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`infections··
`. Genticin,HC '•:.,
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`Eczematous
`periphery of ulcers
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`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1011, p. 1 of 8
`
`

`

`Factors Influencing Drug Stability in Intravenous
`Infusions
`
`JOHN JACOBS, M.Pharm., F.P.S.
`
`Deputy Director of Pharmacy Services, Meyer de Rothschild
`Hadassah University Hospital, Jerusalem, Israel
`
`SUMMARY
`
`In order to preserve the activity of drugs given by infusion, many factors
`must be considered. The infusion fluid must be chosen with care so that the
`presence of any electrolyte or sugar or the pH of the solution does not
`provide an unsuitable medium for the added drugs.
`Where drugs are inherently unstable small infusion flasks may be used
`or the drug may be added to the last few hundred millilitres of the infusion.
`Additional drugs should be added only when no incompatibility occurs. With
`very unstable drugs, injection into the infusion tubing may be undertaken.
`Where a chemical incompatibility occurs between two drugs, !hey should
`be given in separate infusion bottles.
`
`THE traditional role of the pharmacist
`
`is
`the hospital environment
`in
`undergoing rapid change. He has recently
`taken on clinical responsibility by leaving
`the pharmacy and
`in conjunction with
`physicians and nurses has attempted to
`bring safer and more effective procedures
`into practice in the everyday work of drug
`distribution and medication administration.
`A short time ago it was acceptable to think
`that the pharmacist's responsibility ended
`the
`when a drug was dispensed from
`pharmacy. This is no longer true and the
`pharmacist is often present in the ward to
`advise on drug administration. Advice is
`frequently sought on the preparation and
`administration of
`intravenous solutions.
`This is a complex field in which the careful
`consideration of drug properties and
`infusion stability is required to ensure that
`patients receive a drug mixture which will
`bring about the required therapeutic effect.
`in compounding
`II care
`is not
`taken
`infusions a patient may receive an infusion
`which may not be beneficial and may even
`be harmful.
`There is an important area of investiga(cid:173)
`tional work to be covered in the determina(cid:173)
`tion of stability of intravenous solutions
`
`and the results and conclusions of the
`survey described here are the first stage in
`this work.
`During a two-month survey, the use of
`intravenous drugs was observed
`in 17
`departments of the Hadassah University
`Hospital. In the majority of the depart(cid:173)
`ments surveyed, drugs were added to the
`infusion fluid. A single drug was most
`frequently added, with occasional mixtures
`of
`two
`to
`four drugs concurrently
`administered in one infusion bottle. Five or
`even six drug combinations were not
`unknown. This
`reflects
`the physician's
`dilemma in attempting
`to administer a
`large number of drugs
`in an efficient
`manner when the oral route cannot be
`used. Some patients suffering from weight
`loss and emaciation cannot tolerate intra(cid:173)
`muscular injections and the unnecessary
`pain of multiple injections each day can be
`intravenous route of
`avoided when the
`administration is employed.
`The survey showed that 56 drugs and 8
`infusion
`fluids were commonly given.
`Among the drugs used there were 13 anti(cid:173)
`biotics, 11 sympathomimetic and cardio(cid:173)
`vascular agents, 2 antihistamines, 6 vita(cid:173)
`mins and 5 hormones.
`
`Cecember 1969
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`341
`
`This material wast:apied
`
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`
`

`

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`
`342
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`December 1969
`
`This material wast:apied
`
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`
`

