Ajman University of Science & Technology
Faculty Of Pharmacy & Health Sciences
.………………….
LABORATORY MANUAL FOR
DOSAGE FORMS-II
Central Committee
Department of Pharmaceutics
…………………..
2000 - 2001
1
Dear Students,
The central committee of department of pharmaceutics, Faculty of
Pharmacy and Health Sciences, is pleased to introduce to you the Laboratory
Manual of Dosage Forms II (700214). The manual covers experiments deal
with the principles discussed in didactic lectures. These experiments employ
fundamental principles of pharmaceutics required to design and prepare
physically and chemically stable dosage forms and be acquainted with
official quality assurance methods that ensure their therapeutic safety and
efficacy. The central committee set this manual for all the branches to ensure
the uniformity of student outcome.
Best Regards
Central Committee
Department of pharmaceutics,
Faculty of Pharmacy and Health Sciences
2
Table of Content
PART No.
PART 1
Exp.(1)
Exp.(2)
Exp. (3)
PART 2
Exp.(4)
Exp.(5)
Exp.(6)
Content
EMULSIONS
Preparation of Emulsion Using Hydrophilic Colloids as
Emulsifying Agent
 Acacia Emulsion
Preparation of Emulsions Using Finely Divided Particles as
Emulsifying Agent
 Calamine Lotion B.P.
Preparation of Emulsion using Anionic Surfactant
 White Liniment
 Vanishing Cream
Preparation of Emulsion using Non-Ionic Surfactant
OINTMENTS
 Preparation of Simple Ointment
 Preparation of Macrogol Ointment
 Preparation of Absorption Base Ointment
 Preparation of Emulsifying Wax
Evaluation of Drug Release from Ointment Base
Ophthalmic Preparations
Introduction to Pharmaceutical Calculation
Exp.(7)
Preparation of Isotonic Buffer Solution
Exp.(8)
Compounding of Ophthalmic Liquids
 Buffers and buffer capacity
 Isotonicity and sterility
Exp.(9)
 Isotonicity and pH adjustment
PART 4
STERILE PREPARATIONS
Exp.(10)
IV Admixture
Demonstration of TPN Preparation
APPENDIX Guidelines, Equipment, and Supplies for Sterile Compounding
Page No.
5
11
13
14
16
31
32
34
PART 3
3
38
43
48
56
58
59
75-118
PART 1
EMULSIONS
4
Introduction :
Emulsification is the process of preparing emulsions, which are heterogeneous
systems consisting of at least one immiscible liquid intimately dispersed in another
in the form of droplets, whose diameters generally exceed 0.1µ. Emulsions are also
defined as thermodynamically unstable mixtures of two essentially immiscible
liquids and are characterized by a third phase, an emulsifying agent.
The extemporaneous preparation of an emulsion depends on a number of
considerations by the pharmacist. These include the purpose of the drug, internal or
external use, concentration of the active drug, liquid vehicle, physicochemical
stability of the drug, preservation, buffers, solubilizers, emulsifying agents, viscosity
enhancers, colors and flavors.

Definitions and Characteristics :
In emulsions, one phase is dispersed throughout the second phase as
"globules". An emulsion consists, then, of a dispersed phase (internal phase,
discontinuous phase), a dispersion medium (external phase, continuous phase) and a
third component known as an emulsifying agent. There are different types of
emulsifying agents as will be discussed later. The diameter of the dispersed phase
globules is generally in the range of about 0.1 to 10µ, though some as small as 0.01µ
and as large as 100µ are not uncommon.
Emulsions are used when two immiscible liquids must be dispensed in the same
preparation for some designated reason. Ordinarily, this means there is a polar and a
non polar component, each of which is a liquid. When the dispersed phase is non
polar (oil) and the external phase is polar (water), the emulsion is known as an oilin-water emulsion. When the dispersed phase is water and the dispersion medium is
oil, the emulsion is of the water-in-oil kind. Ordinarily, but not always, emulsions
for internal use are of the oil-in-water type and emulsions for external use are of
either type.
Water-in-oil emulsions are insoluble in water, not water-washable, will absorb
water, are occlusive, and may be "greasy". Oil-in-water emulsions are miscible with
water, are water washable, will absorb water, are non occlusive, and are non greasy.
5

Uses and Applications
Emulsions are widely used in the form of topical creams and lotions. Creams
are opaque, soft solids or thick liquids intended for external application, consisting
of medicaments dissolved or suspended in water removable (vanishing cream) or
emollient bases. They are of the water-in-oil or oil-in-water type. The term "cream"
is most frequently applied to soft, o/w, cosmetically acceptable types of
preparations. These usually are applied to moist, weeping lesions as they have
somewhat of a "drying" effect in that the fluids will be miscible with the aqueous
external phase of the creams. Lotions are fluid emulsions or suspensions for external
application. They generally are applied to intertriginous areas, i.e., where skin
rubbing occurs as between fingers, thighs, under the arms, etc., as they have a
lubricating effect.
Emulsions are used internally to dispense oil and water drugs together, mask the
taste of poorly tasting oily drugs and sometimes to enhance the absorption of
selected drugs. Intravenously-administered emulsions are widely used to administer
high calorie oil to severely debilitated patients.

Composition
Generally, emulsions contain three components: a lipid phase, an aqueous
phase and the emulsifier. Of these, the compounding pharmacist generally has
greatest flexibility in the choice of the emulsifier.
The purpose of an emulsifying agent is to minimize the tendency of the globules to
coalesce, or join together to form larger globules, with eventual separation of the
two liquids. The stability of an emulsion is dependent upon the properties of the
emulsifier and the film it forms at the interface between the two phases. The film at
the interface must be both tough and elastic and should be rapidly formed during the
preparation, or emulsification, process.
Emulsifying agents can be divided into three different categories:
1. Surface-active agents
2. Hydrophilic colloids
3. Finely divided solid particles
Surface-active agents are adsorbed at oil: water interfaces to form monomolecular
films, resulting in a decrease in interfacial tension. Hydrophilic colloids form multimolecular films about the dispersed particles. Finely divided solid particles are
adsorbed at the interface between the two liquid phases of the globules and form a
film of particles around the dispersed globules. Common to each of these three
categories is the formation of a "film" .
6
Emulsifiers that can be used are shown in Table 1.
Table 1: Emulsifiers and Stabilizers for Emulsions
Carbohydrates
Acacia
Agar
Chondrus
Pectin
Tragacanth
Proteins
Casein
Egg yolk
Gelatin
Surfactants
Anionic
Cationic
Nonionic
Solids
Aluminum hydroxide
Bentonite
Magnesium hydroxide
High Molecular Weight Alcohols
Cetyl alcohol
Glyceryl monostearate
Stearyl alcohol

