REVIEW ARTICLE Nutrition Vol. 14, No.

9, 1998

Compatibility and Stability of Additives in

Parenteral Nutrition Admixtures

MICHAEL C. ALLWOOD, PHD, AND MELANIE C. J. KEARNEY, PHD

From the Medicines Research Unit, University of Derby, Mickleover, Derby, United Kingdom

Date accepted: 1 September 1997

ABSTRACT
The addition of additives (electrolytes, trace elements, and vitamins) to parenteral nutrition (PN) mixtures can lead to
precipitation as a result of physical incompatibilities and can lead to chemical degradation of individual ingredients. The most
significant cause of precipitation is excessive concentrations of calcium phosphate. The most significant cause of chemical
instability is the oxidation of specific vitamins. The factors influencing calcium phosphate solubility include the commercial
amino acid source, the calcium and phosphate salts used, temperature, magnesium concentration, and final volume. Precipitation
can be avoided by organic phosphates. Trace element precipitation is most commonly caused by the formation of iron phosphate
salts or copper cysteinate in cysteine-containing amino acid infusions. The least stable nutrient is ascorbic acid, which reacts with
oxygen, and is catalyzed by copper ions. Oxygen originates from PN ingredients, the filling process, air remaining in the bag after
filling, and oxygen permeation through the bag wall. Storage in multilayered bags with reduced gas permeability can protect
residual ascorbic acid. Other chemical losses are caused by the reduction of thiamine by metabisulfite, and photodegradation of
daylight-sensitive vitamins, especially retinol and riboflavin, during administration. Nutrition 1998;14:697–706. ©Elsevier
Science Inc. 1998

Key words: parenteral nutrition, additives, electrolytes, trace elements, vitamins, precipitation, chemical degradation

INTRODUCTION viewed include electrolytes, trace elements, and vitamins. Mech-

anisms to avoid these unfavorable reactions are considered.
The compounding of parenteral nutrition (PN) admixtures in
large volume plastic containers (“big bags”) leads inevitably to ELECTROLYTES
infusions that are less stable than the constituent components. The
individual injections used in the compounding of any mixture are All PN regimens must contain a range of essential electrolytes,
manufactured as relatively stable products with shelf-lives mea- some of which must be included within a particular concentration
sured in years. Stability is maintained by optimizing both the range (for example potassium and sodium coincident with the
formulation and packaging of the products. Once each injection or clinical condition of the patient), whereas others must be present
in amounts at least sufficient to provide a minimum daily require-
infusion has been removed from its original container and mixed
ment (for example calcium, magnesium, and phosphate). Individ-
with other parenteral ingredients, the chemical stability of the
ual patient requirements depend on a number of factors, such as
active ingredients and also any excipients will be compromised. In clinical condition, age, renal function, and their level of physical
addition, the mixing of various compounds may lead to loss of activity. Electrolytes in PN mixtures normally retain their chem-
physical compatibility by formation of new salts of low aqueous ical status, although certain electrolytes can cause physical incom-
solubility compared with constituent chemical components, lead- patibilities.
ing to precipitation. The monovalent ions do not pose any significant physical
It is the purpose of this review to consider the possible causes compatibility problems, and high concentrations are generally
for chemical degradation and physical incompatibility in PN ad- tolerated in PN mixtures. In contrast, precipitation can derive from
mixtures that involve parenteral additives, and to relate the sig- di- and trivalent ion interactions, in particular calcium and phos-
nificance of these changes to clinical consequences. phate. Although, in practice, normal daily requirements for adults
For the purpose of this review, the parenteral additives re- can be included in PN mixtures without causing precipitation,

Correspondence to: Professor M. C. Allwood, PhD, Medicines Research Unit, University of Derby, Mickleover, Derby DE3 5GX, UK. E-mail:
M.C.Allwood@derby.ac.uk

Nutrition 14:697–706, 1998

©Elsevier Science Inc. 1998 0899-9007/98/$19.00
Printed in the USA. All rights reserved. PII S0899-9007(98)00063-X
698 ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION

FIG. 1. Speciation of inorganic phosphate in parenteral nutrition mixtures.

