, but does
`not occur as such in nature. It is prepared by the
`hydrolysis of collagen which is the main protein
`constituent of connective tissues. Thus animal
`bones and skins are the raw material
`for the
`
`manufacture. There are two main types of gelatin:
`type A, which is produced by acid hydrolysis, and
`type B, which is produced by basic hydrolysis.
`The choice of manufacturing method depends
`upon the nature of the raw materials, skins are
`mainly acid processed whereas bones are usually
`basic processed. Animal bones need additional
`treatment, in that they first need to be decalcified
`and to produce ossein, a soft sponge-like material.
`The properties ‘of the gelatin which are most
`important for the capsule manufacturer are the
`bloom strength and the viscosity. The bloom
`strength is
`a measure of gel
`rigidity and is
`expressed as the load in grams required to push
`a standard plunger a set distance into a prepared
`gelatin gel (6.660/o solution at 10 °C). The gelatin
`used in hard capsule manufacture is termed high
`bloom gelatin whereas for soft capsules,
`lower
`bloom material
`is used (l50—200 bloom). The
`viscosity of the gelatin solution is used by the
`manufacturers of both types to control the thick-
`ness of the films or sheets.
`
`Plasticizers
`
`The walls of hard gelatin capsules are firm and
`rigid. The walls of soft gelatin capsules on the
`
`Table 19.1 Control of the plasticizer content of shells for
`soft gelatin capsules in conjunction with their intended use.
`Hard gelatin capsules rarely, if ever, contain added
`plasticizer
`
`Glycerol.-gelatin
`ratio
`(parts of dry
`glycerol to one
`part of dry gelatin)
`
`0.35
`
`0.46
`
`O.5S——0.6S
`
`Application
`
`Oral capsules with oil fills where
`final capsule should be hard
`
`Oral capsule with oil fills where shell
`requires to be more elastic
`
`Capsules containing oils with added
`surfactant or products with
`hydrophilic liquid fills
`
`0.76
`Oral capsules where a chewable shell
`
`is required
`
`Colorants
`
`The colorants which are used can be of two
`
`kinds: soluble dyes or insoluble pigments. The
`soluble dyes are mainly synthetic in origin and by
`the use of mixtures of dyes, capsules can be made
`in all colours of the spectrum. The pigments used
`are of two types. The one which is used in the
`largest quantity is titanium dioxide. This is white
`and is used as an opacifying agent. The other class
`of pigments is the oxides of iron; three are used,
`black, red and yellow. The colourants which can
`be used are governed by legislation which varies
`from country to country. In the last few years,
`there has been a move away from the use of
`soluble dyes over to pigments, particularly the
`iron oxides. For the manufacture of bicoloured
`
`soft gelatin capsules, aluminium lakes are used to
`prevent colour transfer between the two layers of
`the capsule.
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`
`Preservatives
`
`Preservatives are sometimes added to capsules as
`an in-process aid in order
`to prevent micro-
`biological contamination during manufacture. The
`manufacturers operate their plants following GMP
`guidelines to minimize this risk. In the finished
`capsules,
`the moisture levels are such that
`the
`capsules will not support bacterial growth. Soft
`gelatin capsules sometimes have antifungal agents
`added to them to prevent growth on their surfaces
`when they are stored in non-protective packages.
`
`HARD GELATIN CAPSULES
`
`Sizes of hard gelatin capsule shells
`
`The hard gelatin capsule is made in a range of
`eight sizes from size 000, the largest, to size 5, the
`smallest
`(see Fig. 19.1). These sizes have been
`standard since the start of industrial manufacture.
`
`The most popular sizes in practice are size 0
`through to 4. The hard gelatin capsule shape
`(Fig. 19.1) has basically remained unchanged
`
`CAPSULES
`
`325
`
`since its invention, except for the development of
`the self-locking capsule. These have a series of
`indentations on the inside of the capsule cap and
`sometimes the external surface of the capsule
`body. When the capsule is closed together after
`filling, these areas form a frictional or interference
`lock. This idea was first patented by Eli Lilly &
`Company in 1963 and since that time the other
`manufacturers have incorporated similar devices
`into their capsules.