Determination of Type of Emulsions
It is important to know whether an emulsion is o/w or w/o in the event
additional ingredients must be added. The type of emulsion can be determined by
some simple tests, including the drop dilution test, dye solubility test electrical
conductivity test, and the filter paper test. The drop dilution test is based on the
principle chat an emulsion is miscible with its external phase and is simply
performed by dropping a small quantity of the emulsion onto a surface of water. If
the drop is miscible with the water, it will spread, indicating that water is the
external phase (an o/w emulsion). The dye solubility test is based on the principle
chat a dye disperses uniformly throughout an emulsion if it is soluble in the external
phase and is conducted by adding a small quantity of a water soluble dye (powder or
solution) to the emulsion. If it diffuses uniformly throughout the emulsion, water is
the external phase (an o/w emulsion). The electrical conductivity test is based on the
principle chat water conducts an electric current while oils do not. Generally, o/w
emulsions have a tendency to conduct electricity better than w/o emulsions, if the
required equipment is available. The filter paper test involves putting a drop of
emulsion onto a clean piece of filter paper. If the drop spreads rapidly into the filter
paper, it is an o/w emulsion as water (the external phase) tends to spread more
rapidly throughout the filter paper than does oil.
Multiple emulsions can be prepared by emulsifying an emulsion to add
another external phase. An example would be the combination of a w/o emulsifier
7
(sorbitan mono oleate) with liquid petrolatum, addition to an aqueous phase to form
a w/o emulsion, followed by dispersion in an aqueous solution of an o/w emulsifying
agent (Tween 80) to form a final w/o/w emulsion. Similarly, an o/w/o emulsion can
be prepared. Numerous applications suggested include detoxification, drug
targeting/localizabon, prolonged acting dosage forms and potential application in
cosmetics.
If two immiscible liquids are in contact with each other, they will tend to maintain as
small an interface as possible. Consequently, it is very difficult to mix the two
liquids. When they are shaken together, spherical droplets will form, as the liquids
tend to maintain as small a surface area as possible and an interfacial tension will be
maintained between the two liquids. When a "surface-active" ingredient is added, its
molecules will tend to be oriented between the two faces with the polar ends in the
polar phase and the non polar ends in the non polar phase, which will lower
interfacial tension. This will result in miscibility of the two liquids.
There are three different general methods whereby emulsifying agents aid in the
formation of emulsions. These include:
1. reduction of interfacial tension
2. formation of a rigid interfacial film
3. formation of an electrical double layer
If the emulsifier concentration is sufficiently high, a rigid film can be formed
between the immiscible phases which can act as a mechanical barrier to coalescence
of the globules. An electrical double layer results in repulsive electrical forces
between approaching droplets to minimize coalescence.

Preparation Methods/Techniques of Emulsions
Emulsions do not form spontaneously when liquids are mixed, but rather
require energy input to break up the liquids, resulting in an increased surface area of
the internal phase. This energy input can be in the form of mechanical agitation,
ultrasonic vibration or heat.
Emulsions generally can be prepared by manual and mechanical methods.
Commonly used techniques involve the use of a mortar and pestle, electric mixer,
hand homogenizer , shaking, sonifiers, and beakers.
A mortar and pestle can be used with both the English and Continental methods
described below. For best results, the mortar should have rough surfaces to aid in
shearing the liquid into small globules.
8
The English Method , also called the ( Wet Gum Method ), relies on the use of
mucilage or dissolved gums and generally involves the use of a mortar and pestle.
The ratio of oil: water: emulsifier often ranges from 3-4:2:1 for forming the primary
emulsion. The mucilage is made first by adding a small quantity of water to the
hydrocolloid, e.g. acacia, with trituration until uniform. The oil is added in small
quantities with rapid trituration. The mixture will become thick and viscous.
Additional water is added very slowly with rapid trituration until complete.
The Continental Method , also called the ( Dry Gum Method ), also generally
uses the mortar and pestle. The ratio of oil: water emulsifier for preparing the
primary emulsion is generally approximately 4:2:1. The dry gum method involves
mixing the hydrocolloid with the oil with rapid mixing for only a very short time,
followed by the addition of all the water at once with very rapid trituration until a
snapping sound is heard, This indicates that the primary emulsion is formed. The
required amount of additional water is added slowly with rapid trituraton until
complete.
The Bottle Method (shaking) can be used in the preparation of emulsions
containing volatile oils and other non-viscous oils. It avoids the splashing problem
sometimes encountered using the mortar and pestle. The bottle method is a variation
of the dry gum method and involves mixing the powder (emulsifier) and oil in a
bottle followed by rapid shaking with short strokes. The required quantity of water is
added all at once and the mixture shaken rapidly to form the primary emulsion (4:2:1
ratio). The additional water, if required, is added in small quantities with shaking
after each addition. It is very important NOT to allow the oil and the gum to be in
contact too long as the gum may imbibe the oil and cause the powder to become
somewhat waterproof.
The Beaker Method is often used with synthetic emulsifying agents. The
prescription ingredients generally are divided into two separate phases: oil and
water. The two phases are heated individually to about 60-70oC, if needed. The
internal phase is then added to the external phase with stirring. The product is
removed from the heat and gently and periodically stirred, until cooled (congealed).
9
Incorporating materials into a water-in-oil emulsion:
Oils and insoluble powders can be incorporated directly using a pill tile and spatula
or mortar and pestle. If large amounts of insoluble powders are required, it may be
necessary to use a levitating agent. In many water-in-oil emulsions, there is
sufficient agent to emulsify an additional reasonable quantity of an aqueous solution
of a drug which can be incorporated on a pill tile with a spatula, mortar and pestle,
or by gentle heat using a water bath. If heat is used, the preparation should not be
held at a high temperature very long as loss of some water may occur, resulting in a
change in volume of the product. The addition of oily ingredients usually poses no
problem. Some crystalline drugs may need to be dissolved in oil first, if possible. It
may be necessary to use the base form and not the salt form of a drug in this case. It
is difficult to add water to these emulsions unless an excess quantity of the
emulsifier is present.
Incorporating materials into an oil-in-water emulsion:
Insoluble powders and aqueous solutions can be incorporated using a pill tile and
spatula or mortar and pestle. It may be advisable to use a levitating agent such as
glycerin or propylene glycol to aid mixing of the insoluble powder with the
emulsion. Crystalline materials should be dissolved in a small quantity of water prior
to adding to the emulsion. Water-soluble materials can be added by dissolving the
powder in a small quantity of water and incorporating the solution into the base. A
small quantity of an oil may be incorporated directly into the base as there is usually
an excess of emulsifying agent, but if larger amounts of an oil must be added, it may
be necessary to add a small quantity of an oil-in-water surfactant to assist in uniform
dispersion of the oil in the vehicle. It generally is easy to add water-soluble
ingredients.
If heat is used while incorporating an ingredient into an oil-in-water vehicle, it is
important to work quickly as water may be lost rather rapidly from the product. If
this occurs, the product will change in volume and, if a semisolid, may tend to
become stiff and "waxy."
10
EXPERIMENT 1

