Am J Hosp Pharm.
1981; 38:1308-14
Interactions between Drugs and Polyvinyl
Chloride Infusion Bags
Elizabeth A. Kowaluk, Michael S. Roberts,
Harvey D. Blackburn, and Alan E. Polack
Forty-six injectable drug products, many of which are admin­
istered hy i.v. infusion, were studied for loss from aqueous solu­
tions stored in polyvinyl chloride infusion bags for various peri­
ods of time.
The polyvinyl bags were stored in the dark at room tempera­
ture for up to three months. Drugs stored in glass vials served as
controls. The solutions were assayed spectrophotometrically at
regular intervals. The effects of drug concentration and pH on '
the loss of drug from solution were studied. Octanol-water p4r-,
tition coefficients were used as a gauge of lipid solubility of the
drugs.
Five of the drug products—clomethiazole edisylate, diaze­
pam, hydralazine hydrochloride, thiopental sodium, and war­
farin sodium—were found to be lost to a substantial extent after '
one week. For all drugs studied, the effect of the initial concen­
tration on drug loss varied. The amount of drug lost over a given
time was a function of the pH of the solution. The main physico'-
chemical determinants controlling drug sorption appeared to Be
the extent of ionization and the lipid solubility of the drug.
For most of the drugs studied, minimal losses from the aque­
ous solutions were observed over short periods of storage time.
Disappearance was slow and time dependent, indicating a diffu­
sion-controlled sorption process. The losses of clomethiazole
edisylate, thiopental sodium, and diazepam may be clinically
important.
Index terms: Absorption; Anesthetics; Anticoagulants; Clo­
methiazole edisylate; Concentration; Containers; Diazepam;
Diffusion; Hydralazine hydrochloride; Hydrogen ion concentre:
tion; Hypotensive agents; Injections; Ionization; Plastics; Poly­
vinyl chloride; Sedatives and hypnotics; Solubility; Stability;
Storage; Thiopental sodium; Warfarin sodium
Previous studies^-® have reported the loss of certain
drugs from aqueous solutions stored in plastic infusion bags,
for various periods of time. Generally, these losses have been
attributed to interaction between the drug and the plastic
infusion bag. Such interaction may result in reduced drug
delivery to the patient arid, in some cases, diminished ther­
apeutic response.
Documentation of the compatibility of substances cur­
rently administered by intravenous administration sets, with-
the plastic infusion bags used in certain systems, is lim­
ited.'"®-®"'' The most detailed evaluation of drug sorption by
plastic infusion bags is in the study of Moorhatch and
Elizabeth A. Kowaluk, Michael S. Roberts, Ph.D., HarveyJD.Blackburn,
M.S., and Alan E.Polack, Ph.D., are associated with theSchool of Pharmacy,
University of Tasmania.
Addresf reprint requests to Ms Kowaluk, School of Pharmacy, Uiiiversity
of Tasmania, Box 252C, GPO, Hobart, 7001, Tasmania, Australia.
The donations of Travenol Laboratories and other pharmaceutical man-
- ufacturers in Australia are acknowledged. The assistance of the hospital
pharmacy departments of Flinders Medical Center in Adelaide, Royal Hobart
Hospital in Hobart, and Alfred Hospital in Melbourne, is acknowledged.
Supported by a grant from the National Health and Medical Research
Council, Australia.
Presented at the Pharmaceutical Sciences Section of the Australian and
New Zealand Association for the Advancement of Science meeting, Adelaide,
Mayl980.,
Copyright © 1981, American Society of Hospital Pharmacists, Inc. All rights
reserved.
1308 American Journal of Hospital Pharmacy Vol 38 Sep 1981
Chiou,^ which reported on the sorption of 17 drugs. Although
only limited information is available on the compatibility
of drugs with polyvinyl chloride (the main resin in com­
mercially available plastic infusion bags), the sorption of
drugs by nylon and polyethylene has been evaluated ex­
tensively.®"'® As the availability of medication through the
iritravenous route is of critical importance in patient therapy,
it is essential to know not only which substances may be lost
• during.intravenous infusion, but also which drugs may be
safely admiriistered using plastic intravenous delivery sys-
.tems.
The present study was undertaken with the following
intentions:
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1. To survey a range of drugs, including those presently being
administered by intravenous infusion, for possible inter­
actions with plastic infusion bags,
2. To establish some of the pbysicocbemical variables that
control the"rate, extent, and mechanism of such interactions
to enable the subsequent development of criteria that may
be used to predict their occurrence, and
.3. Toassessthepossibleclinicalimplications, ifany, ofthose
interactions that were found to occur.
The study consisted of several parts, the first being a
preliminary survey of a ran^e of drugs to identify the drugs
that are lost from aqueous solution during storage in plastic
infusion bags. The main goal of the survey was to evaluate
the compatibility of niedicairients routinely used in infusions
by various Australian hospitals. The compatibility of anti­
neoplastic medications with plastic infusion bags was" not
examined in this survey because of their restricted avail­
ability and cost.