physical incompatibilities can arise in attempting to achieve the largely determined by the concentrations of arginine, histidine,
greater daily needs of children and neonates due to the low final and lysine.5
volume (i.e., highly concentrated) typically delivered. An under-
standing of the causes of calcium phosphate precipitation can lead The amino acid concentration in the final mixture.3,6,7 This
to compounding strategies that maximize the amounts of calcium will depend on both the amino acid concentration in the original
and phosphate ions that can be added safely to PN mixtures. infusion and the total volume of the PN mixture, which results in
altering the buffering capacity (increasing the final amino acid
Factors Influencing Calcium Phosphate Compatibility in Total concentration enhances buffering capacity and vice versa).
PN Mixtures
In aqueous solutions containing phosphate salts, an equilib- The type and final concentration of phosphate injection. In-
rium will be established between the three ionic phosphate spe- organic phosphate additives are available as a mixture of mono-
cies; the trivalent phosphate ion and its monobasic (H2PO2 and dibasic salts with either sodium and potassium as the counter
4 ) and
dibasic (HPO2 ion, producing formulations that form strong buffers with pH
4 ) forms (Fig 1). The pKa values for the two
equilibria give an indication of the predominant phosphate species values in the range of 5.0 – 6.5. This pH depends on the ratio of the
at any particular solution pH. The tribasic phosphate species will two phosphate ions. Alternatively, a monobasic phosphate injec-
not normally be present in PN admixtures because of the extreme tion can be used, containing, for example, potassium dihydrogen
alkalinity necessary for it to become ionized. Both mono- and phosphate. The pH of this injection is approximately 5.0. This
dibasic phosphate salts may form a salt with calcium, but the monobasic phosphate injection can therefore be used to enhance
dibasic salt is the least soluble of the two options. The solubility the amounts of phosphate and calcium that can be added to total
of the monobasic and dibasic calcium salts are 1.8 and 0.03% w/v, parenteral nutrition (TPN) mixtures without causing precipita-
respectively.1 For example, at physiologic pH (7.4), approxi- tion,3,6,8 due to its pH-lowering effect.
mately 60% according to calculations based on the Henderson-
Hasselbach equation of the phosphate is in the dibasic form. The addition of cysteine.7 Cysteine, in sufficient concentra-
Because the dibasic calcium phosphate salt is poorly soluble, this tion, can reduce the pH of the final PN mixture.
enhances the probability of calcium phosphate precipitation. By The final concentration of glucose.2 Although glucose infu-
decreasing the pH by 2 U, approximately 95% of the phosphate is sions are acidic, the buffering capacity of the amino acid infusion
in the monobasic form,1 which is far more soluble. The most
and phosphate additive will predominate as controllers of final pH.
important factor, therefore, governing calcium phosphate compat-
Many other factors influence the physical compatibility of
ibility in any PN mixture is the final pH of the mixture. This will
calcium and phosphate salts in PN mixtures. No single factor can
be determined by range of a factors.
be seen in isolation and the final outcome will be a result of a
These factors that determine the final pH are, in order of
importance: multifactorial interaction.
The second important factor effecting calcium phosphate sol-
The commercial source of the amino acid infusion.2– 4 Amino ubility is the final concentration of free calcium ion,1,2,6,8,9 because
acid infusions from different manufacturers vary in pH between the formation of the poorly soluble dibasic phosphate salt is
around approximately 5.0 and 7.4. In addition, each amino acid dependent on the equilibrium between phosphate and calcium
mixture will vary in buffering capacity (titratible acidity).2 This is ions. Calcium ion concentration depends on a number of factors:
ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION 699

The calcium salt. Calcium additives are available as inorganic phate has also been reported to be effective in providing adequate
salts (calcium chloride) or organic compounds (calcium gluconate requirements of the two elements in infants.15
or gluceptate). Calcium chloride reduces the solubility of calcium
phosphate complexes in PN mixtures compared with calcium The Process of Precipitation
gluconate or gluceptate, because the chloride salt dissociates to a It has been reported that precipitates may form either during
greater extent.1,9 The two organic salts show similar degrees of the mixing process or after some time has lapsed after compound-
dissociation, and there appears, therefore, to be no advantage in ing, referred to as time-mediated precipitation.9 These variations
usage between these two compounds in PN mixtures.1 Organic relate to the chemistry of the system. A precipitate formed during
salts should be the preferred source of calcium. Calcium gluconate the compounding process due to poor mixing and layering of
injection is, however, commonly contaminated with aluminum different ingredients comprises calcium phosphate, whereas the