Preparation of Emulsion Using Hydrophilic Colloids as Emulsifying
Agent .
Acacia Emulsion:
Unless otherwise specific , extemporaneously prepared emulsion for internal
use are made with acacia gum . To prepare acacia emulsions using a pestle and
mortar , thin ( primary ) emulsion must be made first . The quantities for primary
emulsions have been determined by experience are given in Table –1
Table –1 Quantities for primary emulsions
Quantities of primary emulsions ( parts )
Type of oil
Example
Oil
Water
Gum
Fixed
Almond oil
A rachis oil
Caster oil
Cod – liver oil
4
2
1
Mineral
Volatile
Liquid paraffin
Turpentine oil
Cinnamon oil
Peppermint oil
Male fern extract
3
2
2
2
1
1
1
2
1
Oleo – resin
Rx
Caster oil
50 ml
Double strength chloroform water 100 ml
Water
ad 200 ml
Sent 100 ml
HINT :- Double strength chloroform water is prepared by mixing 5 ml of chloroform in 1000 ml of
water
11
Procedure
1- Caster oil is a fixed oil , therefore , the quantities for primary emulsion are
( oil : water : gum = 4 : 2 : 1 )
Caster oil
Water
Acacia
25 ml
12.5 ml
6.25 g
2- use the dry gum technique for Acacia Emulsion as follow
a- Weigh the Acacia powder and place it in dry mortar
b- Disperse the Acacia powder lightly with water
c- Add 12.5 ml oil gradually and triturate until the primary emulsion is well
established (by clicking sound)
d- The primary emulsion is then diluted with the remaining ingredients and
transfer to measuring cylinder to adjust the volume with water
3- Use amber dispensing bottle with a wide mouth
4- Write label & add (shake the bottle before use)
use :- Demulcent and Purgative
AUST
DATE
Acacia Emulsion 100 ml
Use once daily before sleep
Shake well before use
12

Preparation of Emulsion Using Finely Divided Solid Particles as
Emulsifying Agent.
Calamine Lotion B.P
Rx
Calamine
Zinc Oxide
Bentonite
Sodium Citrate
Liquid phenol
Glycerin
Purified Water
15 g
5g
3g
0.5 g
0.5 g
5 ml
100 ml
Procedure
1) Dissolve Sodium Citrate in 35 ml Purified Water
2) Weigh Calamine, Zinc Oxide and Bentonite & triturate it with Sodium Citrate
solution
3) Add Liquid phenol, the glycerin and sufficient quantity of water to make up the
required volume.
4) Write the label as follow:
AUST
DATE
Calamine Lotion B.P 100 ml
Applied when necessary
NAME
Shake before use -- External use only
Use: - Astringent & protective (soothing effect for itching )
13
EXPERIMENT 2