In the secorid part of the study, the relative losses of some
selected drugs in unbuffered aqueous solutions were com­
pared with the losses in solutions buffered at pH 7.4. This
study was undertaken because in situ phMmacologic studies
are usually performed with drug solutions maintained at a
pH of 7.4.13 ^
Methods
Table 1 lists the drug products used in the prelimipary
survey. The drugs norepinephrine bitartrate® and isopro­
terenol hydrochloride® were examiried; however, they were
found to be ui^table on storage and were not considered
further.
Studies of the loss of aU but two of the drugs from aqueous
solution during storage in plastic infusion bags were con­
ducted using 0.9% sodium chloride injection as the solvent.
The study of the loss of sodium nitroprusside was performed
with 5% dextrose,injection as the solvent, and the study with
clomethiazole edisylate used-the infusion solution supplied
by the manufacturer.
The preliminary survey was'conducted using Viaflex,
(polyvinyl chloride) infusion bags® containing'500 ml of 0.9%
sodium chloride injection or 500 ml of 5% dextrose injection,
in the case of sodium nitroprusside.
Each drug was prepared in an appropriate concentration
so that when a practical volume (50 ml or less) was injected
0002-9289/81/0901-1308$01.50
 Dnigs andpolyiriiqrl chlorideifltiision bags

Table 1. Drugs Used In the Preliminary Survey

Initial bifllal
Cone. Cone,
In in
- Infusion Initial infusion biRial
Solu­ pH Solu- pH
tion®" of tion^ of
^ftiax (pg/ Infusion Xma» (pg/ Infusion
Drug Product (nm) ml) Solution Drug Product (run) ml) Soiutlon
Acetazolamlde sodium^ 265 19® 8.4 Lidocaine hydrochloride"" 271 200 5.0
Aminophylline"' 272 9 7.5 Meperidine hydrochi'oride® 258 71 4.9
Amoxicillin trihydrate° 272 400 4.9 Metaraminol bitartrate® 272 68 4.0
Ampiciiiin trihydrate° 256 1400® 4.4 Methiciilin sodium® 281 80 5.3
Cefoxitin sodium' 235 14 5.1 Metronidazoid 277 30® 5.1
Cephaiothin sodium^ 237 10 5.2 Morphine hydrochloride' 285 75

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4.4
Chioramphenicoi sodium succinate'' 276 12 5.2 Phentoiamine mesylate® 278 18 5.0
Clomethiazole edisylate' (chlormethiazoie 257 8000® 5.3 Phenytoin sodium'" 258 114 8.9
edisylate) Practoloi® 245 10 5.5
Chiorpromazine hydrochloridd 254 9 5.1 Prednisoione"" 248 9 5.3
Cimetidine'' 218 6 5.1 Procainamide hydrochioride"" 275 8 5.2
Cloxacillln sodium® 273 500 5.2 Promazine hydrochioride' 252 6.4 5.0
Dexamethasone sodium phosphate' ' 241 9 6.0 FTomethazine hydrochioridei 249 8 5.0
Diazepam'' 275 8® 5.3 Propranoioi hydrochioride"" 290 20 5.2
Diethyistiibestroi diphosphate disodium' (disodium 240 10 6.0 Quinidine suifate®. 235 4.5 5.5
stiibestroi diphosphate) Quinine suifate" 235 6.75 5.3
Dopamine hydrochioride'® 280 72® 5.9 Ribofiavin"" 268 5 5.0
Doxycyiine" 275 15 4.6 Sodium nitroprussidel 394 5000 4.6
Fiucioxaciiiin sodium®- 273 200 5.1 Thiopentai sodiurpl 289 7 6.0
5-Fiuorouracii'" 266 10 5.4 Thioridazine hydrochioride* 263 6 5.0
Gentamicin suifate® . 336 • 40" 5.1 Tobramycin suifate" 336 20" 5.3
Hydraiazine hydrochloride'" 315 27 5.4 Trifluoperazine dihydrochioride'' 257 10 5.0
Hydrocortisone sodium succinate" (cortisoi) 248 9 . 5.6 Trimethoprim"" 280 25 7.4
Kanamycin suifate' • . 336 15" 5.2 Warfarin sodium® 309 22 6.7
® Diluted before assay. ' Bristol Laboratories, Crow's Nest, New South Wales 2065, Australia.
'' Aminoglycoside antibiotics chemicaily derivated before assay. "• Sigma Chemical Co., St. Louis, MO 63178, USA.
= Lederle Labs., St. Leonards, Mew Soutti Wales 2065, Australia. " Pfizer Inc., West Ryde, New South Wales 2114, Australia.
" David Bull Labs., Mulgrave, Victoria 3170, Australia. ° Sobering Corp., ^ulkhamHills, New South Wales 2153, Australia.
® Beecham Research Labs., Clayton, Victoria 3168, Australia. . P Upjohn Co., Rydalmere, New South Wales 2116, Australia.
' Merck Sharpe & Dohme, South Granville, New South Wales 2142, Aus­ Central Medical Store, Hobart, Tasmania 7000, Australia.
tralia. ' British Drug Houses, London, England.
