CHURCHlLL LIVJNGSTONE
`
`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.
`
`© Michael 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, W1P 9HE.
`
`First published 1988
`Reprinted 1989
`Reprinted 1990
`Reprinted 199 1
`Reprinted 1992
`
`ISBN [J-LlLl3-[l3l:Ll3-B
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. Aulton, Michael E.
`615’.19
`RS403
`
`2. Drugs
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gur1n’s tutorial pharmacy.
`6th ed. 1972.
`Includes bibliographies and index.
`1. Drugs — Design of delivery systems.
`— Dosage forms. 3. Biopharrnaceutics.
`4. Pharmaceutical technology.
`5. Chemistry,
`Pharmaceutical.
`6. Microbiology, Pharmaceutical.
`I. Aulton, Michael E.
`2. Chemistry,
`[DNLM: l. Biopharmaceutics.
`Pharmaceutical.
`3. Dosage Forms.
`4. Technology,
`Pharmaceutical.
`5. Microbiology, Pharmaceutical.
`QV 785 P5366]
`RS420.P48
`1987
`
`615.5’8
`
`86-25888
`
`Printed in Hong Kong
`CPP/05
`
`The
`publisher's
`policy is to use
`paper manufactured
`from sustainable forests
`
`Astrazeneca Ex. 2085 p. 2
`
`

`
`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
`
`11 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
`
`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
`
`vii
`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
`
`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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`

`
`21
`_7LFord
`
`
`Parenteral products
`
`
`
`THE BIOPHARMACY OF INJECTIONS
`Routes of administration
`
`Intracutaneous or intradermal route
`
`Subcutaneous or hypodermic route
`Intramuscular route
`Intravascular routes
`Intracardiac route
`
`Intraspinal routes
`Intra-articular and intrabursal routes
`
`Ophthalmic routes
`Bioavailability of drugs from injections
`
`FORMULATION OF INIECTIONS
`
`Volume of the injection
`The vehicle
`
`Water and pyrogens
`W/ater—miscible vehicles
`Water-immiscible vehicles
`
`Osmotic pressure
`Intravascular injections
`Intrathecal injections
`Intramuscular injections
`Intracutaneous injections
`Subcutaneous injections
`Hydrogen ion concentration (pH)
`To increase the stability of the injection
`To minimize pain, irritation and necrosis on
`injection
`To provide unsatisfactory conditions for growth of
`micro—organisms
`To enhance physiological activity
`Buffers
`Specific gravity of injections
`Suspensions for injection
`Wettability
`Sedimentation rate
`
`Claying
`
`Size and shape of particles
`Thixotropy
`Preparation of aqueous suspension injections
`Suspensions in oily vehicles
`Addition of a gelling agent
`Particle size
`
`Emulsions for injection
`Intravenous therapy and emulsions
`Colloidal dispersions and solubilized products
`
`QUALITY ASSURANCE OF INJECTIONS
`
`Microbiological preservation
`The use of bactericides in single-dose injections
`The use of bactericides in multiple-dose injections
`Bactericides suitable for aqueous injections
`Bactericides suitable for oily injections
`Limitations in the use of bactericides
`Incompatibilities of common bactericides
`Chemical stability of the medicament
`Adjustment of pH
`Addition of a reducing agent or antioxidant
`Replacement of air by an inert gas
`Use of a sequestering agents
`Inclusion of specific stabilizers
`Calcium Gluconate Injection BP
`Sodium Bicarbonate Injection BP
`
`Mersalyl Injection BP
`Limitations in the use of additives
`Particulate contamination
`
`PACKAGING OF INJECTIONS
`
`Containers for injections
`
`Ideal properties
`Types of container
`S ingle—dose versus multiple-dose containers
`Materials for injection containers
`Glass
`
`Types of glass
`
`359
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`

`
`360
`
`DRUG DELIVERY SYSTEMS
`
`Associated problems for parenterals
`Plastics
`
`Types of plastics
`Associated problems for parenterals
`Closures
`
`Types and properties of closure materials
`Associated problems for parenterals
`
`layer
`and the outer
`(dermis)
`layer
`inner
`(epidermis). The volume that can be injected
`intradermally is small, usually 0.1-0.2 ml, due to
`the poor vascularity of the site which gives poor
`dispersion of the drug, and leaves blisters or weals
`at
`the site of the injection. The route is used
`mainly for diagnostic tests.