Preparation of Emulsion Using Anionic Surfactants
White liniment B.P
Rx
Ammonium chloride
Diluted Ammonia solution
Oleic acid
Turpentine oil
Purified water
12.5 g
42 ml
85 ml
225 ml
625 ml
After calculation
0.625 g
2 .25 ml
4.25 ml
12.25 ml
31.25 ml
Sent 50 ml
Calculation factor = 50/1000 =0.05
procedure
1- Make emulsifier (Ammonium Oleate ) the reaction between dilute Ammonia and
oleic acid as follow
a) Take 4.25 ml of Oleic acid & 12.5 ml of Turpentine oil and 2.2 ml of
Diluted Ammonia solution (2.5% ) and 10 ml of water.
b) Shake vigorously to form Turpentine H2O emulsion
2- Dissolve 0.625g Ammonium chloride in the remaining water and mix it with to
produce the preparation after adjusting the volume with H2O to 50 ml
3- Write label as follow :
AUST
White Liniment B.P
DATE
50ml
Rub the surface as directed
NAME
EXTERNAL USE ONLY
- use :- Counter – irritant and rubefacient .
14
Vanishing Cream B.P
Rx
after calc.
Stearic acid
Oleic acid
Glycerin
Boric acid
Potassium hydroxide
Purified water Q. S
120 g
40 g
50 ml
10 g
8g
1000 g
6g
2g
2.5 ml
0.5 g
0.4 g
ad. 50 g
Sent 50 g
Calculation factor = 50/1000 =0.05
Procedure: 1)
2)
3)
4)
5)
6)
7)
8)
9)
Weigh all the ingredient accurately
Mix oily substances (stearic & oleic acid) together and heat on water bath
Dissolve Pot. Hydroxide in 20 ml water
Dissolve Boric acid in 20 ml water
Heat aqueous substances at the same water bath
Add Pot. Hydroxide with stirring, then add glycerin
Neutralize with boric acid solution and keep stirring until cooling.
Dispense in container and shake well
Make label as follow :
AUST
DATE
Vanishing cream B.P
Apply when necessary
NAME
External use only
- Use :- As protective when necessary
15
EXPERIMENT 3
Preparation of Emulsions Using Non-Ionic Surfactant as Emulsifying Agent
Utilizing HLB System.
Introduction:
The HLB (Hydrophile- Lipophile Balance) system is used for describing the
characteristics of a surface-active agent. It consists of an arbitrary scale to which
HLB values are experimentally determined and assigned. If the HLB value is low,
there is a low number of hydrophilic groups on the surfactant and it is more
lipophilic (oil soluble) than hydrophilic (water soluble). For example, Span 80 has
an HLB value of 4.3, from Table 2, and is oil soluble. If the HLB value is high, there
is a large number of hydrophilic groups on the surfactant and it is more hydrophilic
(water soluble) than oil soluble. For example, Tween 20 has an HLB value of 16.7
and is water soluble. Some general applications of materials with various HLB
values are as follows:
Low 1-3
3-6
7-9
8-18
13-16
16-18
Antifoaming agents
Emulsifying agents
Wetting agents
Emulsifying agents
Detergents
Solubilizing agents
(w/o emulsions)
(o/w emulsions)
Wetting agents are surfactants with HLB values of 7 to 9. Wetting agents aid in
attaining intimate contact between solid particles and liquids. Emulsifying agents are
surfactants with HLB values of 3 to 6 or 8 to 18. Emulsifying agents reduce
interfacial tension between oil and water resulting in minimizing surface energy
through the formation of globules. Detergents are surfactants with HLB values of 13
to 16. Detergents will reduce the surface tension and aid in wetting the surface and
the dirt. The soil will be emulsified, foaming may occur, and the dirt will wash
away. Solubilizing agents have HLB values of 16 to 18.
An HLB of 10 or greater is primarily hydrophilic and less than 10 would be
lipophilic. Spans have HLB values ranging from 1.8 to 8.6, indicative of oil-soluble
or oil-dispersible molecules. Consequently, the oil phase will predominate and the
emulsion formed will be water-in-oil. Tweens have HLB values ranging from 9.6 to
16.7, indicative of water-soluble or water-dispersible molecules. Therefore, the
water phase will predominate and oil-in-water emulsions will be formed.
16
Blending of Surfactants
Often a blend of emulsifiers produces a more stable emulsion than the use of a
single emulsifier with the correct, calculated HLB. Since the HLB numbers are
additive, the HLB value of a blend can be calculated.
For example, if 20 mL of an HLB of 9.65 are required, then two surfactants (with
HLB values of 8.6 and 12.8) can be blended in a 3:1 ratio. The following quantities
of each will be required:
3/4 x 8.6 = 6.45 (15 mL)
1/4 x 12.8 = 3.20 (5 mL)
TOTAL HLB = 9.65 (20 mL)
Table 2: HLB Values of Emulsifiers
Commercial Name
Chemical Name
Acacia
Glyceryl monostearate
Methocel 15 cps
PEG 400 Monoleate
PEG 400 Monostearate
PEG 400 Monolaurate
Pharmagel B
Potassium oleate
Sodium lauryl sulfate
Sodium oleate
Span 20
Span 40
Span 60
Span 65
Span 80
Span 85
Tragacanth
Triethanolamine oleate
Tween 20
Tween 21
Tween 40
Tween 60
Tween 61
Tween 65
Tween 80
Tween 81
Tween 85
Acacia
Glyceryl monostearate
Methylcellulose
Polyoxyethylene monooleate
Polyoxyethylene monostearate
Polyoxyethylene monolauratet
Gelatin
Potassium oleate
Sodium lauryl sulfate
Sodium oleate
Sorbitan monolaurate
Sorbitan monopalmitate
Sorbitan monostearate
Sorbitan tristearate
Sorbitan monooleate
Sorbitan trioleate
Tragacanth
Triethanolamine oleate
Polyoxyethylene sorbitan monolaurate
Polyoxyethylene sorbitan monolaurate
Polyoxyethylene sorbitan monopalmitate
Polyoxyethylene sorbitan monostearate
Polyoxyethylene sorbitan monostearate
Polyoxyethylene sorbitan tristearate
Polyoxyethylene sorbitan monooleate
Polyoxyethylene sorbitan monooleate
Polyoxyethylene sorbitan trioleate
17
HLB
Value
12.0
3.8
10.5
11.4
11.6
13.1
9.8
20.0
40.0
18.0
8.6
6.7
4.7
2.1
4.3
1.8
13.2
12.0
16.7
13.3
15.6
14.9
9.6
10.5
15.0
10.0
11.0
Preservation of Emulsions
Emulsions will support microbiological growth. Contamination of the
products can occur during the preparation of the emulsion as well as during its use.
To minimize contamination, the work area and equipment should be clean and every
attempt made to produce a "clean" product. However, if the product is to be stored
for any length of time, consideration must be given to the addition of a preservative.
Table 3: Required HLB Values for Some Common Lipid Material to Prepare
o/w Emulsions
Material
Beeswax
Cetyl alcohol
Cottonseed oil
Lanolin, anhydrous
Mineral oil, light/heavy
Paraffin wax
Petrolatum
Stearic acid
Stearyl alcohol
Required HLB
12
15
10
10
12
11
12
15
14
A preservative must be nontoxic, stable, compatible, inexpensive, and have an
acceptable taste, odor and color. It should also be effective against a wide variety of
bacteria, fungi and yeasts.
Preservatives may partition into the oil phase and lose their effectiveness. Bacterial
growth normally will occur in the aqueous phase. Consequently, the preservative
should be concentrated in the aqueous phase. Additionally, since the un-ionized
form of the preservative will be more effective against bacteria, the majority of the
preservative should be present in the non-ionized state. The preservative must
neither be bound nor adsorbed to any agent in the emulsion or the container in order
to be effective. In summary, only the preservative in the aqueous phase in the free,
unbound, unadsorbed, un-ionized state will be effective in emulsions. Example
preservatives often used in emulsions are shown in Table 4. The parabens
(methylparaben, propylparaben, butyl-paraben) are among the most satisfactory
preservatives for emulsions.
Antioxidants for Emulsions
Oils and fats are subject to rancidification resulting in a product exhibiting an
unpleasant odor, appearance and taste. In order to minimize this, antioxidants can be
added to the preparation. Example antioxidants are listed in Table 5.
18
Flavoring Emulsions
The selection of an appropriate flavoring agent must be made with
consideration of the external phase of the emulsion. For example, if a flavoring oil is
used and the majority partitions into the internal phase, the flavor strength will be
reduced. Oils can be incorporated using small quantities of surfactants (usually
surfactants with HLB values of 15-18 are used, often in conjunction with a
surfactant with an HLB value in the range of 8 to 12). As a general rule, from three
to five times as much surfactant as oil is required to insure solubilization. In order to
accomplish this with best results, the oil should be mixed with the surfactants prior
to addition into the aqueous phase. Since there is a loss of some of the potency of the
flavor using this technique, an alternative is to use a cosolvent system rather than a
surfactant system to incorporate the flavor. The use of ethanol, glycerin or some
appropriate solvent often provides acceptable results.
Table 4: Preservatives Used For Emulsions
Alcohol
Benzoic acid, sodium benzoate (pH< or = 1 4)
Benzyl alcohol (pH 5)
Chlorobutanol*
Imidazolidinyl Urea (Imidurea)
Mercurials
Organic Mercurials
Phenylmercuric Nitrate
Phenylmercuric Acetate
Thimerosal
15%
0.05-0.10%
1-4%
0.5%
0.05-0.5%
0.005%
0.002-0.004%
0.002-0.004%
0.005-0.02%
Parabens**
Methylparaben
0.05-0.3%
Propylparaben
0.02-0.2%
Butylparaben
0.02-0.2%
Quaternary Ammonium Compounds
Benzalkonium Chloride
0.002-0.1%
Sorbic acid (pH<6)
0.1-0.2%
*Chlorbutanol needs a pH<5. It will also sorb to plastic.
**Usually used in pairs. Low water solubility. Poor taste. May degrade at a pH>8.
Use at pH 4-8.
19
Emulsion Stability
Emulsion stability can be enhanced by:
1. decreasing the globule size of the internal phase
2. obtaining an optimum ratio of oil to water
3. increasing the viscosity of the system.
Since the oil-to-water ratio is frequently determined by the referring physician
(concentration of active ingredient: oil), the compounding pharmacist can work with
the first and third items listed above to enhance the emulsion's stability.
TABLE 5: Antioxidants for Emulsions
Ascorbic acid
Ascorbyl palmitate
Butylated hydroxyanisole
Butylated hydroxytoluene
Gallic acid
4-Hydroxymethyl-2, 6, -di-tert-buylphenol
Propyl gallate
Sulfites
L-Tocopherol
If the globule size is reduced to less than 5 microns, the stability and dispersion of
the emulsion will increase. This can be accomplished with the shearing action of a
mortar/pestle and an homogenizer.
The optimum phase volume ratio generally is obtained when the internal phase is
about 40-60% of the total quantity of the product. As the percentage of the internal
phase increases, the viscosity of the product also increases.
Enhancement of viscosity of the external phase also will tend to enhance the stability
of the emulsion. This is accomplished by the addition of a substance which is
soluble in or miscible with the external phase of the emulsion. For o/w emulsions,
hydrocolloids can be used. For w/o emulsions, waxes and viscous oils as well as
fatty alcohols and fatty acids can be used.
Of obvious concern in the preparation of emulsions is their physical stability. This is
characterized by an absence of creaming and coalescence and the maintenance of the
original appearance, odor, color and other physical properties.
Creaming occurs when the globules flocculate and concentrate in one specific part
of the emulsion. This results in a lack of uniformity of drug distribution and
unsightly product. Creaming is most often characterized in o/w emulsions by the oil
globules gathering and rising to the top. This is due to a the fact that the oil generally
is less dense than the water phase. Creaming is easily reversible and the product can
be evenly redistributed by shaking. It is reversible because the dispersed globules
20
still have the protective film around them. Two methods of minimizing creaming
include enhancing the viscosity of the external aqueous phase and reducing the
globule size to a very fine state with an homogenizer. Another approach would be to
adjust the densities of both the internal and external phase so that the densities are
the same, which would result in no tendency for either phase to rise to the top or
settle to the bottom.
Coalescence, or breaking, is an irreversible process since the film surrounding the
individual globules has been destroyed. Viscosity alterations may help to stabilize
these and minimize a tendency to coalescence. An optimum viscosity can be
experimentally determined. Another factor is the phase volume ratio, or the ratio of
the internal volume to the total volume of the product. A maximum phase volume
ratio that can be achieved, assuming perfectly spherical particles, is 74%. In general,
a phase-volume ratio of about 50%, which approximates loose packing of spherical
particles (i.e., a porosity of 48% of the total bulk volume of a powder), results in a
reasonably stable emulsion.
Phase Inversion
Phase inversion can be viewed as both good and bad. It occurs when an
emulsion inverts from one form to another, that is, o/w to w/o or w/o to o/w. Phase
inversion can result in the formation of a better emulsion and is the basis for the
Continental method of emulsion preparation. Monovalent cations tend to form o/w
emulsions and divalent tend to form w/o emulsions. If sodium stearate is used
initially to form an o/w emulsion, followed by the addition of a calcium salt to form
calcium stearate, then the emulsion inverts from an o/w into a w/o emulsion. The
Continental method of emulsion preparation involves the use of a small proportion
of water in the presence of a large proportion of oil. The initial emulsion nucleus that
is formed is of the w/o type. Further addition of water, in small quantities, eventually
results in an inversion into an o/w emulsion.
General Comments on Emulsions
- The viscosity of emulsions generally increases upon aging.
- The greater the volume of the internal phase, the greater the apparent viscosity.
- There is a linear relationship between emulsion viscosity and the viscosity of the
continuous phase.
- It has been said that, under a given set of conditions, an oil-in-water emulsion is
more easily produced with glass equipment and a water-in-oil emulsion is more
easily produced with water-repellent plastic equipment. This could be related to the
"wet ability" of the external phase in contact with the surface of the equipment
21
Rx