» Glaxo, Boronia, Victoria 3155, Australia. , p Ciba Pharmaceuticals, Lane Cove, New South Wales 2066, Australia.
" Parke Davis & Co., Caringbah, New South Wales 2229, Australia. 'Wyeth Pharmaceuticals, Parramatta, New South Wales 2150, Aus­
' Astra Pharm. Products, Inc., Sodertalje, Sweden. tralia.
I May & Baker, Footscray West, Victoria 3012, Australia. " Drug Houses of Australia, Turrella, New South Wales 2205, Australia.
Smith Kline & French Laboratories, French's Forest, New South Wales " Sandoz Austraiia, Nth. Ryde, New South Waies 2113, Australia.
2086, Australia. " Eli Liily & Co., West Ryde, New South Waies 2114, Australia.

into the Viaflex bag, the dilution would restilt in the selected
initial concentration (Table 1). This initial concentration
was chosen so that the drug solution gave an ultraviolet ab-
sorbance (at its wavelength of maximum ahsorbance) be­
tween 0.2 and 1.0, which allowed assay without further
dilution in most cases. The exception to this was clomethi-
azole edisylate, where the initial concentration used was the
therapeutic concentration.
The required volume of the freshly prepared concentrated
drug solution was injected into the Viaflex bag, after the
withdrawal of an equivalent volume of the contents of the
bag. Then, the hag was shaken to ensure thorough mixing.
A quantity of each concentrated drug solution, sufficient to
achieve the same initial concentration, was introduced into
glass vials containing 100 ml of 0.9% sodium chloride injec-
tion'i or 5% dextrose solution to act as a control.
' In the case of clomethiazole edisylate, the Viaflex bags and
glass vials were first emptied of the 0.9% sodium chloride
injection, then rinsed with distilled water and left to drain
overnight. The Viaflex bags were then filled with 500 ml of
clomethiazole edisylate 0.8% infusion solution, and the glass
vials with 100 ml of the same solution.
The study of loss of each drug was rim at least in duplicate.
The Viaflex infusion hags and glass vials were stored
(hanging up in the case of the hags) in the dark at room
temperature (15-20 °C) for up to three months in most cases
(one week in the case of some antibiotics). All containers,
Viaflex hags, and glass vials containing sodium nitroprusside
and riboflavin solutions were wrapped in aluminum foil to
minimize exposure to light.
An aliquot of drug solution was removed from each Viaflex
hag and glass vial immediately after the introduction of the
drug and at regular intervals during storage. The solutions
were assayed for drug content. The withdrawal of drug so­
lutions was preceded by agitation of the solution. The pH
of the drug solution in each bag and vial was measured at
time of assay with a Metrohm Hensau E520 pH meter.
Assay of Drug Solutions. All the samples were assayed for
drug content using a Beckman DB-G grating spectropho­
tometer. The wavelength of maximum ahsorbance for each

Vol 38 Sop 1981 American Journal of Hospital Pharmacy 1309

 Drugs and polyvinyl chloride Inluslon bags
drug was determined (Table 1). Blank solutions containing
all components except the drug were used for adjustment of
zero absorbance. In all cases, the drug solutions followed
Beer's law over the concentration range studied. Samples
of the following drug solutions were diluted immediately
before assay: (1) acetazolamide sodium, solutions were di­
luted 1:1 with phosphate buffer pH 8.1; (2) ampicillin Iri-,
hydrate solutions were diluted 1:1 with phosplmte buffer pH
7.4; (3) amoxicillin trihydrate and metronidazole solutions
were diluted 1:1 with 0.2 N hydrochloricacid; (4) diazepam
and dopamine hydrochloride solutions were diluted 1:1 with
0.2 N sulfuric acid; and (5) clomethiazole edisylate solutions
were diluted 1:200 with distilled water.
The aminoglycoside antibiotics, gentamicin sulfate, ka-
namycin sulfate, and tobramycin sulfate, were assayed using
the chemical derivatization procedure of Csiba.!'*-!® This
procedure involved the preparation of Ihe dihydrolutidine
derivative of the aminoglycoside and its subsequent spec-
trophotometric determination. In this study absorbance was
measured at 336 nm rather than at 356 nm as suggested by
Csiba.i5 _ tion:
Samples of all other drug solutions were assayed undi­
luted.
The difference, if any, between the amount of drug in so­
lution in the Viaflex bag and the amount in solution in the
glass vial at any specific time was taken to be the amount of
drug lost from solution during storage in the plastic infusion
bag. Each result reported is the mean of the assays of at least
two containers. The coefficient of variation for the assays was
less than 10%. , -
Effect of pH on Loss. The effect pjf the pH of the drug
solution in the plastic infusion bag on loss of drug from so­
lution was studied for a number of selected drugs by buf­
fering the solutions to a pH of 7.4 with a final phosphate
buffer concentration of 0.02 M.
The experimental procedure was the same as the one used
for the preliminary survey except that 50 ml of 0.9% sodium ^
chloride injection from the Viaflex bags and 10 ml of 0.9%
sodium chloride injection from the glass vials were replaced
by an equivalent volume of a concentrated, solution of the
phosphate buffer (0.2 M). The initial concentrations were
the same as in the preliminary survey.