and a recent study10 indicates it is contra-indicated for use in time-mediated precipitate is normally caused by dibasic calcium
neonates and small children. phosphate crystallization. Although the first type appears as a
white flocculent amorphous precipitate, the latter is identified as
Temperature. Temperature has a major influence on calcium semitransparent and well-defined crystals, commonly adhering to
phosphate solubility, in particular if organic calcium salts are the sides of the container.7,9 In any case, precipitates once formed
employed. This is because temperature effects the dissociation of are highly unlikely to redissolve.16 Formation of the latter may
the organic calcium salts1,2,8,11 and possibly the equilibria between take up to 24 – 48 h at 37°C,6 depending on the relative concen-
the different phosphate species.2 Raising temperature causes a trations of calcium and phosphate salts.
greater dissociation of calcium gluconate to free calcium. This is
significant if temperatures rise from 5 to 37°C. Second, raising the Testing for Precipitation
temperature of a mixture may also shift the phosphate equilibrium The formation of calcium phosphate precipitates can be iden-
from mono- to dibasic salt. Both effects increase the likelihood of tifiable by visual inspection, and this approach has been employed
precipitation. by most investigators. A number of other methods have been
applied in different studies to identify, in particular, critical points
The commercial amino acid source. Some degree of com-
in the solubility matrix of PN mixtures. These can be categorized
plexation between calcium and specific amino acids has been
as methods to detect particulates or methods to quantify calcium
reported.2,9 Computer simulations have suggested the relative
or phosphate solution concentration changes. Methods to detect
degree of complexation with different amino acids. The amino
particulates include light or electron microscopic examination of
acid most likely to complex with calcium is lysine, although
filter surfaces after filtration of the PN mixture3,11 for particulate
glutamic and aspartic acids, arginine, and histidine also form
counts. Methods to quantify concentration changes include cal-
complexes.9 The degree of complexation is also pH-dependent.9
cium concentration measurement by atomic absorption spectros-
Cysteine, in contrast, shows very low levels of calcium
copy, potentiometric titration,6 or spectrophotometry.1
complexation.
No method provides complete confidence in ensuring detection
The final concentration of magnesium. Magnesium influences of all incompatible mixtures. The use of relatively simple meth-
the likelihood of precipitation because it forms relatively more ods, such as visual examination with appropriate illumination and
soluble and stable salts with phosphate ions.4 This effect increases background, the data from which are then used to construct
with pH. It also depends on the molar ratio of calcium and solubility diagrams, are probably as reliable as a general screening
magnesium. Ratios of magnesium/calcium less than two exert a method as the more technical and time-consuming methods used
positive effect on calcium phosphate solubility.4,9 by some laboratories. Particle counting with laser light extinction
can detect particles down to 1.75 mm, as they can be suspended
Other factors. Other factors have also been reported to influ- during the analysis with a magnetic stirring bar. Particles have
ence the final outcome. The order of mixing can affect the final been detected even with time-mediated precipitate formation
solubility profile of calcium phosphate.1,4 The phosphate additive when sampled at different time intervals. Particle counts, however,
should always be added and the mixture thoroughly mixed before will only detect precipitation if the particles are suspended in the
adding calcium. An alternative approach has been reported that mixture, and this may not be the case with time-mediated precip-
also enhances calcium and phosphate additions. Kaminski et al.12 itate formation in which some solid material may adhere to con-
found that mixing the two salts into separate infusions (phosphate tainer surfaces. Microscopic examination of filter surfaces follow-
into the amino acid, calcium into the glucose) and combining these ing the isolation of particles by filtration of PN mixtures is
mixtures slowly reduced the likelihood of precipitation. relatively sensitive but is time-consuming and again depends on
Factors such as the time of storage before administration may particle suspension before filtration. Particle counts will also not
be significant. Experience indicates that calcium phosphate pre- differentiate between calcium phosphate microcrystallization and
cipitates do not necessarily form immediately but may take up to other particles present in the mixture. Filters must also be made
24 h to become evident.1,6 transparent and often the particles may coalesce to form a “carpet”
Finally, it is worth noting that PN mixtures generally have a on the filter surface, which is difficult to identify. Only electron
greater capacity for phosphate than for calcium ions.6 microscopical x-ray energy dispersive spectroscopy (EDX) anal-
ysis, a highly specialized technique, will confirm the presence of
Organic Phosphates calcium and phosphate in isolated precipitates.17