Liquid paraffin
Wool fat
Cetyl alcohol
Emulgent
Water
to
35
1
1
7
100
-Required HLB values of the first three ingredients are respectively 12, 10 and 15
for an o/w emulsion.
The total percentage of oil is ( 35 + 1 + 1 = 37 % ) , and the proportions of the oil
phases ingredients are :- Liquid paraffin
35 / 37 = 94.6 %
- Wool fat
1 / 37 = 2.7 %
- Cetyl alcohol
1 / 37 = 2.7 %
The total required HLB value is obtained as follows :
Liquid paraffin
94.6 % × 12 = 11.4
Wool fat
2.7 %
Cetyl alcohol
2.7 %
( The total required HLB )
× 10
× 15
= 0.3
= 0.4
= 12.1
- Assume that a mixture of sorbitan monolaurate (Span 20 has HLB value = 8.6 )
and polysorbate 80 (HLB value = 15 )is to be used as the emulgent blend . The
proportion of these two substance that will provide the required HLB value of
12.1 is calculated as follows:
- Let x = the percentage of sorbitan monolaurate in the mixture
Then 1 – x = the percentage of polysorbate
- Contribution from sorbitan monolaurate = 8.6 × ( x)
- Contribution from polysorbate 80
= 15 × [(1 – x)]
- since the total contribution must = 12.1 , the expression for calculating ( x ) is ,
8.6 × (x) + 15 × [(1 – x)] = 12.1
8.6 x + 15 - 15x = 12.1
2.90 = 6.4x
x = 45.3 %
22
- Hence , the percentages of the emulsifying agents in the mixture are :
Sorbitan monolaurate
Polysorbate 80
45.3%
54.7%
- Since the total percentage of the mixed emulgents in the formula is 7 , the
percentages of the individual substances are
Sorbitan mono-oleate
Polysorbate 80
7 × 45.3% = 3.17 g
7 – 3.17 = 3.83 g
Procedure:
 Weight 35g of liquid paraffin, 1 g of wool fat, 3.17 g of span 20 and 1 g cetyl
alcohol.
 Place them in a beaker and try to dissolve with gentle heating.
 Dissolve 3.83 g of Tween 80 in 64 ml of water.
 Add Tween solution to the oily phase with stirring
 Write label
23
Part 2
OINTMENTS
24
Introduction :
Ointments are used topically for several purposes, e.g., as protectants,
antiseptics, emollients, antipruritics, kerotolytics, and astringents. The vehicle or
base of an ointment is of prime importance if the finished product is expected to
function as any one of the above categories. In the case of a protective ointment, it
serves to protect the skin against moisture, air, sunrays and other external factors. It
is necessary that the ointment neither penetrates the human skin barriers nor
facilitates the absorption of substances through this barrier. An antiseptic ointment is
used to destroy or inhibit the growth of bacteria. Frequently bacterial infections are
deeply seated; a base that has the capacity to either penetrate or dissolve and release
the medication effectively is therefore desired. Ointments used for their emollient
effect should be easy to apply, be non-greasy and effectively penetrate the skin.
Physical Characteristics of Ointment Bases
There are five (5) classes or types of ointment bases that are differentiated on
the basis of their physical composition. These are:
 Oleaginous bases
 Absorption bases
 Water in oil emulsion bases
 Oil in water emulsion bases
 Water soluble or water miscible bases
Each ointment base type has different physical characteristics and therapeutic uses
based upon the nature of its components. The following table summarizes the
composition, properties, and common uses of each of the five types. For more
information consult Remington's.
25
PROPERTIES OF OINTMENT BASES
Oleaginous
bases
Composition
Water
Content
Affinity for
Water
oleaginous
compounds
anhydrous
Absorption
Bases
W/O Emulsion
Bases
O/W Emulsion
Bases
Water
Miscible
Bases
oleaginous base
oleaginous base +
oleaginous base
+ water (> 45% Polyethylene
water (< 45% w/w)
+ w/o
w/w) + o/w
Glycols
+ w/o surfactant
surfactant
surfactant (HLB
(PEGs)
(HLB <8)
>9)
anhydrous,
anhydrous
hydrous
hydrous
hydrous
hydrophobic
hydrophilic
hydrophilic
hydrophilic
hydrophilic
Spreadability
difficult
difficult
moderate to easy
easy
moderate to
easy
Washability
nonwashable
nonwashable
non- or poorly
washable
washable
washable
unstable,
oils poor;
unstable, especially especially alkali
hydrocarbons
alkali soaps and soaps and natural
stable
Stability
better
natural colloids
colloids;
nonionics better
solids, oils, and
solid and
solids or oils
solids, oils, and
solid and
Drug
aqueous
aqueous
aqueous solutions
aqueous
Incorporation (oil solubles
solutions (small
solutions (small
only)
(small amounts)
solutions
Potential
amounts)
amounts)
poor, but >
Drug Release
poor
fair to good
fair to good
good
oleaginous
Potential*
yes
yes
sometimes
no
no
Occlusiveness
protectants,
emollients (+/protectants,
emollients,
emollients,
), vehicles for
emollients (+/cleansing creams,
vehicles for
aqueous
), vehicles for
vehicles for solid, solid, liquid, or drug vehicles
Uses
solutions,
hydrolyzable
liquid, or non- non-hydrolyzable
solids, and nondrugs
hydrolyzable drugs
drugs
hydrolyzable
drugs
Hydrophilic
Cold Cream type,
Petrolatum,
Hydrophilic
White
Hydrous Lanolin,
Anhydrous
Ointment,
PEG
Petrolatum,
Rose Water
Lanolin,
Dermabase™,
Ointment,
Examples
White
Ointment,
Aquabase™,
Velvachol®,
Polybase™
Ointment
Hydrocream™,
Aquaphor®,
Unibase®
Eucerin®, Nivea®
Polysorb®
*Varies depending upon specific content of the ointment base and the relative polarity of the
drug(s) incorporated. This table refers more generally to the release of a typical nonelectrolyte
(primarily lipophilic) drug.
26
oils poor;
hydrocarbons
better