`
`STERILIZATION OF INJECTIONS
`
`Injections are sterile products intended for admin-
`istration into the bodily tissues. Their formulation
`involves careful consideration of all the following
`inter-relating factors:
`
`the proposed route of administration,
`1
`2 the volume of the injection,
`3 the vehicle in which the medicament is to be
`dissolved or suspended,
`,
`4 the osmotic pressure of the solution,
`5 the use of preservative,
`6 the pH of the solution,
`7 the stability of the medicament and methods
`of sterilization,
`8 the specific gravity of the injection,
`9 the properties of suspensions for injection,
`10 the properties of emulsions for injection,
`11 containers or closures for injections,
`12 particulate contamination,
`13 biopharmacyof injections.
`
`THE BIOPHARMACY OF INJECTIONS
`
`Injections are administered into the body by many
`routes. The route of administration affects the
`formulation and biopharmaceutics of the prep-‘
`aration. There now follows a description of routes
`of administration to clarify nomenclature used
`throughout
`the rest of the chapter. Fig. 21.1
`shows the sites of injection.
`
`Routes of administration
`
`The most important routes are as follows.
`
`Intracuzaneous or intradermal route
`
`Injections are made into the skin between the
`
`Subcutaneous or hypodermic route
`
`Injections are made under
`
`the skin into the
`
`injected is
`tissue. The volume
`subcutaneous
`usually 1 ml or less. This route is not used for
`
`aqueous suspensions or oily suspensions and fluids
`since these would cause pain and irritation at the
`injection site.
`
`Intramuscular route
`
`Injections are made by passing the needle into the
`muscle tissue via the skin, subcutaneous tissue
`and membrane enclosing the muscle. The volume
`is usually no greater than 2 ml and should not
`exceed 4 ml. This route is used for aqueous and
`oily suspensions and oily solutions, since if they
`were injected intravenously blockage of small
`blood vessels might occur leading to poor vascular
`supply of
`local
`tissues possibly resulting in
`gangrene.
`
`Intravascular routes
`
`These are either intra-arterial (into arteries) or
`intravenous (into veins). The intra-arterial route
`is used for an immediate effect in a peripheral
`organ, e.g. to improve circulation to the extrem-
`ities when arterial flow is restricted by arterial
`spasm or early gangrene. Tolazoline hydrochlor-
`ide, a peripheral vasodilator, is sometimes admin-
`istered by this route.
`Substances are introduced directly into the
`blood stream by the intravenous route. The most
`common site is the median basilic vein at
`the
`anterior surface of the elbow. The volume can
`vary from less than 1 ml to in excess of 500 ml.
`Small volumes may be administered for a rapid
`effect
`(e.g.
`anaesthetics)
`and large volumes
`(perfusion or infusion fluids) to replace body fluid
`loss in shock, severe burns, vomiting and diar-
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`
`PARENTERAL PRODUCTS
`
`361
`
`vein
`
`Median
`-‘ basilic
`
`(b)
`
`Nerve
`fibres
`
`.
`Fllum
`terminale
`
`Dura mater
`
`Arachnoid
`
`_Pla mater
`
`Subcutaneous
`tissue
`
`(a)
`
`
`
`
`terminale
`
`_ Subarachnoid
`space (nerve
`fibres omitted)
`
`Subarachnoid
`space
`
`Needle in
`
`subarachnoid
`space
`
`
`
`(d)
`
`Fig. 21.1 Routes for injection. Key: (a) i.c., intracutaneous route; s.c., subcutaneous route; i.m., intramuscular route: (b)
`i.v., intravenous route into the median basilic vein at the anterior surface of the elbow: (c) p.d., peridural route; i.t.,
`intrathecal route: (d) subarachnoid route.