`

`Only in a few of the world's largest
`hospitals does the pharmacy department
`provide an
`intravenous additive service
`which prepares and dispenses individual
`infusion bottles containing the necessary
`drugs prescribed by the physician. One
`such unique and comprehensive intraven(cid:173)
`ous solution service is provided by the
`Ohio State University Hospitals, and intra(cid:173)
`venous infusions containing added drugs
`are prepared under direct pharmaceutical
`supervision and are available on demand
`day and night. 1
`
`Whether the pharmacy provides such a
`service or not, pharmacists should have
`knowledge of the stability factors involved
`when a drug is added to an infusion fluid.
`They can then advise the nursing staff how
`the infusion can be prepared and safely
`given to the patient without decomposition
`and loss of activity, or the formation of
`toxic products.
`
`The factors influencing drug stability in
`intravenous infusion include:
`
`Time of preparation: The interval between
`the preparation and the administration of
`the infusion should be minimal. In the event
`of contamination
`this does not allow
`excessive multiplication
`of
`bacteria,
`reduces drug decomposition and, perhaps
`even more important, the possibility that
`the wrong patient may receive the infusion
`due to a change in nursing shift. This
`interval should never be longer than one
`hour. Infusions of drugs not used soon
`after preparation should be rejected. They
`must not be refrigerated and used at a
`later stage.
`
`Duration of infusion: The survey showed
`that the duration of infusion was commonly
`from ½ hour to 12 hours, and occasionally
`24 hours. Bacterial contamination would
`be more likely in infusions administered
`long periods and many drugs
`over
`decompose within a
`few hours.
`It
`is
`suggested that infusion time should not
`
`exceed 12 hours per flask and preferably
`8 hours per flask.
`
`pH of the solution: Many drugs decompose
`rapidly when added
`to a solution of
`unsuitable pH.
`(See
`table 1) Dextrose
`infusions are the common cause of stability
`problems since they are almost always
`acid
`in
`reaction. The
`lower pharma(cid:173)
`copoeia! limit is pH 3.5. In solutions of
`very low pH, methicillin sodium may be
`free methicillin acid
`decomposed and
`precipitated
`in
`the
`infusion
`flask. With
`other drugs, e.g. ampicillin, heparin, etc.,
`no precipitate may be formed, but much of
`the drugs' activity is rapidly lost.
`
`Electrolytes: The presence of electrolytes
`in
`the
`infusion, especially
`in high
`concentration,
`may
`cause
`drug
`decomposition or precipitation.
`( See
`table 2)
`
`Sugars and polysaccharides: The presence
`of apparently
`innocuous sugars may
`cause
`instability. Sulphadiazine sodium
`injection has a pH of about 10.5. When this
`is added to dextrose solutions of pH 4.4,
`the pH of the solution is raised to 8.5 and
`a deep yellow colour develops over some
`hours.
`
`infusion: Not all
`Physical state of the
`infusions are simple solutions. Blood is
`a coarse suspension, mannitol in the high
`concentration usually employed for forced
`diuresis is a supersaturated solution and
`emulsions of
`fats are also used, e.g.
`lntralipid.®
`In
`some
`cases
`room
`temperature
`can
`influence
`solubility.
`Infusion fluids may have to be warmed to
`to ensure
`that
`the solids are
`37'C
`completely dissolved and that the solution
`is homogenous, e.g. 25% mannitol. Super(cid:173)
`saturated
`solutions
`can
`be
`readily
`crystallised out and it is recommended
`that no additions be made to mannitol,
`inulin, etc., in these concentrations. Fat
`emulsions may be "cracked" and separa(cid:173)
`tion of the pharns or enlargement of the
`globule size may occur if drugs are added
`
`December 1969
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`343
`
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`