Oleaginous Bases
To incorporate an insoluble drug into these bases, pulverize the powder on the
pill tile or with a mortar and pestle (above/right). Use a levigating agent to wet the
powder and then incorporate the wetted powder into the ointment base. Generally,
the amount of drug to be incorporated into the ointment will be much less than the
amount of ointment. In other words, a small amount of drug will be incorporated
into a large amount of ointment. The processes of geometric dilution will "diluted"
the drug into the ointment. Geometric dilution involves a series of dilution steps. It
begins by incorporating the drug into an amount of ointment of approximately the
same size. Then a second amount of ointment approximately equal to the first
mixture is added and mixed. This stepwise dilution process is continued all of the
ointment has been used.
A good levigating agent is mineral oil since it is compatible with oleaginous bases.
Sometimes using a small quantity of the base itself as the levigating agent is
sufficient.
Soluble drugs can be incorporated into oleaginous bases by fusion. The base is
liquefied over low heat (not to exceed 70°C) and then the drug is added to the
molten base. The mixture is then allowed to cool with occasional stirring.
Show how to incorporated a drug into an ointment using geometric dilution & 2
spatulas

Absorption Bases
An absorption base is an oleaginous base that contains a w/o emulsifying
agent. When water is taken up into the base, it will form a w/o emulsion. Absorption
bases typically can incorporate about 50% of their volume in water.
Incorporating insoluble drugs into these bases can be done mechanically or by
fusion. The final destination (internal or external phase of the emulsion) of the drug
must be considered when selecting a levigating agent. If the drug will reside in the
internal phase (water phase), then the levigating agent should be water soluble or
miscible. Water, glycerin, alcohol, or propylene glycol would be suitable levigating
agents. If the drug will reside in the external phase, then mineral oil should be used.
Water soluble ingredients can be added to the water phase of the w/o
emulsion. If the drug will dissolve in a small amount of water, the aqueous solution
can be added directly to the base using a pill tile and spatula. If a larger quantity of
water is needed to solubilize the drug or if an aqueous solution is being added to the
base, heat may be needed to compound the formulation. It may be necessary to add
additional emulsifier to the emulsion to accommodate the added water. Some
commercial emulsions do have the necessary excess emulsifier.
27

W/O Emulsion Bases
Oils and insoluble powders can be directly incorporated into the external
phase using a pill tile and spatula. If a levigating agent is to be used with the
insoluble powders, it should be miscible with the oil phase; mineral oil would be a
suitable agent. Levigating agents may be needed with larger quantities of insoluble
powders. If the insoluble powder has a different salt form that is oil soluble,
consideration should be given to using that salt form.
The same comments that apply to incorporating water-soluble ingredients into
absorption bases also apply to w/o emulsion bases.