`
`rhoea. The route ensures rapid body dispersion
`and generally administration of volumes in excess of
`10 ml is termed intravenous infusion. Oil—in—water
`emulsions may be administered by this route if the
`globule size is controlled but the route cannot be
`used for w/o emulsions.
`
`Intracardiac route
`
`This is used for emergencies only when stimu-
`lants, e.g. adrenaline or isoprenaline sulphate, are
`given directly into the heart muscles or ventricles.
`
`Intraspinal routes
`
`These routes involve access into or around the
`
`spinal cord. Single dose injections, no greater than
`20 ml, are used. Intrathecal or subarachnoid injec-
`tions are made into the subarachnoid space that
`surrounds the spinal cord which is enclosed in
`three coats. The outer one is known as the dura
`
`mater, the middle one as the arachnoid and the
`inner one as the pia mater. The subarachnoid
`space lies between the arachnoid and pia mater
`and contains the cerebrospinal fluid (c.s.f.). The
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`

`
`362
`
`DRUG DELIVERY SYSTEMS
`
`route is used for spinal anaesthetics (e.g. bupiva-
`caine) and antibiotics (e.g. streptomycin in the
`treatment of tubercular meningitis).
`into the
`Intracisternal
`injections
`are made
`cisterna magna which lies directly below the_
`medulla. Although the route is primarily used to
`remove c.s.f., it is occasionally used for antibiotic
`treatment or for
`the investigation of the c.s.f.
`circulation by dye injection.
`Peridural injections are made into the peridural
`space which is located between the dura mater and
`the inner aspect of the vertebrae. This space
`extends throughout the full length of the spinal
`column and injections may be made at different
`regions, e. g. thoracic, lumbar or sacral. The route
`is used for spinal anaesthesia although careful
`consideration of the specific gravity of the injec-
`tion has to be made to allow exact positioning of
`the injection.
`Great care should be taken to ensure that any
`chosen buffering agent does not damage the deli-
`cate nervous tissue or its coats.
`
`Intra-articular and intrabursal routes
`
`Intra—articular
`
`injections
`
`are made
`
`into
`
`the
`
`fluid which lubricates the articulating
`synovial
`ends of bones in a joint. Intrabursal injections are
`similar, being given into the bursae which are
`small sacs of fluids between movable parts such
`as tendons and bones. The common sites are the
`subacromial bursa
`in the
`shoulder
`and the
`olecranon bursa in the elbow. Both solutions and
`
`suspensions may be administered by these routes.
`
`Ophthalmic routes
`
`Because of the restricted target areas the dose-
`volume is never greater than 1 ml. Four routes are
`used; the subconjunctival route (beneath Tenon’s
`capsule, close to the eye but not
`into it),
`the
`intravitreous route (into the vitreous chamber),
`the intracameral route (into the anterior chamber)
`and the intraocular
`route (into the posterior
`segment of the globe). Great care should be given
`to the choice of any prospective buffering agent.
`
`route and,
`intrapleural
`mammary route.
`
`in cattle,
`
`the
`
`intra-
`
`Bioavailability of drugs from injections
`
`Injections are often used for either rapid or local-
`ized activity. An injection directly into the blood
`stream ensures that
`the drug is spread rapidly
`throughout
`the body before other factors,
`like
`plasma bonding, binding to selective sites and
`metabolism will
`reduce the achieved concen-
`
`tration.
`Intrathecal,
`instracisternal,
`intracardiac
`and the intravenous routes can be used for rapid
`onset of drug action. Unlike tablets, where there
`are disintegration and dissolution stages prior to
`absorption, injections achieve a rapid high blood
`level. However, formulation, coupled with vari-
`ation in the site of administration may affect
`markedly the biopharmacy of drugs. The pH of
`an injection may effect the degree of ionization of
`a drug, rendering it more or less likely to pass
`through biological membranes.