`

`Table 1
`
`Drug
`
`DRUG STABILITY
`
`IN SOLUTION ACCORDING TO pH
`
`Stability characteristics
`
`Aminophylline
`
`Ampicillin sodium
`
`Unstable in neutral or acid solution.
`
`Loses 10% activity in 4 hours in dextrose or dextrose-saline.
`Preferable to administer in saline or Ringers solution.
`
`Amylobarbitone sodium
`
`Should not be added to solutions with a pH below 8.0.
`May be given in saline.
`
`Benzylpenicillin sodium
`
`Unstable in highly acid solutions.
`
`Carbenicillin sodium
`
`Unstable in alkaline solutions. Given in saline,
`dextrose or dextrose-saline during 6 hours or less.
`
`Heparin
`
`Methicillin sodium
`
`Rapidly inactivated in solutions with a pH below 6.0
`Should not be infused in dextrose or dextrose-saline
`over a long period.
`
`Acid solutions may cause cloudiness or precipitation.
`Check dextrose solutions frequently for clarity during infusion.
`Adminisler during 6-8 hours.
`
`Novobiocin sodium
`
`Must not be added to dextrose infusions.
`Administer in saline or Ringers solution.
`
`Sulphadiazine sodium
`
`Incompatible with laevulose and very acid dextrose infusions
`may cause precipitation. May be administered in normal saline.
`
`pH of common infusion fluids (B.P.* or U.S.P. •• limits)
`
`Ammonium chloride
`Dextran 40 in 5% dextrose (Rheomacrodex in dextrose)
`Dextran 40 in Normal saline (Rheomacrodex in saline)
`Dextrose 5%
`Hartmann 's so:ution
`
`Mannitol 10%
`Protein hydrolysate
`Sodium chloride
`Sodium chloride 0.18% with Dextrose 4.3%
`Sodium lactate 1/6 molar
`
`4.o - 6.o··
`3.5 - 6.5·
`4.o
`7.o•
`3.5 - 6.5'
`5.o - 7.o·
`6.0 - 7.5 ..
`4.5
`7.o·
`5.0 - 7.0 ..
`4.5 - 7.0 ..
`3.5 - 6.5'
`5.0 - 7.0'
`
`indiscriminately. The makers recommend
`that apart from the cautious addition of
`heparin no other drug be added to infusion
`bottles of fat emulsions. These emulsions
`may however be given concurrently with
`saline or dextrose solutions provided that
`they are administered through a Y-tube
`placed just before the needle.
`Drug reaction with containers, closures or
`the
`Infusion set: A few drugs may be
`
`absorbed by rubber stoppers, e.g. those
`containing phenolic groupings, and glass
`itself has been reported to adsorb insulin
`from solution.2 Mercaptomerin must be
`injected
`through
`rustless needles and
`must not come into contact with aluminium
`fittings." The use of non-neutral glass
`containers,
`or
`surface-treated
`glass
`containers in which the film has become
`worn or scratched, may liberate alkali into
`
`344
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`December 1969
`
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`
`

`

`Table 2
`
`EFFECT OF ELECTROLYTES ON DRUG STABILITY
`
`Drug
`
`Amphotericin-8
`
`Electrolyte
`
`Sodium chloride
`
`Mannitol 20% (or
`higher concentra(cid:173)
`tions)
`
`Sodium bicarbonate
`
`Tetracycline or
`oxytetracycl ine
`
`Potassium chloride or
`sodium chloride
`
`Calcium ions
`
`Calcium (in neutral or
`alkaline solution) in
`alkaline Ringers or
`Ringer-Lactate solution
`
`Result
`
`Colloidal suspension
`broken, and coarse
`precipitate produced
`
`Crystallisation of mannito\
`due to "salting out"
`process
`
`Insoluble calcium salt
`precipitated
`
`Insoluble calcium complex
`precipitated
`
`the solution. Citrates and phosphates
`readily produce glass spicules in these
`bottles and the problem of preparing and
`storing sodium bicarbonate solutions in
`has been suspected of dissolving small
`quantities of electrolytes from solution.
`Reaction with oxygen or carbon dioxide:
`The bubbling of air through an infusion
`over a long period may cause a reaction
`with carbon dioxide or oxygen. Phenytoin
`sodium reacts with carbon dioxide libera(cid:173)
`ting the free base and producing a cloudy
`solution, and ascorbic acid, sodium
`p-amino hippurate and
`riboflavine are
`glass bottles without the deposition of a
`is still
`largely
`fine white precipitate
`unsolved. Doubts have also been raised
`about the inertness of plastic containers
`which may liberate plasticiser into solu(cid:173)
`tions stored in them and polypropylene
`sensitive to oxidation. Such solutions must
`be checked during the infusion for clarity
`and possible colour change.
`Light sensitivity: A few drugs are unstable
`to light and infusion bottles should not be
`exposed for prolonged periods to direct
`sunlight or strong artificial light. (See table
`3)
`It
`is
`recommended
`that bottles of
`amphotericin-B infusion be covered with
`black paper to prevent decomposition
`during administration.
`
`Microbiological contamination: Growth of
`micro-organisms within the infusion fluid
`may occur, particularly in warm climates
`and where the infusion is continued for a
`long period. This may produce either a
`febrile pyrogen reaction or infection. It
`may be preferable to use two half-litre
`flasks in place of a sin'gle litre bottle.
`Care should be exercised when adding
`infusion bottle. Although
`drugs to
`the
`completely aseptic conditions are unlikely
`to be attainable
`in
`the normal ward
`atmosphere, nursing personnel preparing
`infusions must wash their hands, work
`with a no-touch technique, preferably use
`a mask, and swab all rubber caps, etc_,
`with disinfectant before puncturing them
`with a needle.
`
`Table 3
`
`DRUGS SENSITIVE TO LIGHT
`
`Amphotericin-8
`
`N itrofurantoin-Sodium
`
`Su\phadiazine sodium
`
`Ribof\avine
`
`Tetracyclines
`
`Oestrogenic substances
`(f'remarin ®)
`
`December 1969
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`345
`
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`
`