Effect of Initial Concentration on Loss. The effect of
varying the initial concentration of a drug solution on the loss
of the drug was studied for a selection of drugs that showed
losses of greater than 10% either from solutions buffered to
pH 7.4 or from unbuffered solutions after storage for one
week in plastic infusion bags.
These drugs were clomethiazole edisylate, hydralazine
hydrochloride, thiopental sodium, and warfarin sodium in
unbuffered solutions and chlorpromazine hydrochloride,
promazine hydrochloride, and promethazine hy^ochloride
in buffered solutions.
Octandl-Water Partition Coefficients. Literature vedues
for octanol-water partition coefficients have been used for
all drugs studied where possible. When these values were not
available for given compounds, partition coefficients were
determined experimentally as follows. An aliquot of each
1310 American Journal of Hospital Pharmacy Vol 38 Sep 1981
drug solution was added to an aliquot of n-octanol® (ana­
lytical grade), which h^ Bfeen saturated with the particular
, diluent being used, in a glass bottle. (The proportions of
aqueous phase to octanol phase were varied from 1:1to 250:1
according to the affinity of a given drug for octanol.) Each
bottle was sealed and agitated periodically during its storage
in the dark at room temperature. Two aliquots of the drug
solution were also placed into separate 50-ml glass bottles
to act as controls. The aqueous phase was analyzed at weekly
intervals until equilibrium was achieved. To prepare the
solutions for assay, the content of the sample bottles was
centrifuged at 3000 rpm for 10 minutes to.achieve as com­
plete as possible separation of aqueous and octanol phases.
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The octanol was aspirated off together with about,1 ml of the
aqueous phase. The remainder of the aqueous phase was
assayed spectrophotometrically (Table 1) and compared
with the absorbance of the drug solutions from the control
bottles.
The apparent octanol-water partition coefficients were
determined for each drug according to the following equa­
K = [(Awi - AWF)/AWF] [V„A^O] (1)
where K is the apparent octanol-water partition coeffi­
cient, AWI is the initial absorbance of the aqueous drug so­
lution, AWFis the the final absorbance of the aqueous drug
solution, Vw is the volume of the aqueous phase, and VQ is
the volume of the octanol phase. .
The apparent octanol-water partition coefficients for all
of the drugs were adjusted for the pH of the individual
infusion solutions using the following equation:
Pinfus ~ Pcopr (1 ~ Cfinfus) ~ Papp (1 ~ OJjnfualAl ~ O^app) (2)
where Pinfua is the apparent octanol-water partition coeffi­
cient for a drug in a given infusion solution, Pcorr is the true
octanol-water partition coefficient (i.e., octanol-water par­
tition coefficient of the unionized drug), Pgpp is the experi­
mentally determined octanol-water partition coefficient, and
.«mfu8 and ftapp are the degree of ionization of drug in the
infusion solution and aqueous solution used for partition
coefficient determination, respectively.
Results and Discussion
Preliminary Survey.-Only five of the 46 drug products
examined showed substantial loss after storage in plastic
infusion bags for one week—clomethiazole edisylate, di­
azepam, hydralazine hydrochloride, thiopental sodium, and
warfarin sodium (Table 1). Except for the phenothiazines,
quinine sulfate, quinidine sulfate, and prednisolone, all drugs
showing negligible loss from solution, had apparent octa­
nol-water partition coefficients less than 5.
The majority of drugs appeared to be relatively stable in
aqueous solutions stored in glass containers. After one week
of storage, only methicillin sodium and cephalothin sodium
showed any change in absorbance. Iii both cases an increase
in absorbance was observed.

Figure 1shows the time course of the disappearance of
clomethiazole edisylate, diazepam, hydralazine hydrochlo­
ride, thiopental sodium, and warfarin sodium from aqueous
solutions stored in plastic infusion bags. For clomethiazole
edisylate, diazepam, and thiopental sodium, approximately
. 33, 20, and 23%, respectively, was lost after 24 hours of
storage. Such losses can clearly ^fect clinical studies because
it is necessary to know the . rate of drug delivery during
, infusion to correctly calculate bioavailability and phar­
macokinetic variables such as the clearance and apparent
volume of distribution.^ In addition, the losses may prove
to be of clinical importance if these drugsare administered
by intravenous infusion using plastic infusion bags as part
of the delivery system.
Concentration. The extent of the loss of solutes from
aqueous solutions stored in plastic infusion bags was found
to be concentration-dependent; for each drug studied, the
greatest amount was lost at the highest concentration used.
Figures 2,3, and 4, respectively, show representative plots
of the'percentage of thiopental sodium, chlorpromazine
Figure I, Percentage of selected drugs remaining in unbuffered aqueous
solutions during storage in plastic infusion bags: (•) warfarin sodium 22
pgiml,(•) hydralazine hydrochloride 27 pg/ml,(A) diazepam 8 pg/ml, (•)
clomethiazole edisylate 8 mg/ml, (O) thiopental sodium 7 pg/ml.