One method of avoiding the risk of calcium phosphate precip- Compatibility Assessment of Calcium Phosphate in All-in-One
itation is to use organic phosphate compounds. The disodium salts Mixtures
of glucose 1-phosphate, glycerophosphate, and arginine glucose The rate and spectrum of calcium phosphate particulate for-
1-phosphate have been employed. These compounds have been mation is very different from flexible lipid droplet enlargement
reported to be fully compatible in a range of PN mixtures, and to (fat emulsion instability). In the case of calcium phosphate par-
be at least equally bioavailable when compared with inorganic ticulate formation, calcium phosphate precipitates when formed
phosphate,9,13,14 although some dissociation or degradation to show dramatic increases in the number and size spectrum, whereas
release phosphate ions cannot be ignored. Calcium glycerophos- in the case of flexible lipid droplet enlargement, enlargement of fat
700 ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION

globules is slow, such that the number and size gradually increase or manganese as contaminants, in some cases significantly con-
from one sampling interval to the next. These characteristics, in tributing to final concentrations in PN mixtures, an observation
terms of particle growth, may help discern calcium phosphate also reported by Kartinos,22 who noted that amino acid infusions
from coalesced lipid droplets in these opaque formulations. The may contain detectable quantities of iron, cobalt, manganese,
technical aspects of this differentiation are difficult and require molybdenum, fluorine, and iodine. The compatibility of zinc,
further study. Precipitation in all-in-one mixtures cannot readily manganese, copper, chromium, and iodine in TPN mixtures after
be detected by visual inspection, due to the fat emulsion.18 Light 24 h of storage at ambient temperature or 4°C has been confirmed
microscopy has been employed18 to detect crystalline precipita- (by M.C.A.). In a longer-term storage study, it has been shown
tion, although the limit of detection with regard to particle size is that zinc, copper, manganese, and chromium are compatible and
5 mm. The sensitivity of the microscopic method was not deter- stable in PN mixtures containing one particular amino acid source
mined. An alternative approach is to evaluate the compatibility of (Synthamin, Baxter, Baxter Health Care, Ltd., Wallingford, UK)
the mixture with the exclusion of the fat emulsion, and test for for 4 mo at 2– 6°C.24 It was, however, noted that copper showed
incompatibility in the normal manner. Because removal of the fat some evidence of physical incompatibility in Synthamin alone, but
emulsion will reduce the volume and hence increase the concen- not in PN mixtures containing Synthamin, even after only 2 d
tration of each ingredient, it can be argued that in such an ap- storage. Copper precipitates have also been recovered from PN
proach the mixture tested is at least as likely to precipitate as the mixtures containing Novamine as the amino acid source.25 It was
same mixture with fat emulsion. However, this makes the assump- hypothesized that the precipitate consisted of copper sulfide, due
tion that increasing the concentration of other ingredients does not to reaction with cysteine.26 A more recent study has also noted
significantly enhance calcium phosphate solubility. This may not copper and sulfur ions present on in-line filters after delivery of
be true for amino acids, for example. It also assumes that the PN mixtures containing Vamin (Pharmacia & Upjohn Ltd., Milton
emulsion does not influence calcium phosphate compatibility. The Keynes, UK) as amino acid source.27
alternative, therefore, is to replace the fat emulsion with an equiv- Precipitation of iron added to PN mixtures has been reported.28
alent volume of glucose infusion. This appeared to relate to a specific amino acid infusion used to
compound the mixture. It has been reported that iron dextran28 and
Clinical Effects ferrous citrate29 are compatible in PN mixtures, although the study
The recent US incidences have highlighted the consequences periods were related to infusion times (18 –24 h) only.
of infusing precipitates such as calcium phosphate.15 Knowles et The stability of selenium has also received some attention
al.19 report a case of pulmonary deposition of calcium phosphate since Levander30 reported that high concentrations of ascorbic
crystals in a patient on home PN. The patient developed diffuse acid reduced the soluble selenite ion to insoluble elemental sele-
granulomatous interstitial pneumonitis after approximately a 14-d nium. This reaction may be further enhanced by the high reduction
infusion of PN. The cause was directly linked to calcium phos- potential of other cations, such as the cuprous ion. Shils and
phate deposition in the lung. Calcium phosphate precipitation has Levander31 reported that ascorbic acid 5 g/L induced significant
also been identified as a cause of blocking in-dwelling catheters selenite reduction, but McGee et al.32 noted that PN mixtures
through which PN was being administered.19 containing 1 g/L ascorbic acid did not cause loss of selenium in
The Federal Drug Administration (FDA) has now recom- solution, even after extended periods of storage up to 10 wk. A
mended that in-line filters should be used in all TPN administra- later report indicated that reduction of selenite was only detected
tion to avoid calcium phosphate precipitates entering the patient.15 if the pH of the TPN mixture was # 5.0. In mixtures with pH
This recommendation applies to non-fat containing and all-in-one , 5.0 ascorbic acid at concentrations as low as 100 mg/L could
PN mixtures. cause selenite reduction to elemental selenium.32 It would there-
fore appear that reduction of selenite to free selenium is not likely
TRACE ELEMENT INCOMPATIBILITY to occur in PN mixtures, provided the pH remains . 5.0. Allwood
A wide range of trace elements are necessary to meet the and Greenwood17 reported evidence of selenium precipitation in
nutritional needs of patients receiving PN. The list of recognized PN mixtures containing ascorbic acid, after deliberately reducing
requirements has grown with our increasing knowledge of micro- the pH to , 5.0, using EDX to analyze filters for precipitated
nutrient functions in nutrition. The list includes such elements as selenium after filtration of stored PN mixtures.
selenium, molybdenum, chromium, and bromine, as well as the Other potential losses of trace elements, including, for exam-
more obvious iodine, fluorine, manganese, and copper. Daily ple, reduction of iodide to iodine, have not been reported in
requirements remain, in many cases, poorly defined, although both practice, although Allwood and Greenwood17 reported that cal-
the minimum and maximum amounts are defined for most ele- cium phosphate precipitates in TPN mixtures also contained evi-
ments, because both clinical evidence of deficiencies and toxic dence of other phosphate salts, including iron and manganese.
levels have become evident (e.g., manganese). There are two
aspects to be considered with regard to the stability of trace SUMMARY OF PHYSICAL INCOMPATIBILITY
elements in PN mixtures. First, assurance is required that each The risk of calcium phosphate precipitation is the major prob-
element is chemically stable, and second, that each element is lem regarding the addition of electrolytes and trace elements to PN
physically compatible with other ingredients. The very low con- mixtures. The mechanisms and consequences are now well rec-
centrations used in PN mixtures pose analytical challenges to ognized. Clear strategies are available to avoid this physical in-
determine both of these aspects. This probably accounts for the compatibility. The most promising development is the availability
fact that there is a sparsity of information on trace element of organic phosphate injections that provide a means of avoiding
stability and compatibility in PN mixtures. any risk associated with calcium phosphate precipitation. Our
Investigations into the stability of trace element additives to limited knowledge of trace element stability in PN mixtures sug-
PN mixtures have, in most studies, relied on analysis of specific gests that incompatibilities are generally avoided in compounded
trace element concentrations by atomic absorption spectroscopy. mixtures, and that extended shelf-lives can be assigned to many
Zinc, copper, manganese, and chromium were reported to be mixtures containing trace elements. However, until further evi-
stable and compatible in PN mixtures for 48 h at ambient tem- dence is available, caution is necessary when extending shelf-lives
perature, and after passage through a 0.45 mm in-line filter.21,22 It of untested PN mixtures, in particular those with high levels of
was also noted that certain PN ingredients contained copper, zinc, sulfhydryl-containing amino acids.
ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION 701