`

`is a special risk with
`Contamination
`blood and deaths have been reported when
`in gross
`faulty technique has resulted
`contamination of these infusions. It seems
`advisable that no drugs whatsoever be
`added to blood prior to transfusion. Anti(cid:173)
`histamines
`and
`steroids
`are
`best
`administered separately to the patient and
`not added to the transfusion as is common
`practice in many hospitals.
`
`Dissociation constants of the drug: If the
`time taken for a certain percentage of a
`drug to react or break down under certain
`conditions
`is known, estimates can be
`made of the optimal and maximum time
`infusion can
`take place.
`during which
`Carlin and Perkins4 have published the Tm
`per cent values
`for several penicillins
`using the reaction data from chemical
`stability studies. The Tm per cent repre(cid:173)
`sents the time it takes for ten per cent of
`the drug to react, and has been taken as
`a reasonable standard for the
`time to
`measure the 10 per cent loss
`in drug
`potency which is acceptable during an
`infusion. At pH 5.0 the Tiu per cent of
`potassium penicillin-G is about 12 hours
`at 25°C. If ascorbic acid and vitamin B
`complex are added to a 5% dextrose
`solution of the antibiotic and this infusion
`has a pH of 3.65, the resulting T111 per cent
`is only 1.2 hours. The importance of these
`values is obvious since in the latter case
`the concentration of the penicillin in the
`vitamins-dextrose
`infusion during
`the
`last hour of an 8-hour infusion period
`would be about half that of the
`initial
`concentration, and after 12 hours only
`about one third of the original percentage
`would be left in the solution.
`
`Drug additives: The addition of a second,
`third or any additional drug to an infusion
`may seriously reduce the stability of the
`mixture and sometimes results in gross
`incompatibility. A great many charts
`reporting such drug incompatibilities have
`• 9• 111· and even a
`been pub I ished :,, G,
`7
`8
`•
`computerised compatibility-incompatibility
`
`print-out of mixtures of two drugs has been
`described.ll
`Many of these schemes utilise informa(cid:173)
`tion obtained from other charts since little
`basic data of the actual mechanism of
`drug instability and interaction has ~e~~
`published. Obvious visible incompat1bI1l(cid:173)
`ties have been noted where evolution of
`gas, change of colour or pH or preci~!ta(cid:173)
`tion occur, but many decomposItIon
`mechanisms result
`in no such obvious
`phenomena. The mixture is then reported
`as 'not incompatible' or 'not known', neither
`of which statement helps either the com(cid:173)
`pounder or the patient. These charts may
`be useful but suspect. More charts
`documenting substantiated drug com(cid:173)
`patibilities are urgently needed.
`
`Manufacturers' Information: It should be
`axiomatic that every drug firm should be
`able to provide full information on its own
`products, yet when letters were despatch(cid:173)
`ed
`to 26
`international and
`local
`firms
`asking for details on the stability of their
`products under varying conditions, only
`four manufacturers were able to provide
`comprehensive replies and of these only
`two producers gave actual percentage
`assay figures. Some firms did not reply.
`Some replies were ambiguous or unhelp(cid:173)
`ful. One firm stated that their product, a
`corticosteroid, should not be mixed with
`other drugs in the infusion flask, and that
`the pH of the infusion should be greater
`than 7.4, despite the fact that almost every
`common infusion fluid has a pH below 7.0.
`Another firm stated that to determine the
`stability of their anticoagulant would be a
`matter of trial and error, and that they
`could be of no further service!
`
`Previous surveys of commercial drug
`literature 1~- 1" have shown deficiencies in
`in manu(cid:173)
`the
`information published
`reference booklets
`facturers' standard
`and package leaflets. It is obvious that a
`very unsatisfactory situation exists if data
`are not available in reference books, have
`not been the subject of pharmaceutical
`
`346
`
`THE JOURNAL OF HOS!'ITAL PHARMACY
`
`December 1969
`
`This material wast:apied
`
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`
`