200 . 400 eoo
TIME (HOURS)
Figure 2:- Effect of initial concentration on percentage of thiopental sodium
remaining inunbuffered aqueous solution during storagein plastic infusion
bags: (•) 2.8 pg/ml, (•) 14 pg/ml, A 28 pg/ml.
50 • 100 lio
TIME (HOURS)
Dnigt andpolriinyl cMoiide kKiolonbagi
hydrochloride, and clomethiazole edisylate remaining for
various initial concentrations. The percentage of thiopental
sodiiun remaining in solution at any speciHc time was
greatest at the highest concentration used (Figure 2). This
suggested that thiopental sodium interacts with only a
limited number of "binding" sites, resulting in a saturable
sorption process. This type of sorption process was also ob­
served for warfarin sodium and hydralazine hydrochloride.
Similar processes have been reported previously for the
uptake of warfarin sodium by infiision-hag plastic^ and for
butyric acid by nylon.®
For phenothiazine drugs, the percentage remaining in
solution during storage in plastic bags v/as independent of
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initial concentration (Figure 3). For these drugs binding
appears to foUow a "partitioning" process. A similar rela­
tionship between fractional loss and concentration was de­
scribed for nitroglycerin,® vitamin A acetate, sodium
methohexital,'' and isosorbide dinitrate.^
The percentage of clomethiazole remaining in solution at
a specific time was found to decrease with increasing con-
Figures. Effect of initial concentration on percentage of chlorpromazine
hydrochloride remaining in buffered (pH 7.4) aqueous solution during
storage in plastic infusion bags: (O) 9 pg/ml, (•) 18 pg/ml, (A)27 pg/ml.
S"
i
S
iW
50 no 150
TIME (HOURS)
Figure 4. Effect of initial concentration on percentage of clomethiazole
edisylate remainingin unbuffered aqueous solution during storagein plastic
infusion bags: (A) 2 mg/ml, (•) 4 mg/ml,(•) 6 mg/ml,(•) 8 mg/ml
Vol 38 Sep 1981 American Journal of Hospital Pharmacy 1311
 Drugs and polyvinyl chloride Infusion bags
centration (Figure 4). During storage, the bags containing
clomethiazole edisylate solutions seemed to become softer
and more pliable, particularly at the higher concentrations.,
The distinctive odor of the solution was detectable in the
immediate vicinity of the bags. It was apparent that clo­
methiazole edisylate altered the prpperties of the plastic and
that this effect was a function of its concentration. Autian®
reported a similar effect for the sorption Of phenol by nylon
and for the interaction of certain types of esters with rigid
polyvinyl chloride bottles. He suggested that this occurred
as a result of the tendency of these substances to act.as sol­
vents for the plastics,® in some instances causing greater
polymer-chain flexibility through plasticization.^^ It is
probable that clomethiazole acts in asimUar manner. At high
concentrations it "plasticizes" or ^'swells" the polyvinyl-
chloride resin of the infusion bag. In this way, it enhances
its own sorption and possibly its permeation through the
plastic also. Fluck® and Roberts et al.^® reported altered
sorption and permeability characteristics for plastics in
contact with some organic solvents, as well.
pH and Partition Coefficient. Figures 5 and 6 show plots
of the percentage of thiopental sodium and promethazine
hydrochloride, respectively, remaining in unbuffered and
buffered (pH 7.4) aqueous solutions stored in plastic infusion
bags for various periods of time. For the acidic drug thio­
pental sodium, sorption was fastest when the solution was
unbuffered (pH 6.0) (Figure 5). At this pH, a greater pro­
portion of the drug was unionized than at a pH of 7.-4. In
contrast, sorption of the basic drug promethazine was much
greater at a pH of 7.4 when 1.96% of the drug was unionized,
rather than at a pH of 5 when only 0.008% of the drug was
present as the unionized form (Figure 6).
Table 2 sbows that the percentage of other drugs lost from
aqueous solutions stored in plastic infusion bags for one week
was also a function of the solution pH. For a given drug, the
extent of loss appeared to be directly related to the fraction
unionized. In accordance with the classical pH-partition
hypothesis, the greatest loss occurred for the drugs with the
highest apparent octanol-water partition coefficients (Table
FJgure B. Effect of pH of infusion solution on percentage of thiopental
sodium remaining in aqueous solution during storage in plastic infusion
bags: (•) buffered pH7.4, (•) unbuffered pH cs 6.0.
100 "soo MO"
TIME (HOUMI
1312 American Journal of Hospital Pharmacy Vol 38 Sep 1981
2). The correlation between percentage of drug lost during
the storage of aqueous solutions in plastic infusion bags for
one week and the apparent octanol-water partition coeffi­
cient (Papp) (Table 2) was poor (r = 0.645, n = 23). There­
fore, equation 3, which describes that relationship, was of
limited value in predicting the probable losses of other
drugs.
percentage loss = 0.005 Papp + 20.3 (3)
The poor correlation between the percentage loss and the
apparent octanol-water partition coefficient can be partly
ascribed to the inability of equation 3 to encompass thedy­
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namic nature of the sorption process. For example, drugs
with a high apparent octanol-water partition coefficient and
a low percentage unionized (less than 0.1%) show a lower
percent loss than predicted by equation 1; for those the
percentage loss is governed by the rate of sorption of un­
ionized drug.