VITAMIN STABILITY tion.35–38 Photolysis proceeds both in the bag and during passage
Vitamins are commonly believed to be among the least stable through the administration set.
ingredients in PN mixtures, and it is generally recommended that A light-protecting overwrap to the container and the use of
vitamins be added immediately before commencing infusion or special light-protecting administration sets is therefore commonly
that infusion should be commenced within 24 – 48 h of addition. recommended,40 unless the patient is being fed in a position away
This constraint poses severe limitations on the ability of com- from strong daylight or at night.36 Administration in a room with
pounding units to provide aseptically prepared complete PN mix- only artificial lighting will lead to minimum degradation. It should
tures. A careful consideration of the stability of vitamins is crucial also be noted that fat emulsion will protect retinol from photoly-
to the operation of safe and effective compounding services. sis,32,41 both in the big bags and during infusion, although direct
Stability must be considered in the context of both storage after sunlight may penetrate the emulsion sufficiently to cause some
compounding and during administration, because some vitamins degradation during administration.
can undergo degradation during administration. With the increas- Sorption of retinol has been reported,39,42 and has also lead to
ing demand for extended storage of complete PN mixtures, espe- clinical manifestations of vitamin deficiency in long-term PN
cially for home patients, investigation of vitamin stability during feeding.39 It was shown that substantial amounts of retinol (ace-
storage has become an important development in contributing to tate) in PN mixtures prepared in glass bottles was lost by absorp-
improving the quality of patient care. tion to the administration set during simulated infusion.31,39 In
Various vitamins are known to be degraded under particular contrast, other studies have been unable to confirm retinol binding
conditions and in the presence of specific PN ingredients. The to plastic bags or sets.36,37 Further investigations have confirmed
major physico-chemical considerations are exposure to light, the that sorption to PVC depends on the ester used. Whereas the
type of plastic used to manufacture the PN container and infusion acetate ester (used in most US-manufactured products) binds
equipment, and storage temperature. The chemical parameters of strongly to PVC bags and administration sets, with losses up to
concern relate to the oxidation or reduction of particular vitamins. 90% being reported,39 the palmitate ester commonly used by
Photodegradation of Vitamins European manufacturers shows no evidence of binding to plastics
used to store and administer PN, in either two-in-one35,43 or
Vitamins most sensitive to photolysis are retinol (vitamin A) three-in-one37,44 TPN mixtures.
and riboflavin (B2). The nature of the light is extremely important,
because it is exclusively the ultraviolet (UV) component that
causes chemical photolysis of vitamins.34,35 Most artificial light Tocopherol
sources, including fluorescent light, contain insignificant emis- All fat emulsions contain some tocopherol, although it will be
sions in the UV range. It is therefore only daylight exposure that present as a mixture of isomers, some of which are more biolog-
causes serious photolytic losses in practice. Photolysis during ically active than others.45 However, the proportions of the iso-
storage should be readily avoidable.
mers vary widely, both between batches of the same product, and
Plastic Interactions between products.42,44
Tocopherol appears to be relatively stable in PN mixtures.
The vitamin most liable to bind with plastics is retinol. How- Billion-Rey et al.37 reported that this vitamin was stable for 20 d
ever, only the acetate ester form has been shown to exhibit at 4°C, with or without fat emulsion. Dahl et al.35 reported that
sorption to polyvinyl chloride (PVC) bags and administration total tocopherol in all-in-one PN mixtures was stable for 6 d at
sets.36
2– 8°C and during simulated infusion over 24 h in normal room
Chemical Degradation illumination conditions. However, the relative proportions of the
different isomers was not assessed.
Chemical degradation is the most important cause of vitamin Kishi et al.46 reported that tocopherol was stable during sim-
losses in PN mixtures. Although many vitamins are likely to ulated infusion in PN mixtures, both with and without light-
degrade eventually after addition to TPN mixtures, two particular protective measures. McGee et al.32 monitored the stability of
reactions are of major concern: the oxidation of ascorbic acid and a-tocopherol (5 IU in a 2.5-L mixture) in PN mixtures exposed to
the reduction of thiamine, being the most readily oxidized and
fluorescent light at room temperature in the bag and during sim-
reduced vitamins, respectively.
ulated infusion through in-line filters. No significant losses were
The stability of all vitamins added to TPN mixtures will be
reported. No losses were reported by Dahl et al.35 during simu-
considered, both during storage and administration.
lated infusion in fat emulsion. Kishi et al.46 reported similar results
FAT SOLUBLE VITAMINS after 24-h storage, although McKenna and Bieri47 reported a 10%
loss during infusion. Billion-Rey et al.37 reported that tocopherol
Retinol was stable during exposure to sunlight for up to 8 h. In contrast,
Multivitamin additives intended for PN may contain either the Gillis et al.48 reported that only 63% of the added a-tocopherol
acetate or palmitate ester of retinol. The former compound is was delivered during administration of the PN mixture (monitored
commonly used in formulations originating from the USA. using a radioactively labeled vitamin source). Drott et al.49 also
The stability of retinol in PN mixtures during storage has been reported some loss during simulated infusion, amounting to ap-
widely reported. Allwood35 has shown that retinol (palmitate) is proximately 10% during 20 h of administration. The role of light
stable in two-in-one mixtures for at least 28 d during storage at (the nature of which was not described) in this reported tocopherol
5°C. Billion-Rey et al.37 reported that retinol (palmitate) was loss was not clear, as the vitamins were added to the fat emulsion,
stable for 20 d in all-in-one PN mixtures stored at 4°C, although which was then infused into the same line with mixing only during
degradation was observed in some PN mixtures containing trace delivery.
elements, depending on the amino acid source. It should also be noted that some multivitamin additives con-
Retinol is the most light sensitive of the vitamins. Exposure of tain tocopherol as the acetate whereas others contain tocopherol
PN mixtures in bags to daylight can show up to 90% loss in 2– 4 base. It is not clear whether this difference has any significance
h, whereas direct sunlight will cause even more rapid degrada- regarding delivery.
702 ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION

Ergocalciferol
Information on the stability of ergocalciferol in PN mixtures
during storage is sparse. The stability of ergocalciferol during
administration from PN mixtures has been investigated. Gillis et
al.48 reported that average losses amounting to 32% were recorded
during simulated infusion from PN mixtures without fat emulsion.
Dahl et al.35 reported that no losses occurred during simulated
infusion in fat emulsion. Indirect data from bioavailability studies
in children suggest that ergocalciferol delivery from PN mixtures
is at least sufficient to maintain vitamin D status.50,51
Phylloquinone
Commercially available fat emulsions contain some phylloqui-
none. Lennon et al.52 report, for example, that one product con-
tained between approximately 30 – 60 mg/dL, the quantity being
proportional to fat concentration. The concentration is also fairly
consistent between batches of fat emulsion. In contrast, other
products contain substantially less phylloquinone. This is due to
the type of vegetable oils used.52
Phylloquinone has been reported by Billion-Rey et al.37 to be
stable in PN mixtures, with or without fat emulsion, stored in
ethylene vinyl acetate (EVA) bags, for 20 d at 4°C.
Phylloquinone losses of between 5 and 17% were reported
during simulated infusion over 24 h in an all-in-one TPN mixture
exposed to indirect daylight or fluorescent light.53 Billion-Rey et
al.37 indicated that greater degradation occurred during simulated
infusion in sunlight, amounting to at least 50% losses over a 12-h
period, even in all-in-one mixtures.
Phytomenadione
Phytomenadione was reported to be stable for at least 10 d after
addition to all-in-one PN mixtures, although light protection may
be indicated following a reported 6 – 8.5% degradation after a
4.5-h exposure to artificial daylight.55
WATER-SOLUBLE VITAMINS