`Increasing the
`viscosity of an injection will slow the absorption,
`especially from intramuscular injections, and drug
`solubility, dependent on polymorphism, will affect
`the activity of drugs. Thus the polymorphism of
`novobiocin and chloramphenicol can alter their
`biological properties. For suspensions, the particle
`size of the drug influences absorption rate and
`increasing the particle size of a drug, e.g. insulin,
`will decrease
`the available
`surface area
`and
`
`decrease its absorption from an injection site,
`giving a sustained release effect. Similarly,
`the
`blood levels of procaine penicillin G increase as
`the particle size of the suspension decreases.
`The routes of administration markedly affect
`the disposition and biopharmacy of drugs. The
`intravenous route gives immediate and total access
`of the drug molecules to the body. Maximum
`plasma concentrations may be achieved after 4
`minutes. The duration of action may be affected
`by dose, distribution, metabolism and excretion
`of the drug but
`the elimination usually follows
`first order kinetics. Constant blood levels may be
`obtained by intravenous drips. Intramuscular and
`subcutaneous routes can act as sustained release
`
`Other routes which may be used include the
`intra-ossicular route, the intracerebral route,
`the
`intraperitoneal route (for dialysis solutions),
`the
`
`this depends on the dosage form.
`routes but
`Aqueous solutions are most rapidly absorbed into
`the blood stream and aqueous suspensions show
`
`Astrazeneoa Ex. 2085 p. 7
`
`

`
`retarded release due to the dissolution step intro-
`duced into the absorption process. The use of
`oleaginous vehicles may further delay absorption
`due to a partitioning of the drug from the oil to
`the aqueous body fluids and oleaginous suspen-
`sions provide a retarding dissolution process prior
`to partitioning. For these routes, viscosity, drug
`concentration and the patient’s movement may
`further alter absorption rates. Even differences in
`the choice of muscle may ~influence absorption.
`Generally ‘the subcutaneous route provides slower
`absorption due to the low vascular supply to the
`skin (for further information see Gibaldi, 1977).
`
`FORMULATION OF INJECTIONS
`
`reference is made to
`this section,
`Throughout
`injections of the British Pharmacopoeia. These are
`included as illustrative examples for which the full
`formula can be obtained. The reader can extra-
`polate the principles discussed to other, non-offi—
`cial or novel formulations.
`
`Volume of the injection
`
`The volume of an injection primarily depends on
`the solubility of the medicament, but may be
`influenced by preference for a particular route.
`Intracutaneous injections have to be small
`to
`prevent the formation of blisters. Only the intra-
`venous route is suitable for large volumes which
`must be made isotonic.
`Intravenous injections
`with doses greater than 15 ml must not contain a
`bactericide and therefore cannot be sterilized by
`heating with a bactericide. When the volume is in
`excess of 15 ml the injection should be free from
`pyrogens.
`The volume should be convenient
`
`to admin-
`
`ister. Volumes greater than 20 ml are unsuitable
`for injections by a syringe and infusions are not
`worth setting up for less than 250 ml. The volume
`can often be reduced by dispensing a hypertonic
`solution and administering by slow intravenous
`infusion.
`
`The vehicle
`
`Any vehicle used should be pharmacologically
`inert, non-toxic (i.e. compatible with blood, non-
`
`PARENTERAL PRODUCTS
`
`363
`
`sensitizing, non-irritating), maintain the solubility
`of the drug, be chemically and physically stable
`and be unaffected by pH changes. Vehicles should
`not interfere with the therapeutic activity of the
`injection. They must be exhaustively tested for
`freedom from toxicity,
`they must be pure and
`have no pharmacological activity of their own.