O/W Emulsion Bases
Water-soluble powders can be directly incorporated into the external phase
using a pill tile and spatula. If the powder is insoluble, the levigating agent should be
water miscible so glycerin, propylene glycol, polyethylene glycol (PEG) 300 or 400,
or alcohol would be acceptable. If the insoluble substance has a different salt form
that is aqueous soluble, consideration should be given to using that salt form.
It may be more difficult to incorporate oil soluble ingredients into the o/w
formulation. A small amount of oil can be incorporated into the base if there is
excess emulsifier. Some commercial products do have the necessary excess
emulsifier. If a larger portion of oil is to be added, the addition of more emulsifier
may be necessary. If heat is used to incorporate the oil, it is important to work
quickly so that water is not evaporated from the product. This will cause the product
to become stiff and waxy.

Water Miscible Bases
Water soluble drugs can be dissolved in a small quantity of water and
incorporated using a pill tile and spatula. Insoluble powders will require a water
miscible levitating agent such as glycerin, propylene glycol, or polyethylene glycol
400. Oils can be added into these bases by first mixing the oil with glycerin or
propylene glycol, and then incorporating the mixture into the base. Heat may be
necessary if the quantity of liquid to add to the base is large.
28
GENERAL COMMENTS ABOUT COMPOUNDING OINTMENT BASES
 Between 2 and 4 grams of an ointment may be lost in the compounding
process. The ointment is lost as it adheres to beakers, ointment tiles, or
ointment pads. To compensate for this loss, make an excess of the
ointment. Some general rules might be to add 10% or 3 grams excess to
the prescribed amount.
 When heat is used to melt ingredients, use a water bath or special low
temperature hotplate. Most ingredients used in ointment bases will
liquefy around 70°C These two heating devices provide adequate
control over the heating and will ensure that the ingredients are not over
heated. A water bath will only heat to the boiling point of water which
is 100°C. Special "low temperature" hotplates (full range is 25°C to
120°C) are not a standard laboratory type hotplate; those hotplates heat
at 125°C to 150°C at their lowest setting.
 When both an oil and aqueous phase are being mixed together to make
an ointment, it is helpful to heat the aqueous phase a few degrees higher
than the oil phase prior to mixing. The aqueous phase tends to cool
faster than the oil phase and may cause premature solidification of some
ingredients. However, use the lowest temperature possible and keep the
time of heating as short as possible. This will minimize the quantity of
water lost through evaporation.
 When melting a number of ingredients, melt the ingredient with the
highest melting point first. Then gradually reduce the heat to melt the
ingredient with the next lowest melting point. Continue this process
until all ingredients have been added. This will ensure that the
ingredients were exposed to the lowest possible temperature and thus
enhance the stability of the final product.
 The cooling step in an ointment's preparation is an important part of the
compounding process.
 Do not accelerate the cooling process by putting the melt in water or
ice. This will change the consistency of the final product making it
more stiff than desired.
29
 If adding volatile ingredients such as oils, flavors, or drugs, add them
when the product is "cool to the back of the hand." The melt will still be
fluid enough for adequate mixing but not hot enough to evaporate the
ingredient.
 Ointments should be cooled until just a few degrees above solidification
before they are poured into tubes or jars. They should be thick, viscous
fluids. This will minimize "layering" of the ointment in the packaging
container. However, this is not the preferred method of packing an
ointment tube or jar.
 Most bases achieve their final consistency and texture several hours
after they are compounded.
30
EXPERIMENT 4
 Simple ointment
Rx
 Hard paraffin
 White soft paraffin
 Send 20g
50g
950g
Procedure :
1- The weighed amount of hard paraffin is placed in a dish and heated on a water
bath until complete melting.
2- Then add the weighed amount of white soft paraffin to the dish content and mix
complete melting.
3- Remove the dish from water bath and mixes well until complete congeal.
4- Transfer into a wide mouthed screw capped jars.
Uses :
Emollient and as vehicle for other preparation .
Storage : In cool place in a wide mouth screw capped jar .
 Macrogol ointment BP.
Rx
 Hard Macrogol
 Liquid Macrogol
 Send 20g
500g
500g
Procedure:
Melt the hard Macrogol, add the liquid Macrogol, and stir until cold.
Note:
Hard Macrogol is polyethylene glycol 4000and liquid Macrogol is polyethylene
glycol 400.Store it in cool place in wide mouth screw capped jar.
Uses: Emollient
31
EXPERIMENT 5
 Absorption base ointment
Rx




Hard paraffin
Wool fat
White soft paraffin
Send 20g
50g
50g
900g
Label: to be applied as directed.
Procedure:
1- The weighed amount of white soft paraffin, wool fat and hard paraffin are placed
in a dish and heated on a water bath until complete melting.
2- Remove the dish from water bath and mixes well until complete congeal.
3- Transfer into a wide mouthed screw capped jars.
Uses: Emollient and as a vehicle for other preparation.
Storage: To be stored in cool place in a wide mouthed screw capped jars.

Rx
Emulsifying wax BP.




Cetostearyl alcohol
Sodium lauryl sulfate
Purified water
Send 20g
90g
10g
4ml
Procedure:
Melt the cetostearyl alcohol and heat to about 85 add the sodium lauryl sulfate, mix
add the purified water, heat to 85, and maintain at this temperature , stirring
vigorously , until frothing ceases and the product is translucent . Cool quickly.
Storage: Store it in cool place in wide mouth screw capped jar.
Uses: To prepare emulsifying ointment
32

Rx
Emulsifying Ointment BP




Emulsifying wax
White soft paraffin
Liquid paraffin
Send 20g
300g
500g
200g
Procedure:
Melt emulsifying wax, white soft paraffin and liquid paraffin together in water bath
and stir until cold.
Note: Emulsifying ointment is used to prepare aqueous cream BP. which contains
almost 70 percent of water.
Storage: Store it in cool place in wide mouth screw capped jar.
33
EXPERIMENT 6
Evaluation of Drug Release from Ointment Bases
Introduction:
One of the most important functions of an ointment is the control it exerts
over the release and therefore the therapeutic activity of the medication, which it
carries. Although the vehicles, or base may not penetrate the skin to any extent , it is
known that the clinical effectiveness of a drug may vary when it is incorporated in
different vehicles . These variations in drug release and absorption are a function of
the physical and chemical properties of both the vehicles and the drug.
In the present experiment, you will evaluate the facility with which a number
of vehicles, or ointment bases release salicylic acid. The ointment bases involved in
this study include:
Oleaginous base (white ointment USP)
Water soluble base (polyethylene glycol ointment USP)
Emulsion base:
a. Hydrophilic ointment USP.
b. Cold Cream.