Riboflavin
Riboflavin has been reported to be stable for at least 4 d in
all-in-one PN mixtures stored at 2– 8°C,35 and for 48 h at 5°C or
ambient temperature in a range of PN mixtures.54 Kearney et al.54 FIG. 2. Ascorbic acid degradation pathway.
reported that riboflavin is relatively stable (. 80% remaining)
after 8 wk of storage at 5°C in two-in-one PN mixtures containing
different amino acid infusions.
Riboflavin is degraded by exposure to daylight,56 although it is was relatively stable (, 25% degradation) in a range of two-in-
less sensitive than retinol. Chen et al.56 reported total degradation one PN mixtures for 8 wk at 5°C.
of riboflavin after an 8-h exposure to direct sunlight and 47% loss Direct sunlight causes degradation of pyridoxine. Chen et al.56
during exposure to indirect daylight. In contrast, the vitamin was reported almost 90% losses after 8 h of exposure to sunlight,
not degraded by exposure to fluorescent light. Losses of ribo- although pyridoxine was stable during exposure to indirect day-
flavin from all-in-one PN mixtures during simulated infusion over light or fluorescent light.
24 h can amount to 10 –20% during indirect daylight exposure.40 Nicotinamide, Biotin, Pantothenate, and Cyanocobalamin
Provided direct exposure to sunlight is avoided, light protec-
tion during administration is therefore unnecessary to protect Although there is virtually no information on the stability of
riboflavin. vitamins nicotinamide, biotin, pantothenate, and cyanocobalamin
Riboflavin has been reported to accelerate the photodegrada- in PN mixtures, Dahl et al.35 reported that these vitamins were all
tion of certain amino acids.57 Enhanced degradation of methio- stable in an all-in-one PN mixture for 4 d at 2– 8°C.
nine, tryptophan, proline, and tyrosine accelerated in the presence
of riboflavin was reported during simulated infusion over a 24-h Ascorbic Acid
period. The conditions involved extended exposure to intense Ascorbic acid is the least stable of all the vitamins added to
phototherapy illumination. Riboflavin concentrations decreased TPN mixtures. The mechanism of degradation is oxidation, and
by approximately 50% after 24 h of exposure to phototherapy the compound readily reacts with oxygen. The degradation path-
light. way was described by Tolbert and Ward,58 and is summarized in
Figure 2. The first stage of the reaction, to dehydroascorbic acid
Pyridoxine (DHA), is reversible. It is also important to note that DHA is
Pyridoxine has been reported to be stable for 4 d at 20°C in an biologically active, with biological activity similar to that of
all-in-one PN mixture.35 Kearney et al.54 reported that pyridoxine ascorbic acid. The second and later stages are not reversible,
ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION 703