`Water is the ideal vehicle for most
`injections
`since aqueous preparations are well tolerated by
`the body and are the safest and easiest to admin-
`ister. However, a change from water may be
`required for a variety of reasons. Hydrolysis of
`certain drugs may result in the formation of inert
`or toxic byproducts. Some poorly water-soluble
`drugs may be so insoluble that they cannot be
`administered in water. Consequently, the use of
`cosolvents, e. g. propylene glycol for Dimenhydri-
`nate Injection BP or oily vehicles such as benzyl-
`benzoate and arachis oil for Dimercaprol Injection
`BP, is permitted. Oily vehicles often give a- depot
`effect over their aqueous counterparts and steroid
`drugs, e.g. progesterone, which are poorly water
`soluble are formulated in ethyl oleate or fixed oils
`to enable depot release to continuously replace
`deficient secretions. Oily media may indeed be
`preferable to aqueous vehicles. Propyliodone,
`although present in the British Pharmacopoeia as
`both an aqueous suspension and an oily suspen-
`sion in arachis oil,
`is often preferred in oily
`suspension as a contrast medium of X-ray exam-
`ination of the respiratory tract because this is less
`irritating than the aqueous suspension.
`Oily injections suffer from many disadvantages
`including the following.
`
`the site of
`
`1 They may be too viscous in cold weather to
`administer without warming.
`2 They often cause pain at
`injection.
`3 They will contaminate the syringe and needle
`making them difficult to clean.
`4 They must be used only by the intramuscular
`route, since their accidental intravenous injec-
`tion may lead to thrombosis.
`
`the
`
`However, contrast media, e.g. Iodised Oil Fluid
`Injection BP or Propyliodone Oilylnjection BP,
`may be given by other routes because they are not
`injected into tissues but into the internal cavities
`that are under investigation, e.g. the lungs. Very
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`

`
`364 DRUG DELIVERY SYSTEMS
`
`occasionally alcohol is used to dissolve the medi-
`cament but the solution must be diluted with an
`aqueous vehicle shortly before administration to
`avoid pain and tissue damage.
`
`Water and pyrogens
`
`Before potable water can be rendered suitable for
`use in injections it has to be specially purified.
`The injection of distilled water may cause a rise
`of body
`temperature; water producing
`this
`reaction is said to be pyrogenic (fever producing)
`and water free from this effect
`is described as
`
`apyrogenic. Substances which are pyrogenic may
`be produced by many micro—organisms including
`moulds, yeasts and bacteria. The most potent are
`those associated with Gram-negative bacteria and
`are endotoxins originating from the cell wall. The
`main causative substance is lipid in nature but its
`potency is enhanced by protein and especially
`polysaccharide fractions which appear to increase
`the solubility of the lipid fraction. Pyrogenic
`molecules have a high molecular weight often in
`excess of 1 000 000.
`
`The sources of pyrogens may be the solvent, the
`medicament, any added buffering. or stabilizing
`substance, the apparatus used in manufacture, the
`final containers and the method of storage between
`preparation and sterilization. Undoubtedly,
`the
`major source is the solvent and especially Water
`for Injections BP.
`Injection of pyrogens into the body produces
`various physiological responses including erythema
`at the injection site, pain in the legs and trunk
`with general discomfort and high temperature. It
`is thisilast response that the British Pharmacopoeia
`uses as the basis to estimate pyrogens by studying
`temperatures in specially treated rabbits, although
`other methods especially the limulus amoebocyte
`lysate test have been developed (Thomas er al.,
`1980).
`injections
`Pyrogen tests are applied to all
`claimed to be apyrogenic, i.e. to Water for Injec-
`tions BP,
`to single dose injections of volume
`greater than 15 ml and powders which require
`making up to a solution with vehicle prior to
`administration, when _the reconstituted injection
`is tested. However,
`it
`is vital
`that
`intravenous
`
`infusions should be free from pyrogens since a
`large volume injection will contain a correspond-
`ingly large amount of pyrogen. As large volume
`injections
`(perfusion fluids) are usually given
`intravenously the pyrogen will have a more rapid
`effect. Patients receiving infusion fluids are often
`dangerously ill and the effect of rise of tempera-
`ture could be fatal.