`
`Detennination of capsule Ifill weight
`
`To determine the size of capsule to be used or the
`fill weight for a formulation the following practical
`relationship is used:
`
`Capsule fill weight = tapped bulk density of
`formulation >< capsule
`volume
`
`For example:
`
`1 A formulation has a theoretical fill weight of
`
`Actual size
`
`Volume in ml
`
`Fig. 19.1 Hard gelatin capsule sizes and fill volumes. The larger, narrower part of the capsules is the body and the smaller,
`wider part is the cap
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`
`326
`
`DRUG DELIVERY SYSTEMS
`
`350 mg and a tapped bulk density of 0.75 g ml‘ 1.
`What size capsule is required?
`
`Volume occupied by fill weight =
`
`0.35
`
`0.75
`
`= 0.47 ml
`
`From Fig. 19.1 it can be seen that a size 1
`capsule has a volume of 0.48 ml and is therefore
`the size required for this particular formulation.
`This is, of course, fortuitous. What happens
`when the calculation yields a volume that does
`not coincide with a standard capsule size?
`2 A preliminary mixture has a fill weight of
`500 mg and a tapped bulk density of 0.80 g ml"1.
`.
`0.5
`Volume occupied by fill weight = T8
`= 0.63ml
`
`Volume of size 0 capsule
`
`= 0.67 ml.
`
`Thus a size 0 capsule is to be used. How much
`further diluent could be added to the mixture
`
`to improve its performance?
`
`Volume unoccupied
`Weight additional
`diluent
`
`= 0.04 ml
`
`0.04 X 0.8 = 32 mg
`
`Filling
`
`Hard gelatin capsules are most frequently filled
`with powders. In the last few years there have
`been significant developments in formualtion tech-
`niques and the filling equipment available which
`have enabled a range of materials to be handled.
`The only limitation is that they should not react
`with the gelatin, e.g. aldehydes, or interfere with
`the integrity of the shell, e.g. water which will
`soften the wall. The materials which can be
`
`handled are listed in Table 19.2.
`
`In addition,
`
`Table 19.2 Types of materials for filling into hard gelatin
`
`capsules
`V
`
`Dry solids
`Powders
`Granules
`Pellets
`Tablets
`
`Semisolids
`Thermosoftening mixtures
`Thixotropic mixtures
`Pastes
`
`machines can fill more than one type of substance
`into the same hard gelatin capsule, e.g. Inderex
`of ICI Pharmaceuticals which contains a tablet and
`a quantity of pellets to produce a special release
`dosage form.
`All formulations for filling into capsules must
`possess two basic requirements. They must:
`
`1 be able to be accurately dosed into the capsule
`shell,
`2 release their active contents in a form which is
`
`available to the patient.
`To accomplish this the formulation is usually a 2
`simple blend of the active ingredients together
`with adjuvants which aid the process,
`e.g.
`diluents, glidants, lubricants and surfactants.
`
`Formulation of powders for filling
`
`The factor which contributes most to a uniformly
`filled capsule is powder flow. This is because the
`- powder bed from which the dose of mix is
`measured needs
`to be homogeneous, packed
`reproducibly, in order _to give uniform fill weights.
`Good packing is assisted by good powder flow and
`this is aided by mechanical devices on the filling
`machine. Low dose drugs can be made to flow
`well by mixing with free flowing diluents, e.g.
`maize starch. For higher dose drugs the space
`available within the capsule shell for formulation
`aids is minimal. Small quantities (up to about
`5% w/w) of highly active materials are used:
`glidants, which improve flow by reducing inter-
`particulate friction (e.g. Fumed Silicon Dioxide
`BP) and lubricants, which reduce powder
`to
`metal adhesion (e.g. magnesium stearate)
`thus
`enabling the dosing devices to function properly.
`The literature indicates that the rate—controlling
`step in disintegration of an encapsulated product
`is the formulation of the contents. To achieve
`good drug release the contents should be readily
`wetted and dispersed by biological fluids. The
`factors in the formulation which control drug
`release are the natures of the active ingredient and
`the adjuvants. Several workers have demonstrated
`that the smaller particles of drug give higher blood
`levels than the same dose given as larger particles.
`This is because the surface area of the drug is
`greater the smaller the particle size and this influ-
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`

`
`this phenomenon
`ences solution rate. However,
`cannot_ be utilized to improve availability in all
`cases because of particle aggregation. These aggre-
`gates may possess large surface areas, but only
`part of
`this can be reached by the solution
`medium. The important measure is the ‘available
`surface area’ which is sometimes greater with
`larger particles.