leading to loss of biological activity. The reaction rates are gov- were always substantial and often greater than ascorbate concen-
erned by temperature and are accelerated rapidly by catalysts, trations during 7 d of storage at 2– 4°C. The authors conclude that
especially copper ions, but also to a lesser extent by ferric, zinc, a 7-d shelf-life is acceptable, although the effect of the container
and manganese ions.59 remained unclear.
The total quantity of ascorbic acid lost during storage depends Smith et al.65 examined ascorbic acid degradation (100 mg/PN
on the amount of oxygen present.60 This oxygen originates from a mixture) in a variety of PN mixtures containing trace elements,
number of sources, including the infusions and additives (but with or without fat emulsion. Stability was monitored over a 48-h
excluding amino acid and fat emulsion, which are either packed period at 25°C. Losses accumulated to between 10 and 80%,
under vacuum or are nitrogen-overlaid), aeration during fluid depending on the amino acid used and the type of container. They
transfer into the bag, any residual headspace in the bag after filling reported also that no losses were recorded at 5°C.
and sealing, and permeation through the bag wall during storage. Dahl et al.53 determined the degradation of ascorbic acid (in-
Rates of oxygen transmission of plastic film used to fabricate PN cluding DHA) in fat emulsion during infusion. The vitamin
bags have been reported as follows (conditions 5 100% oxygen, source, Soluvit N, was added to fat emulsion before administra-
1 atmosphere, RH; conditions 5 50% side one, 90% side two):61 tion. Recovery from the infusate fell to approximately 70% after
1. EVA: Approximately 1000 mL z (m2)21 z 24 h21 8 h and to approximately 50% after 24 h.
2. Multilayered bags (composition commonly consists of a It should also be noted from this summary that levels of DHA
triple layer of EVA/ethyl vinyl alcohol [EVOH]): Approx- reported in different PN mixtures during storage appear to vary
imately 10 mL z (m2)21 z 24 h21 widely, although the reasons are not immediately apparent.
Ascorbic acid degradation in PN mixtures during storage in big Allwood43 investigated the causes of ascorbic acid degradation
bags and during administration has been widely reported and there in PN mixtures. Results confirmed the importance of copper as a
is general agreement that ascorbic acid is the least stable compo- catalyst for oxidation of ascorbate. The quantities of ascorbate
nent in any PN mixture. Most studies have measured ascorbate degraded directly correlated with the amount of oxygen present in
only, and have not reported DHA concentrations. West et al.62 the solution. Removal of oxygen prevented significant degrada-
reported rapid degradation of ascorbic acid in two-in-one PN tion. It was estimated that the oxygen present in infusions and
mixtures, with . 80% loss after 24 h at 25°C in one mixture. additives, together with the oxygenation of solutions during com-
These authors also highlighted the importance of air causing the pounding, would account for between 30 and 50 mg ascorbic acid
greatest and most rapid losses in PN mixtures. Nordfjeld et al.44 degradation. This loss would occur within 2– 6 h of compounding,
described the degradation of ascorbate in two-in-one PN mixtures although the rate of degradation was reduced in cysteine-contain-
with trace elements in PVC bags. The vitamin source was either ing amino acid infusions. A secondary degradation would then
MVI-12 or Soluvit and the initial concentrations were 30 and 9
commence due to the permeability of EVA for oxygen. This could
mg/L respectively. Concentrations of ascorbate in MVI-12 were
account for another 5–10 mg/d. The importance of removing all
reduced by 50%, in 2– 4 hours at 24°C, or 8 h at 4°C.
air from the bag before sealing to minimize ascorbic acid losses
Allwood63 reported ascorbate degradation in a range of two-
was emphasized. Recent studies have shown that this secondary
in-one PN mixtures in PVC bags stored at 5°C. The multivitamin
stage of ascorbic acid degradation can be largely avoided if
source was Multibionta, which contains 500 mg ascorbic acid.
multilayered bags replace the more oxygen-permeable EVA bag.66
Losses of ascorbate without trace elements accumulated to a
maximum of 20% after 3 d, 30% after 7 d, and greater than 90% PN mixtures with or without fat emulsion stored in multilayered
after 28 d. Losses, however, were influenced to some extent by the bags retained up to 80% of added ascorbic acid after 3 mo storage
amino acid source. In the presence of trace elements, losses were from the vitamin source Multibionta. In EVA bags, the same
greater, with up to 80% loss after 3 d, and complete disappearance mixtures showed complete loss of ascorbic acid after 4 –5 d.
by 28 d, in all mixtures tested. Additional losses will also occur during administration, due to
In a later study,60 it was reported that degradation was deter- reaction with air (oxygen) present in the administration set.
mined by the amount of oxygen present, and rates of degradation The final stage of the ascorbate degradation pathway results in
were greatly enhanced in the presence of copper. Degradation oxalic acid, a potentially toxic compound. Although little is
during storage at 5°C in two-in-one PN mixtures in PVC bags known about its possible toxic effects, Das Gupta67 reported
containing Multibionta as the vitamin source showed losses of evidence for calcium oxalate precipitation in a PN mixture during
30 – 40% in 1 d, 60% in 7 d, and 95% in 28 d. Losses during administration. Perhaps the recommendation to separate vitamin
simulated infusion of a two-in-one TPN mixture with trace ele- and trace element additives by administration on alternative days
ments amounted to approximately 30% in 3 h, after which deg- requires careful consideration.68
radation proceeded more slowly. DHA concentrations were also In summary, ascorbic acid is the least stable vitamin, degrading
measured during simulated infusion, never apparently rising above by direct reaction with oxygen, which originates from infusions
5 mg/mL (equivalent to only approximately 2–3% of ascorbic acid containing dissolved air such as glucose, and additives; by aera-
added). tion of infusions during transfer from bag or bottle to PN bag; by
Dahl et al.35 also determined the degradation of combined total residual air in the compounded bag after sealing; and by trans-
ascorbate (ascorbate 1 DHA) in all-in-one PN mixtures, the mission through the bag wall. Degradation is accelerated by trace
vitamin source being Soluvit N (Pharmacia Upjohn Ltd.) (which elements, especially copper, but this effect is reduced by cysteine.
contains 100 mg ascorbic acid), but only one-half vial per bag. Removal of oxygen will stabilize ascorbic acid in TPN mixtures.
Losses amounted to approximately 40% in 24 h and 60% in 4 d at The key nutritional point, however, is that the amount of
2– 8°C in EVA bags. However, the DHA levels contributed more ascorbic acid delivered to the patient depends on the amount of
than half of this total. Degradation during simulated infusion over oxygen, and is unrelated to the concentration of ascorbic acid
24 h was also monitored. This amounted to an additional 15–20% added to the bag.60 The oxygen present in any compounded bag
total ascorbate/DHA. will depend on PN mixture composition, but estimates suggest that
Proot et al.64 examined ascorbic acid and DHA concentrations typically 10 –50 mg can be degraded by reaction with residual
in an all-in-one PN mixture stored in a variety of containers. The oxygen. The possible formation of oxalic acid as the final degra-
vitamin additive was Cernevit (Baxter Health Care, Ltd.) (con- dation product and subsequent formation of calcium oxalate pre-
taining 125 mg ascorbic acid). DHA levels present during storage cipitate requires further investigation.
704 ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION

FIG. 3. Thiamine degradation pathway.