`
`Water for Injections BP is sterilized distilled
`water free from pyrogens and is prepared from
`potable water. Since tap water may be pyrogenic,
`the first aim in the preparation of Water for Injec-
`tions BP must be to remove or destroy pyrogens.
`This is complicated as pyrogens are thermostable,
`water soluble and are unaffected by common
`bactericides and, therefore, none of the methods
`used to sterilize injections can be relied upon to
`eliminate pyrogens.
`However, pyrogens are also non-volatile and
`they can be removed from water by distillation.
`Ordinary distillation is not
`satisfactory since
`pyrogens may be carried over in the receiver,
`dissolved in the spray which is entrailed in the
`steam. Therefore, a trap is fitted to the distilling
`flask to stop this entrainment. Certain bacteria are
`able to multiply in distilled water.
`Inadequate
`protection from air and storage at a temperature
`that favours bacterial growth may cause a rapid
`increase in the bacterial count.
`Ideally distilled
`water for parenteral solutions should be sterilized
`immediately after collection from the still. The
`exception is when the water is used at once for
`making an injection that
`requires sterilization.
`Then, provided the injection is sterilized irn—
`mediately after preparation (i.e. within 4 hours),
`freshly distilled non-sterilized water may be used.
`Distilled water may be used after a much longer
`storage provided it
`is maintained -at
`a high
`temperature, e.g. 80 °C, when bacterial growth
`and hence pyrogen production will be prevented.
`Because of the great danger from pyrogens in large
`volume infusion fluids, the British Pharmacopoeia
`gives a special warning of the need for
`their
`immediate sterilization, e.g., Laevulose Intra-
`venous Infusion BP.
`
`For further information on the preparation of
`Water
`for
`Injections BP see Perkins,
`1969;
`Ridgway,
`1973;
`or Groves,
`1973a. Another
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`
`

`
`method of preparing water for injections is reverse
`osmosis which is accepted by the USP (see Frith
`er al., 1976).
`Water for Injections BP is suitable as a vehicle for
`many official preparations. However, it may some-
`times be necessary to further improve its quality
`by removing dissolved gases. Some medicaments,
`e.g.
`the barbiturates and sulphonamides, are
`weakly acidic and only slightly soluble in water
`and they are therefore administered as the more
`soluble sodium salts. For instance, amylobarbi-
`tone sodium (solubility 1
`in less than 1) when
`dissolved in water containing carbon dioxide will
`rapidly precipitate the free base amylobarbitone
`(solubility 1 in 1500) rendering it dangerous and
`unsuitable for injection. Examples of other injec-
`tions requiring water free from carbon dioxide are
`Aminophylline
`Injection BP, Methohexitone
`Injection BP and Sodium Bicarbonate Intravenous
`Infusion BP. However, Water for Injections BP
`free from carbon dioxide is unnecessary for thio-
`pentone injection BP because the official substance
`is a mixture of thiopentone and sodium carbonate
`and the latter will keep the salt
`in solution.
`Carbon dioxide may be removed from water for
`injections by boiling the water for 10 minutes.
`Water for injections free from dissolved air is
`produced in a similar manner and the residual air
`space at the top of the ampoules is replaced by
`nitrogen or another inert gas after packing, before
`sealing. This product replaces normal water for
`injections in products containing medicaments
`which are sensitive to low levels of oxygen and
`hence can be protected from oxidation. Examples
`include Chlorphenirarnine Injection\ BP, Chlor-
`promazine Injection BP, Phenylephrine Injection
`BP, Sulphadimidine Injection BP and Promazine
`Injection BP.
`
`W/ater—miscible vehicles
`
`PARENTERAL PRODUCTS
`
`365
`
`logical activity and the pain and tissue damage it
`causes unless administered with special care, are
`serious disadvantages. It is not the main solvent
`in any official injection but a few (e.g. Digoxin
`Injection BP, Ergotamine Injection BP and Pheny-
`toin Injection BP) contain a low concentration to
`
`the active ingredient.