`The, adjuvants are often described as the inert
`components in a formulation.
`In release terms
`they can frequently play an active role. The major
`component of a mixture after the activeidrug is
`usually_the diluent. This needs to be chosen in
`relationship to the solubility of the active ingre-
`dient.
`Insoluble drugs are mixed with soluble
`diluents, e.g.
`lactose,
`in order
`to make the
`mixture more hydrophilic. Soluble drugs can be
`mixed with insoluble diluents, e.g.
`starch,
`in
`order to avoid competition for solution.
`A formulation has to be designed for both good
`machine performance and good release properties.
`Some of the materials used to improve the filling
`performance, e.g. lubricants, magnesium stearate,
`are hydrophobic in nature, thus tending to slow
`down release. This effect can be minimized by
`using simplex mathematical optimization tech-
`niques or by the inclusion of a wetting agent, e.g.
`sodium lauryl sulphate, into the mix.
`
`Formulation of non-powders for filling
`
`Table 19.2 shows that a variety of materials other
`than powders can be filled into hard gelatin
`capsules. The formulation requirements are the
`same as for powders but are achieved in different
`ways.
`
`Granules and pellets
`
`Both particles should be as near spherical in shape
`as possible. Granules are produced by granulation
`and tend to be more irregular than pellets which
`__are produced by a coating or microencapsulation
`technique. ‘Both are often formulated to produce
`:rr~1odifiedrelease patterns.
`The machines which ‘fill
`
`these materials into
`
`capsules use either a gravitational system or-more
`frequently a metering chamber. Uniform filling
`depends therefore on the granules or pellets being
`
`CAPSULES
`
`327
`
`free flowing, regular in shape and size to give
`uniform packing and non—friable to reduce dust.
`
`Tablets
`
`Tablets are filled into capsules either to produce
`special release forms or to separate incompatible
`ingredients. The filling machines use storage
`hoppers which can release one or more tablets into
`the open capsule body. A physical sensor then
`checks for the presence of the tablet before the
`machine continues..
`For ease of filling the tablets need to be smooth,
`i.e. preferably film coated which also reduces
`dust, and of a diameter and shape that will easily
`fit into a capsule body.
`‘
`
`Semisolids
`
`innovation in hard gelatin capsule
`This recent
`filling is, in fact, a revival of a practice which was
`common at the beginning of the century. It fell
`into disrepute because of the problem of capsules
`coming apart and the product leaking out. This
`difficulty has been overcome by the use of self-
`locking capsules and by formulation techniques.
`Mixtures for filling need only be ‘liquid’ when
`filled and should be ‘solid’. when inside the
`
`capsule. This is achieved by using mixtures and
`materials which are either
`thermosoftening or
`thixotropic in nature. They are liquefied for filling
`by either heat or shearing forces respectively and
`revert to the solid state within the capsule shell
`when these are withdrawn. This system can be
`used for both liquid and solid active ingredients.
`Filling machines have been developed for hand-
`ling these formulations which are basically the
`same as standard powder filling ones except that
`they have a heated hopper with a stirrer to hold
`the formulation which is dosed into the capsules
`through a volumetric pump.
`The applications of semisolid filling are only
`just being investigated. It
`is a means of safely
`handling toxic drugs in that
`it reduces signifi-
`cantly the rate of cross—contamination associated
`with the filling of powders. For potent drugs it is
`_ a way in which uniformity of fill weight and of
`content can be improved“‘be‘cause of the use-of
`solutions and volumetric dosing pumps. Labile
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`
`328 DRUG DELIVERY SYSTEMS
`
`materials can be incorporated into a matrix which
`reduces moisture and oxygen ingress. The release
`rate of drugs can simply be varied from rapid to
`prolonged by using excipients with different
`melting points and HLB values. The more hydro-
`phobic the base, the slower the rate of release. It
`provides a system for handling liquid mixes which
`every pharmaceutical manufacturer can perform
`in-house and not have to go out to a third party
`contractor.