Since the pH values of various infusiqn solutions available
for clinical use vary,i® it is possible to minimize tbe sorption
of some lipophilic drugs by plastic infusion bags over short
storage times by using infusion solutions with a pH such that
the drugs are almost completelylonized in solution. Alter­
natively, a different J.v. delivery,system i or storage in a re­
frigerator" could be used to minimize loss. Consideration
of the pH of the solution in studies on drug-plastic interac­
tion should'be applied in clinical situations.
The extent of loss of drugs stored in plastic infusion bags
may be enhanced by a reduction of the solution volume® or
chemical instability.^®'^® These effects should be considered
also in the use and storage of solutions in plastic infusion
bags.
Conclusion
For most of the drugs studied, minimallosses of the drug
from its aqueous solutions stored in plastic infusion bags over
short time periods were observed. However, losses of clo-
Figure S. Effect of pH 6f infusion solution on percentage of promethazine
hydrochloride remaining in aqueous solution during storage in plastic
infusion bags: (•) buffered pH 7.4, (•) unbuffered pH 5.0.
i
w
o 40
loo "MO JOO"
TIME (HOURSI
 Drugs and polyvinyl chlmtde Infusionbags

Table 2. Loss of Drugs from Buffered and Unbuffered Aqueous Solutions Stored In Plastic Intusion Bags for One Week
Buffered (pH 7.4) UniNiflered
Apparent Apparent
Initial Acid Octanol-Water Octanol-Water
Concentration or % Partition % Partition
Drug (pg/ml) Base pKa %L0St Unionized Coefficient pH %Lost Unionized Coefficient
Clomethlazole edisylate 4000 . base 3.2 42 99.99 132® 5.9 43 99.8 132®
Chlorpromazlne hydrochloride 9 base 9.3 86.3 1.24 1778® 5.1 5 0.006 9®
Diazepam 8 base 3.4 36 99.99 457® 5.3 32 98.7 456®
Hydralazine hydrochloride 15 base 7.0 —h 71.0 573® 5.1 10 1.24 10®
LIdocalne hydrochloride 200 base 7.9 3.5 24.0 24® 5.0 Ni 0.13 <1®
Procainamide hydrochloride 8 base 9.2 3 1.56 <1® 5.2 N 0.01 <1®
Promazine hydrochloride 6.4 base 9.4 47.6 0.99 355® 5.0 N 0.004 1®
Promethazine hydrochloride 8-. base 9.1 59.1 1.96 • 759® 5.0 5 0.008 3®
Thiopental sodium 7 acid 7.6 27.5 61.3 606®. 6.0 36.5 97.6 965'

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Thioridazine hydrochloride 6 base 9.5 89.2 0.79 6275® 5.0 N 0.003 24®
Trifluoperazine dihydrochlorlde 10 base 8.1 90.5 16.6 17915® 5.0 N 0.08 86®
Warfarin sodium 22 acid 5.0 N 0.4 1.2S 6.7 15.3 1.96 68
® Determined experimentally.
'' Calculated from experimental values.
•= Reference 19.
" Calculated using ttie values In reference 19.
® Reference 20.
' Calculated using ttie values In reference 20.
3 Calculated using the values In reference 21.
'' No value was obtained because of degradation.
' Negligible loss was observed.

methiazole edisylate, thiopental sodium, and diazepam, as
well as previously reported losses of nitroglycerin® and iso-
sorbide dinitrate,^ are important in clinical pharmacokinetic
studies involving continuous intravenous infusions of these
drugs. These losses may also prove to be clinically important
if these drugs are administered parenterally with plastic
intravenous delivery systems.
In addition, the observed losses of a number of drugs from
aqueous solutions buffered at a pH of 7.4 are of importance
in pharmacologic studies. Such losses may provide sources
of error if the solutions of the drugs, which are maintained
at physiological pH, come in contact with a plastic perfusion
apparatus.
The extent of ionization and the lipid solubility of a drug
are among the main physicochemical determinants of its
sorption by plastic infusion bags. For the majority of ther­
apeutic substances, most of which are either ionized in
infusipn solution or polar, sorption by the infusion bag is
unlikely to he proven to be clinically important. However,
this study and previous studies have demonstrated that
substantial sorption of a number of drugs to plastic infusion
hags does occur. Therefore, caution should he exercised in
the administration of new therapeutic substances by plastic
intravenous delivery systems.
• Levophed, Winthrop Labdratories, Ermington, New South Wales 2115,
Australia. (Previously named Levarterenol bitartrate).
Isuprel bydrocbloride, Winthrop Laboratories.
® Travenol Laboratories, Old Toongabbie, New South Wales 2146, Aus­
tralia, (Batch Nos. P65S1, P67S9, P69S6, PTOWS for 0.9% sodium chloride
injection and P66X4 for 5% dextrose injection).