`solution of
`facilitate
`Melphalan Injection BP is a solution in a vehicle
`containing 95% ethyl alcohol but is diluted before
`use.
`
`Propylene glycol is included in _several prep-
`arations
`including
`Cotrimoxazole, Digoxin,
`Dimenhydrinate, Melarsoprol, Phenobarbitone
`and Phenytoin injections BP. In the British Phar-
`macopoeia (1958), Digoxin Injection BP contained
`70% ethyl alcohol which had to be diluted with
`Sodium Chloride Injection BP 1958 and given
`intravenously by slow injection to ensure rapid
`dilution with blood. The official preparation is
`now a stable solution in a solvent containing 40%
`propylene glycol, 10% ethyl alcohol and water
`buffered to about pH 7 and does not require dilu-
`tion before use.
`
`Until 1968, Phenobarbitone Injection BP was
`prepared by aseptically dissolving sterile pheno-
`barbitone sodium in Water for Injections BP free
`from carbon dioxide immediately before use. The
`current injection is a solution in 90% propylene
`glycol which is stable enough to be sterilized at
`98-100 °C and has a satisfactory storage life.
`Although propylene glycol
`is relatively non-
`toxic (possibly because it is rapidly metabolized
`and excreted),
`it
`causes
`severe irritation on
`subcutaneous and intramuscular
`injection and
`preferably should not be given by these routes,
`unless an anaesthetic such as benzyl alcohol
`is
`included,
`e.g. Dimenhydrinate
`Injection BP.
`Although the liquid macrogols have been recom-
`mended as prospective vehicles (Carpenter and
`Shaffer, 1952) care must be taken during their
`sterilization as formaldehyde can be generated.
`
`It is often not possible to dissolve the medicament
`in water for injections. To increase the solubility,
`non-toxic solvents can be used and these include
`
`Water-immiscible vehicles
`
`ethyl alcohol, glycerol, propylene glycol,
`pmacrogols and benzyl alcohol.
`Ethyl alcohol is used only when other methods
`of presentation are impracticable. Its own physio-
`
`liquid
`
`Eight of the oily injections of the British Phar-
`macopoeia are simple solutions (e.g., deoxycortone
`Acetate Injection BP, Hydroxyprogesterone Injec-
`tion BP and Oestradiol Benzoate Injection BP).
`
`Astrazeneca Ex. 2085 p. 10
`
`

`
`366 DRUG DELIVERY SYSTEMS
`
`Their prescribed solvents are a suitable fixed oil,
`a suitable ester (e.g. ethyl oleate) or a mixture of
`both. Suitable alcohols may be included in the
`solvents
`for Deoxycortone Acetate, Oestradiol
`Benzoate and Progesterone Injections BP.
`Fixed oils must not contain mineral oils or solid
`
`paraffins as these cannot be metabolized by the
`body and might eventually cause tissue reaction
`and even tumours. They must be free from
`rancidity (since rancid oils contain free fatty
`acids) and from any material
`that might cause
`irritation.
`_
`Arachis oil
`is specified for Dimercaprol Injec-
`tion BP and Propyliodone Oily Injection BP but
`has the disadvantages of thickening slowly on
`exposure to air and becoming rancid. Alternatives
`include sesame oil
`(probably the most stable
`because it contains natural substances that prevent
`rancidification),
`cotton seed and maize oils.
`Sensitivity to these oils may cause problems.
`Esters give less viscous preparations that are
`easier
`to inject, particularly in cold weather.
`However, a reduction in the length of action of
`depot preparations has been found when ethyl
`oleate has been used instead of oil. The maximum
`
`prolongation effect is obtained from the depot if
`it is spherical and, therefore, absorption is prob-
`ably more rapid from the less viscous ester prep-
`arations because of
`their greater
`tendency to
`spread and offer a larger surface to the tissue
`fluid.