`
`Bioavailability aspects of hard gelatin capsules
`
`The formulation of a product in a hard gelatin
`capsule presents the industrial pharmacist with
`two distinct requirements: first the filling of the
`powder into the capsule and second, the release
`of the ingredients into the gastrointestinal
`tract
`when the capsule shell disintegrates. These factors
`are inter-related but
`for convenience the tech-
`
`nology of capsule shell manufacture and filling is
`discussed in Chapter 41 in the technology section
`of the book, and the factors in the formulation of
`products to be filled in hard gelatin capsules which
`affect drug release are discussed here.
`
`Disintegration and dissolution
`
`The first stage in drug release from a capsule is
`disintegration of the capsule shell. It has been
`shown in the literature that whilst products which
`disintegrate satisfactorily do not necessarily give
`good results, disintegration must
`take place for
`some to occur.
`.
`
`How do capsules disintegrate? When they are
`placed in a suitable liquid at body temperature the
`gelatin starts to dissolve, within 1 minute the shell
`splits, usually at
`the ends and with a properly
`formulated product, the contents start to empty
`before all the gelatin has dissolved.
`A formulation for filling into a capsule in the
`majority of cases is a simple powder mixture of
`the active ingredients
`together with diluents,
`lubricants, glidants or surfactants as required. The
`powder mass in the capsule should be such that
`it does not interfere with the dissolution of the
`
`gelatin shell and such that it will break up. With
`this in mind, what factors can be modified in a
`formulation to ensure that the active ingredients
`
`are released from the capsule and in an optimum
`form for absorption?
`
`Formulation factors affecting release from hard
`gelatin capsules
`
`Active ingredient The first consideration is
`the active ingredient. It is necessary to know its
`physicochemical properties
`such as
`solubility,
`melting point, crystalline form, etc. Most of the
`properties of the active ingredient are beyond the
`control of the formulator but one factor which can
`
`be modified is its particle size.
`It has been shown for several drugs in capsules
`that their rate of absorption is governed by their
`particle size. Fincher et al. (1965) showed that this
`was true for sulfisoxazole (see Fig. 19.2). They
`filled three different particle sizes of the drug into
`capsules and administered them to dogs. The
`blood levels they obtained demonstrated that the
`smallest particle size gave the maximum blood
`level.
`
`This can simply be explained by the fact that
`solution rate is directly proportional to the surface
`
`
`
`
`
`Meanbloodlevelmg100ml”
`
`0
`
`'
`01234567 89101112
`
`Time(h)
`
`O—:O Sample A (1.7 gm).
`
`BTU Sample
`
`B (39 pm).
`
`Asa Sample C (95 nm).
`
`Fig. 19.2 Effect of particle size on bioavailability (Fincher,
`J. H., Adams, ]. G. and Beal, H. M. (l965)_7. pharm. Sci.,
`54, 704-708)
`
`Astrazeneca Ex. 2099 p. 10
`
`

`
`area of drug. The smaller the particle the greater
`the relative surface area. Unfortunately, this is not
`a panacea for all problems because when powders
`are made smaller they tend to aggregate together
`and this effect is lost.
`
`The major properties of the active ingredient
`are out of the control of the formulator. The
`
`factors which he can manipulate are the other
`components in the formulation: diluents,
`lubri-
`cants, glidants and surfactants.
`in the largest
`Diluent The material present
`quantity is usually the diluent which was always
`classically described as an inert material added to
`a
`formulation to increase the volume of
`the
`
`mixture to a more manageable quantity.
`Unfortunately, diluents are not always inert as
`was demonstrated in the case of the reformulation
`
`of diphenylhydantoin which occurred in Australia.
`The diluent in this case was changed from calcium
`sulphate to lactose and in the months following
`the change there was an upsurge in the reported
`side effects on treatment with this drug.
`It was demonstrated that
`the change of the
`diluent had a significant effect on the bioavail—
`ability of the drug (see Fig. 19.3). The change of
`diluent to lactose gave higher blood levels, and
`because this drug is taken by chronic adminis-
`tration the change had a significant effect.
`Since this instance the phenomenon has been
`shown to occur with other drugs. The diluent
`should be chosen with reference to the solubility
`and proportion of the active ingredient.
`
`CAPSULES
`
`329
`
`the soluble drug
`On the other hand for
`chloramphenicol,
`it has been shown that an
`increase in the quantity of lactose in the formu-
`lation decreased its dissolution rate. This can be
`
`readily
`lactose is
`explained by saying that as
`soluble it passes into. solution preferentially and
`thus the dissolution rate measured is that of chlor-
`
`amphenicol in saturated lactose solution.