•' Astra Chemicals, Nth. Ryde, New South Wales 2113, Australia, Batch
No. 9094/1.
» British Drug Houses Chemicals Ltd., Poole, England.
References
1. Clossum PA, Roberts MS. Availability of isosorbide dinitrate,
diazepam and chlormethiazole from i.v. delivery systems. Eur
J Clin Pharmacol. 1981; 19MI-5.
2. Parker WA, Morris ME, Shearer CA. Incompatibility of di­
azepam injection in plastic intravenous bags. Am J Hasp
Pharm. 1979; 36:505-7.
3. Cloyd JC, Vezeau C, Miller KW. Availability of diazepam from
plastic containers. Am J Hasp Pharm. 1980; 37:492-6.
4. Moorhatch P, Chiou WL. Interactions between drugs and
plastic intravenous fluid bags, part 1: sorption studies on 17
drugs. Am J Hasp Pharm. 1974; 31:72-8.
5. Roberts MS, Cossum PA, Galbraith AJ et al. The availability
of nitroglycerin from parenteral solutions. J Pharm Pharmacol.
1980;32:237-44.
6. Weber SS, Wood WA, Jackson EA. Availability of insulin from
parenteral nutrient solutions. Am J Hosp Pharm. 1977; 34:
353-7.
7. Chow Tung E, Gurwich EL, Sula JA et al. Stability of five an­
tibiotics in plastic intravenous solution containers of dextrose
and sodium chloride. Drug Intell Clin Pharm. 1980; 14:848-
50.
8. Autian J. Interaction between medicaments and plastics. J
Mond Pharm. 1966; 4:316-41.
9. Fluck H. Permeability and sorption of plastic containers. J
Mond. Pharm. 1966; 3:282-303.
10. Roberts MS, Polack AE, Martin G et al. The storage of selected
substances in aqueous solution in polyethylene containers: the
effect of some physicochemical factors on the disappearance
kinetics of the substances. Int J Pharm. 1979; 2:295-306.
11. Jordan DO, Polack AE. The permeation of organic solutes in
aqueous solution through polyethylene membranes. II. Effect
of concentration, temperature and other variables. Aust J
Pharm Sci. 1972; NSl:82-7.
12. Autian J. Plastics and medication. In: Martin EW ed. Dis­
pensing of medication. Easton, PA: Mack Publishing Company,
1971:652-715.
13. Krieglstein G, Krieglstein J, Urban W. On the interaction of
various drugs with synthetic materials used in pharmacological
apparatus. Arzneim Forsch. 1972; 22:1538-40.
14. Csiba A. Spectrofluorimetric method for aminoglycoside anti­
biotics. J Pharm Pharmacol. 1979; 31:115-6.
15. Csiba A. Colprimetric determination of aminoglycoside anti­
biotics as dihydrolutidine derivatives. Magy Kem Foly. 1979;
85:166-70. In: Ana( Afcsfr 1980; 38:198. Abstract.
16. Australian pharmaceutical formulary and handbook, 12th ed.
Unley, South Australia: Pharmaceutical Association of Australia
and New Zealand; 1978,256.
17. McNiff BL, McNiff EF, Fung HL. Potency and stability of ex­
temporaneous nitroglycerin infusions. Am J Hosp Pharm. 1979;

Vol 38 Sep 1981 American Journal of Hospital Pharmacy 1313

 Drugs and polyvinyl chloride Infusion bags/Catecholamlnes and terbutallne sulfate
36:173-7.
18. Newton DW. Physicochemical deteiininantsof incompatibility
and instability in injectable drug solutions and admixtures. Am
JHosp Pbarm. 1978; 35:1213-22.
19. Hansch C, Leo A. Substituent constants for correlation analysiis
in chemistry and biology. New York: John Wiley & Sons,
Am J Hosp Pharm. 1981; 38:1314-9
Stability of Five Catechoiamines and
Terbutaiine Sulfate in 5% Dextrose
injection in the Absence and Presence of
Aminophyiiine
David W. Newton, Esther Yin Yee Fung, and
David A. Williams
The stability of dopamine hydroc^ride, epinephrine hydro­
chloride, isoproterenol hydrochloride, methyldopate hydro­
chloride, horepinephrine bitartrate, and terbutaiine sulfate" in
5% dextrose injection with and without aminophyiiine was eval­
uated.
Kinetic data were obtained from the stability-indicating,
high-performance liquid chromatographic assay method for au-
toxidation of the five sympathomimetic catecholamines and
terbutaiine sulfate. ,
The autoxldation of epinephrine hydrochloride, isoprotere­
nol hydrochloride, norepinephrine bitartrate, and terbutaiine
sulfate was much faster in the alkaline solutions (pH 7.7-8.1)
containing aminophyiiine than in the acidic solutions (pH 3.9-
4.5) without aminophyiiine. On a molar basis among ^2 agon­
ists, terbutaiine sulfate was considerably more stable than epi­
nephrine hydrochloride or isoproterenol hydrochloride. The au­
toxldation of terbutaiine sulfate and the five catecholamines
followed apparent zero-order kinetics. The rate constants "and
degradation times to fall to 90% df original potency were deter­
mined for each drug. Visual Inspection was found to be grossly
inadequate for estimating the stability of catecholamines to au-
.toxidation.