Thiamine Travasol (Baxter Health Care, Inc., Deerfield, IL, USA), which
Thiamine is degraded by a number of mechanisms.69 The nominally contained 3 mmol/L bisulfite, showed losses of up to
compound is increasingly unstable as the pH rises and is decom- 25% after 48 h at 25°C. In contrast, thiamine was stable in PN
posed by oxidizing or reducing agents. The predominant cause of mixtures containing amino acid infusions that did not contain
degradation in TPN mixtures is by reduction, caused in particular bisulfite. A further study confirmed that bisulfite at concentrations
by sodium metabisulfite, used as an antioxidant in some commer- above 1 mmol/L caused thiamine degradation.64
cial amino acid infusions.70 The route of degradation is summa- Because thiamine degradation in PN mixtures is a result of a
rized in Figure 3.69 Sulfite cleaves the molecule into pyrimidine chemical reaction with metabisulfite, the rates of degradation will
and thiazole moieties. The rate of this cleavage increases with depend on metabisulfite concentration. As metabisulfite is added
increased pH to a maximum rate of pH 6.70 as an antioxidant, some variable losses of this reducing agent can
The degradation of thiamine in TPN mixtures has been widely be expected during manufacture of the amino acid infusion. In
investigated. Early work by Scheiner et al.70 indicated that losses addition, losses can also occur during PN mixture storage after
of thiamine were relatively rapid after addition to amino acid compounding by reaction with oxygen. This will in turn depend on
infusions containing bisulfite, with almost complete loss recorded the amount of oxygen in the bag and on the oxygen permeability
after 24 h at ambient temperature. Allwood63 reported that thia- of the bag wall. Consequently, degradation of thiamine in stored
mine (50 mg/bag, Multibionta) was relatively stable during stor- PN mixtures will depend on a number of factors and predicting
age in two-in-one PN mixtures, using amino acid infusions with or losses is, therefore, difficult. For example, recent work in our
without metabisulfite. Greater than 75% remaining after 28 d of
laboratory indicate that thiamine is stable in PN mixtures for
storage at 5°C, although degradation was slightly greater in PN
periods in excess of 28 d in mixtures without metabisulfite.54
mixtures containing metabisulfite.
It has been suggested, however, that, after dilution of meta- Other reducing agents used in amino acid infusions as reducing
bisulfite-containing amino acid infusions in PN mixtures, the agents, such as malic acid, do not degrade thiamine. In contrast,
degradation of thiamine becomes relatively unimportant. For ex- degradation in mixtures formulated using Freamine III 8.5% show
ample, Bowman et al.71 reported that thiamine in PN mixtures was approximately 50% loss in 5–7 d and greater than 90% loss in
stable for 22 h at 30°C. It was assumed that dilution of metabisul- some mixtures after 21 d.72 Because degradation is first order with
fite below 4.8 mmol was sufficient to prevent thiamine reduction. respect to metabisulphite, degradation rate is independent of thi-
Schmutz et al.55 investigated the effect of fat emulsion, amino amine concentration.
acid, container, and temperature on the stability of thiamine. Chen et al.56 noted a 26% loss of thiamine in PN mixtures after
Losses were greatest when Freamine III (contains 9.6 mmol/L 8 h of exposure to sunlight, but no significant losses after exposure
bisulfite nominal) was used as the amino acid source. Only 25% to indirect daylight or fluorescent light. Thiamine in TPN is not
remained after 48 h of storage at 25°C. PN mixtures containing degraded by exposure to phototherapy light,55 fluorescent, or
ADDITIVES IN PARENTERAL NUTRITION ADMINISTRATION 705

indirect daylight, but exhibits approximately 26% degradation Louie and Stennet77 investigated the stability of folic acid in
after 8 h of exposure to direct daylight.56 amino acid dextrose mixtures under light (fluorescent illumina-
As acute thiamine deficiency caused by failure to include tion) and dark conditions, at 2– 8°C or ambient temperature, and
multivitamin additives in PN has been shown to be fatal,73 it is reported that the compound was stable for 48 h under any com-
important to ensure that patients receive adequate amounts. bination of these conditions.
Finally, there is evidence to suggest that certain B vitamins
Folic Acid may cause folic acid degradation.78
Folic acid is included in many multivitamin preparations de- The conflicts in published results make it difficult to reach firm
signed for PN addition. An alternative form is folic acid injection. conclusions. Results obtained in our laboratory have indicated that
The pH of this product is in the range of 8 –11 to ensure folic acid folic acid is stable in a range of two-in-one PN mixtures tested in
remains in solution. The compound will precipitate, especially in multilayered bags, with greater than 80% remaining after 2 mo of
solutions below pH 4.5–5.74 storage (M.C. Allwood and M.C.J. Kearny, unpublished data).
Early reports suggested that folic acid was unstable in PN
mixtures stored in plastic (PVC) bags, leading to losses of between SUMMARY
2 and 33% after 42 d of storage at ambient temperature.75 It was
suggested that losses were due to absorption to the PVC bag. Later Common practice is to avoid adding vitamins to PN mixtures
studies suggest that folic acid in PN mixtures is compatible with until immediately before administration, in which case the addi-
plastic bags and sets.76 tion is commonly made by ward staff at the bedside, without
Nordfjeld et al.44 reported very poor stability of folic acid after pharmaceutic control. The least stable vitamin is undoubtedly
addition to two-in-one TPN mixtures, with losses of at least 75% ascorbic acid, and losses during administration can be substantial,
after 24 h of storage. Degradation was even greater if exposed to although these can, to some extent, be predicted by our knowledge
light (although the nature of this light was not described). In of the mechanisms involved in ascorbate oxidation. Because deg-
contrast, in another report folic acid was shown to be relatively radation is directly related to oxygen content of compounded PN
stable in many PN mixtures. Barker et al.74 reported that folic acid mixtures, the use of the multilayered reduced-gas-permeable bag
in a range of complete PN mixtures was relatively stable when can prevent substantial ascorbate losses during storage. Paradox-
stored at 4°C. Losses generally amounted to not more than 10% ically, the presence of ascorbic acid then enhances the overall
after 14 d of storage. However, whereas Nordfjeld et al.44 tested stability of the PN mixture by creating a highly reduced chemical
two multivitamin preparations containing folic acid (400 mg/vial), environment. Two other important mechanisms lead to vitamin
Barker et al.74 used folic acid injection to supplement the low folic losses. Thiamine reduction can be rapid in PN mixtures containing
acid content of a multivitamin additive (Solivito, Pharmacia Up- metabisulfite, but this stabilizer is now absent from most amino
john, Ltd.) to increase final concentrations to between 0.40 and acid infusions. Photodegradation, especially of retinol, can be
0.566 mg/L. prevented during storage and controlled during administration by
Folic acid has also been shown to be stable in all-in-one minimizing exposure to daylight. All-in-one mixtures protect
mixtures for 4 d at 4°C or at ambient temperature.77 Chen et al.56 photo sensitive ingredients to all light except direct sunlight.
reported that folic acid in PN mixtures was stable for 8 h of Retinol absorption to plastic bags and administration equipment
exposure to either florescent light, indirect, or direct daylight. can be prevented by using the palmitate ester.
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