`Perhaps in the case of a readily soluble drug an
`insoluble diluent such as starch should be chosen.
`
`On disintegration of the capsules the starch grains
`would help the powder mass to break up without
`interfering with the
`solubility of
`the
`active
`ingredient.
`Glidants and lubricants Two of the other
`materials present in a formulation, glidants and
`lubricants are added to improve the filling prop-
`erties of the powder mixture. These substances
`can have an effect on drug release.
`The important thing to avoid in the formulation
`are materials which tend to make the mass hydro-
`phobic. The lubricant which is probably the most
`commonly used one
`in the pharmaceutical
`industry for both tablet and capsule formulations
`is magnesium stearate which is hydrophobic.
`Simmons et al.
`(1972) studied the dissolution
`rate of chlordiazepoxide formulations with three
`levels of magnesium stearate, 0,
`l and 5% (see
`Fig. 19.4). They found that the dissolution was
`greatly reduced at the highest level of magnesium
`stearate.
`
`100
`
`Phenytoin Phenytoin Phenytoin
`(CaSO4)
`(lactose)
`(lactose)
`
` Blood
`
`phenytoin(pigml”)
`
`Days8
`
`16
`
`24
`
`32
`
`0
`
`8
`
`
`
`Faecalphenytoinexcretion(mgday")
`
`
`
`
`
`%Dissolved
`
`80
`
`60
`
`20
`
`40
`
`048 12 Time (min)
`
`Fig. 19.3 Effect of diluent on bioavailability (Tyrer, J. M.,
`Eadie, M. J. , Sutherland, I. M. and Hooper, W. D. (1970)
`Br. med. _7., 4, 271-273)
`
`Fig. 19.4 Effect of lubricant on drug release (Simmons,
`D. L., Frechete, M., Lanz, R. J., Chen, W. S. and Patel,
`N. K. (1972) Can. ]. pharm. Sci., 7, 62-65)
`
`Astrazeneca EX. 2099 p. 11
`
`

`
`330 DRUG DELIVERY SYSTEMS
`
`Wetting; effects of porosity and the addition
`of surfactants Aguiar er al. (1967) with poorly
`soluble benzoic acid derivatives, measured the
`dissolution rate of the material presented as a loose
`powder, and the same quantity of powder filled
`into a size 00 and a size 1 capsule. The slowest
`dissolution rate was “obtained with the size 1
`capsule in which the powder
`is most
`tightly
`packed. They overcame this problem by adding
`0.5% of polyol surfactant
`into the formulation.
`This greatly improved the dissolution rate which
`they showed was due to an increase in the
`deaggregation rate of the material.
`If hydrophobic compounds have to be included
`in formulations because of filling machine require-
`ments, their deleterious effect on drug release can
`be overcome by the addition of wetting agents,
`surfactants at levels of 0.1—O.S%. Another solution
`
`such as
`is by the use of soluble lubricants
`sodium stearyl fumarate which has been recently
`developed.
`The type of filling machine used can affect drug
`release. The effect of how the powder is packed
`into the capsule has been shown to be important
`for some drugs and not for others.
`Samyn and Jung (1970) investigated the system,
`drug,
`lactose plus magnesium stearate 0°/o or
`5%. This was filled into capsules at a ‘normal
`packing’ and a ‘dense packing’ and measured the
`dissolution rate. They showed that
`the denser
`packing reduced the dissolution rate and also
`added to the effect of the magnesium stearate (see
`Fig. 19.5).
`
`This effect, however, does not happen with all
`drugs. In the two cases mentioned above there was
`an effect but with cephalosporine no difference
`was found in viva, between ‘tight’ and ‘loose’ filled
`capsules.
`The type of filling machine may also have an
`indirect effect. A capsule formulation is designed
`for the requirements of both capsule filling and
`drug release, and these are interdependent.
`
`SOFT GELATIN CAPSULES
`
`Description
`
`Soft gelatin capsules (SGCS, also referred to as soft
`elastic gelatin (SEG) capsules or softgels) consist
`of units with a continuous gelatin shell surrounding
`a liquid fill material. The capsules are formed,
`filled and sealed in one operation and may be of
`different sizes and shapes (see Fig. 19.6).
`
`Round
`0-0543 ml
`(0.15—0.3 mll
`
`0