`
`for
`the solvent
`Peroxide—free ethyl oleate is
`Calciferol Injection BP. Peroxides are the inter-
`mediates in the auto-oxidative rancidification of
`
`oils and fatty acids, and they are undesirable in
`injections, particularly when the medicament
`is
`susceptible to oxidation. Calciferol injection also
`requires storage in ampoules from which the air
`has been displaced by an inert gas.
`Alcohols may be used in three official prep-
`arations because occasionally the medicament
`concentration may be greater than its solubility in
`fixed oils, ethyl oleate or a mixture of both. Either
`benzyl alcohol or ethyl alcohol can improve the
`solvent properties of these vehicles in concen-
`trations that are harmless and non-irritant by the
`intramuscular route.
`
`Table 21.1 indicates the advantage of using a
`
`Table 21.1 Solubility of steroids in different vehicles
`
`Water
`
`Arachis
`oil
`
`Ethyl
`clears
`
`Alcohol
`95%
`
`Deoxycortone
`acetate
`
`Almost
`insoluble
`
`l in 140
`
`1 in 150
`
`1 in S0
`
`Oestradiol
`benzoate
`
`Insoluble
`
`1 in 500
`
`1 in 200
`
`1 in 150
`
`Progesterone
`
`Insoluble
`
`1 in 60
`
`Testosterone
`
`Insoluble
`
`1 in 35
`
`1 in 60
`
`l in 20
`
`1 in 8
`
`1 in 6
`
`solvent containing an alcohol for deoxycortone
`acetate, progesterone and to a less extent oestra‘-
`diol benzoate. Conversely the high solubility of
`testosterone propionate in arachis oil and ethyl
`oleate makes the use of alcohols unnecessary.
`Other oily bases include almond oil (for Oily M
`Phenol Injection BI’), poppyseed oil,
`isopropyl
`myristate and polyoxyethylene oleic triglycerides
`(Labrafils). Another solvent, benzyl benzoate is
`used for Dimercaprol Injection BF. Dimercaprol
`is a liquid formulated in oil because aqueous
`solutions are unstable. For strong preparations,
`the required amount of dirnercaprol would not
`completely dissolve in arachis oil but was miscible
`with benzyl benzoate. The resulting mixture can
`be diluted with arachis oil to give an injection that
`is stable, even to dry heat sterilization, if protected
`from air. Although the official strength is below
`that which gives solubility problems,
`the British
`Pharmacopoeia uses benzyl benzoate because of its
`stabilizing effect.
`
`Osmotic pressure
`
`Great care has to be taken to make certain injec-
`tions
`isotonic with plasma. Husa and his
`colleagues (Husa and Adams, 1944; Hartman and
`Husa, 1957; Thornasson and Husa, 1958) have
`reported that certain medicaments in solutions iso-
`osmotic with plasma can pass through the red
`blood cell membrane, i.e. these solutions are not
`isotonic and may be harmful
`in use. Although
`normal practice is
`to adjust solutions to iso-
`osmoticity with plasma,
`iso-osmotic solutions of
`new drugs should be checked for isotonicity and
`haemolytic activity on red cells before using them
`by the intravenous route.
`
`AstraZeneca Ex. 2085 p. 11
`
`

`
`Intraoascular injections
`
`Solutions with a lower osmotic pressure than
`blood are said to be hypotonic and those with
`higher pressure are hypertonic. Both may be
`termed paratonic,
`i.e. not
`isotonic. Blood cells
`swell rapidly and burst (haemolysis) in hypotonic
`solutions. This damage
`is
`irreversible and
`dangerous if a large number of cells is involved.
`A very hypotonic solution or a large volume of less
`hypotonicity can cause this damage on intra-
`‘ Vascular
`injection. When placed in hypertonic
`solutions, water passes outwards from blood cells
`and they shrink, becoming crenate in outline.
`When the osmotic pressure returns to n