Epinephrine hydrochloride, norepinephrine bitartrate, and
isoproterenol hydrochloride should not be combined with ami­
nophyiiine or similarly alkaline drugs in LVP solutions. The
stability of very potent and life-saving drugs prepared for i.v.
admixtures must be studied with stability-indicating assay
methods.
Index terms: Additives; Aminophyiiine; Bronchodilators; Dex­
trose; Dopamine hydrochloride; Epinephrine hydrochloride;
Hydrogen ion concentration; Incompatibilities; Injections; Iso­
proterenol hydrochloride; Kinetics; Methyldopate hydrochlo­
ride; Norepinephrine hydrochloride; Rate constants;Spasmoly­
tics; Stability;Sympathomimetic agents; Terbutaiine sulfate
David W; Newton, Ph.D., is Associate Professor, Department of Pharma­
ceutics, College of Pharmacy, The University of Nebraska Medical Center.
Esther Yin Yee Fung, M.S., is a pharmacist. Tiers Drug Store, Uxbridge,
Ontario, Canada. David A. Williams, Ph.D., is Associate Professor, De­
partment of Chemistry, Massachusetts College of Pharmacy and Allied
Health Sciences, Boston.
Address reprint requests to Dr. Newton, Department of Pharmaceutics,
The University of Nebraska Medical Center, 42nd and Dewey Avenue,
Omaha, NE 68105.
Donations of drug samples by American Critical Care, Ciba Pharmaceutical,
Merck Sharp & Dohme, and Sterling-Winthrop are acknowledged. The as­
sistance of Donna Eamshaw is acknowledged.
Abstracted in part from a thesis submitted to the graduate school, Mas-
sachusetto College of Pharmacy and Allied Health Sciences, in partial ful­
fillment of the requirements for the M.S. degree.
Copyright © 1981, American Society of Hospital Pharmacists, Inc. All rights
reserved.
1314 American Journal of Hospital Pharmacy Vol 38 Sep 1981
,1979.
20. Kurz H, Michels H, Stickel HH. Differences in the binding of
drugs to plasma proteins from newborn and adult man II. Eur
J Clin Pharmacol. 1977; 11:469-72.
21. Julkunen RJK. The absorption of warfarin from the rat small
intestine in-situ. J Pharm Pharmacol. 1976; 28:493-7.
The autpxidation® of phenolic drugs, catecholamines,
and related sympathomimetics is a common stability
problem. Several of these life-saving drugs, particularly
the ^2 agonists epinephrine hydrochloride and isoproterenol
hydrochloride, may be administered concurrently by in­
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travenous infusion, possibly in i.v. admixtures, with ami­
nophyiiine in clinical exigencies such as status asthmaticus
and anaphylaxis.''-"' The pharmacologic efficacy of these
drugs is directly related to the stability of %ir phenolic
hydroxy (Ar—OHjb groups.^-H.iz An alkaline pH, such as
that of aminophyiiine injection (8.6-9.0),i3 is a major de­
terminant of the autoxidation of Ar—OH to form lesssym-
pathomimetically potent quinones (Ar=0).i-® -
The usual agents that catalyze the oxidation of colorless
phenolic drugs, often to colored products such as the semi-
quinones, quinones, and adrenochromes, were reviewed
elsewhere.'^-'® The phenoxide anion (Ar—0") is more sus­
ceptible to oxidation than the undissociated Ar—OH group,,
and the oxidation rate of the—OH, group decreases in the
order of the ortho, para, and meta positions.
The chemical stability of several sympathomimetic cat­
echolamines mixed with large-volume parenteral (LVP)
solutions has been reported.These studies^®''''-^!
found that catecholamine degradation (autoxidation) in­
creases sharply above a pH of 6. Thus, substituting a typical
pKa of 9 for the most acidic phenolic —OH group into
equation 1,14-22 it is apparent that as little as 0.1% of phen­
oxide ion can catalyze the oxidation of Ar—OH to Ar=^ at
apHofe.
% dissociated = 100/[1 -I- antilog (pKa - pH)] (1)
There appear to be no published data on'the stability of
catecholamines in i.v. admixtures with aminophyiiine, al­
though warnings against preparing such solutions ^ve been
proffered.i®-2® The purpose.of this investigation was to obtain
kinetic data through a stability-indicating assay method for
the autoxidation of five sympathomimetic catecholamines
and terbutaiine sulfate mixed with 5% dextrose injection in
the presence and absence of aminophyiiine. Although cur­
rently terbutaiine sulfate is only approved for subcutaneous
injection, it was included because of its investigational i.v.
use in treating premature labor.
Methods °
HPLC Assay. A paired-ion high-performance liquid
chromatographic (HPLC) assay using a variable wavelength
fluorometric detector was developed because it offered the
advantages of: (1) expediency, (2)specificity and sensitivity
0Q02-9289/81/0901-1314$01.50