`

`research, and cannot be supplied by the
`manufacturers of the drug itself.
`As almost every large hospital routinely
`I. V.
`infusions containing added
`uses
`drugs, it would seem essential that this
`neglected field of drug research should be
`explored with vi'gour and in depth.
`Successful therapy is dependent upon
`a consideration of the causes of drug
`instabability and the correct application
`of knowledge to preserve the full activity
`of the drug and the vehicle during the
`period of the infusion.
`
`Acknowledgement
`Thanks are due to Dr. E. Superstine. Director of
`Pharmacy Services. and Dr. T. Sacks. Director of
`Clinical Microbiology, of
`the Hadassah Medical
`Organisation.
`for help and advice during
`the
`preparation of this work.
`
`References
`1. Developing a Parenteral Admixture Program-
`
`Laboratories
`
`Latiolais. C. J. and Godwin. H.N., Ohio State
`University Hospitals (1968)
`2. Hill, J. B .. Proc. Soc. exp. Biol. Med. 102.
`75-78 (1959)
`3. Myers. J. A., Pharm. J. 186, 245-247 (1961)
`4. Carlin, H. S. and Perkins, A. J., Am. J. Hosp.
`Pharm. 25, 271-279, (1968)
`5. Compatibility Guide - Cutter
`(1965)
`6. Patel, J. A. and Phillips, G. L., Am. J. Hosp.
`Pharm. 23, 409-411 (1966)
`7. Fowler, T. J., Am. J. Hosp. Pharm. 24, 450-457
`(1967)
`8. A Study on Parenteral
`Baxter Laboratories (1967)
`9. Physical Compatibilityof Parenteral Mixtures(cid:173)
`Abbott Laboratories (1968)
`10. A Guide for Combining Drugs in Intravenous
`lnfusions-Ben-Zeev, Z., Beilinson Hospital,
`Petach-Tiqvah, Israel (1969)
`11. Hodges, T. H. and Allen Scott, I., Hospitals,
`42, 103-105 (1968)
`12. Jacobs, J., Practitioner, 201, 483-490 (1968)
`13. Jacobs, J., Pharm. J. (In the press.)
`
`Incompatibilities(cid:173)
`
`Patients and their Hospitals
`KING Edward's Hospital Fund
`for
`Many complaints could be cured by
`London has recently published a
`imaginative
`organisation
`and
`good
`report on a survey intended to discover to
`management. At a press conference held
`to launch the report it was stated that there
`what extent the customers ( i.e. hospital
`appeared
`to be a close correlation
`patients) were
`satisfied with
`their
`between staff contentment and patient
`experiences
`in hospital. Questionnaires
`contentment and the report will surely
`were distributed to be answered in some
`underline to hospital authorities the need
`leaving hospital
`in
`cases just prior to
`for enlightened policies in the field of staff
`others at home immediately afterwards. A
`recruitment and training. The report gives
`response rate of 62% was achieved. No
`no support to those who would restrict the
`attempt was made to evaluate medical
`numbers of "visitors" to patients on wards
`treatment. The questions related to the
`(such as the various technicians and the
`experiences of patients with regard to the
`ward
`and
`its
`equipment,
`sanitary
`ward pharmacist) since 111 out of 131
`accommodation and
`facilities, meals,
`patients commenting on one question
`activities, care of patients and overall
`complained of boredom! I wonder if those
`who have visited the wards in this capacity
`contentment.
`The answers reflected grateful satis(cid:173)
`would support the contention that most
`faction
`in nearly all aspects but some
`patients welcome a friendly word with the
`criticisms stood out painfully-inadequate
`ward pharmacist as he or she examines
`sanitary facilities, early waking,
`lack of
`the prescription at the foot of the bed.
`information and so on. The overall picture
`pointed to the fact that patient satisfaction
`depends primarily on human or organisa(cid:173)
`tional factors rather than physical factors.
`
`(Patients and their Hospitals- A King's
`Fund Report. 12/6d. King Edward's
`Hospital Fund for London.)
`
`December 1969
`
`THE JOURNAL OF HOSPITAL PHARMACY
`
`347
`
`This material was copied
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1011, p. 8 of 8
`
`