This study will involve determining the rate of drug release from ( one side of ) a
layer of ointment in which the drug is initially dissolved , as well as to study the
effect of the drug concentration and the presence of an inert filler on the drug release
from that ointment ( review Higuchi’s equation ) .
Procedure:
1. The students will be divided into seven groups . Each group will study
salicylic acid release from one of the following preparations :
A.
B.
C.
D.
E.
F.
G.
34
10% salicylic acid in white ointment (USP)
2% salicylic acid in PEG ointment (USP)
5% salicylic acid in Cold cream .
5% salicylic acid in hydrophilic ointment (USP)
10% salicylic acid in hydrophilic ointment (USP)
10% salicylic acid in hydrophilic ointment (USP) + 2% talc.
10% salicylic acid in hydrophilic ointment (USP) + 10% talc.
2. Each group will be provided to be studied , bottle-cap , rubber band , semi –
permeable membrane (dialysis tubing 1¼  ) stand , magnetic stirrer ,
magnetic bar , 2-7 ml pipettes , two cuvetts , one 600 ml beaker and 600 ml of
1% Trinder’s reagent .
3. Place the ointment in the bottle cap and level the ointment with the edge of
the cap .
4. Place the semi-permeable membrane over the ointment and use the rubberband to hold the membrane in place .
5. Use the camp to hold the bottle cap with the ointment surface downwards.
6. Measure 400 ml of 1% Trinder’s reagent and put it in 600 ml beaker . Put the
magnetic bar in the beaker and then place it on the magnetic stirrer. Start the
stirrer at its lowest speed .
7. Lower the clamp into the 1% Trinder’s reagent so that the ointment surface is
just immersed in the reagent and note the time .
8. Take a 5 ml sample every 15 minutes, and replace it with fresh 5 ml of 1%
Trinder’s reagent. Tabulate the result in the following sheet:
Ointment used : -------------------------------------------------------------------Sample #
Time (mins)
1
2
3
4
5
6
7
8
9
10
15
30
45
60
75
90
105
120
135
150
Absorbance
Total amount
released
9. Assay for salicylic acid in each sample. To assay your solutions two
spectrophotometer cuvettes are needed, one for the blank and the second to be
used for the solution to be assayed.
I.
35
Fill the blank cuvette with 1% Trinder’s reagent solution, and wipe it free
of the dust oil. Insert it in the holder of the Spectro 22RS, close top and
adjust to 100 % Transmittance, Make sure you position the etched marking
on the cuvette toward the front of the holder each time you insert it.
II. Remove the blank from the holder of the Spectro 22RS and make sure the
needle returns to zero transmittance , if not adjust it and repeat procedure
again .
II.
Fill the second cuvette with the sample. Insert it in to the Spectro 22RS
holder , close cover and read the absorbance value on the meter . Start with
the most dilute sample and progress to the most concentrated. Raise the
cuvette each time with a small amount of the sample being assayed. Repeat
procedure with each sample and check to the 100 % reading with the blank
solution between each sample reading.
10. At the end of the lab. , each student should have a set of data for each of the
experiments .
11. Calculate the amount of Salicylic acid released from the ointment as a function
of time using the following equation:
n
Amount released = An/a x (400) + (5/400) i
Where (A)
(a)
(i)
(n)
Ai /a x (400)
= the absorbance .
= the absorptivity (i.e. slope of Beer’s plot = 12.25 mg/ml )
= Sample number
= Integar
(5/400) i Ai /a x (400) = the amount due to dilution effect upon replacing
the sample with release medium .
n-1
12.List the amount of salicylic acid released ( calculate in step 10 ) on the working
sheet .
13.Calculate the surface area of the bottle cap.
Data Analysis :






36
Using the working sheet for the seven experiments , calculate the amount
released per unit area of ointment .
Plot the amount released per unit area vs. time and draw a smooth curve
through the data points for each ointment.
Plot amount released per unit area vs. the square root of time and draw the best
line through the data points for each ointment.
Compare the release rate of salicylic acid from the different ointment bases
Observe the effect of salicylic acid concentration on the release rate.
Observe the effect of Talcum powder (and its concentration) on the release
rate.
Part 3
OPHTHALMIC AND PARENTRAL
PERPARATIONS
37
Calculations required for Intravenous Admixture and TPN
Prescription compounding is a rapidly growing component of pharmacy
practice. This can be attributed to a number of factors, including individualized
patient therapy, lack of commercially available products, home healthcare,
intravenous admixture programs, total parenteral nutrition programs and "problem
solving" for the physician and patient in enhancing compliance with a specific
therapeutic regimen. Pharmacists are creative and should have the ability to
formulate patient-specific preparations for providing pharmaceutical care. Most
compounded prescriptions require a number of calculations as part of preparation,
packaging and dispensing. These calculations include milliequivalents, millimoles,
osmolality, concentration terms, and dilution of stock solutions.
Experiment 7
Preparation of Solution with given milliequivalents, millimoles and
milliosmoles:
Equivalent weight is the molecular weight divided by the valence of the molecule
and milliequivalent is one thousandth of the Equivalent. However, Moles are weight
of solute in gm/formula weight [i.e (w2/M2 ) and millimoles are one thousandth of
the moles [[(w2/1000*M2 )]. Where, w2= wt. of solute and M2 = molecular weight
of solute. On the other hand, Osmolality = [number of moles * number of ions] and
milliosmoles = [ # of moles /(1000* # of ions)]
For Examples;
1.
Preparation of one liter of 25 milliequivalents of sodium chloride.
1 equivalent NaCl = 58.5 gm, 1 milliequivalent = 58.5mg;
Therefore,
The quantity of NaCl required = 25 mEq x 58.5 mg/mEq
= 1.463 g
2.
Preparation of one liter of 10 mEq of Ca++ using a standard 10%
CaCl2 .
Ca++ = 40/2 = 20 mg/mEq
Using proportionality. Then
1/10 mEq = 20 mg/ x
and
x = 200 mg of Ca++ required
Since, CaCl2 = 40 + 71 = 111, Then
40/111 =200/ x mg
and
x = 555 mg CaCl2 required
38
10 /1000ml = 0.555 g / x and
x = 55.5 mL of the 10% CaCl2 solution
Millimoles:
How many millimoles of NaCl are contained in 1 liter of 0.9% Sodium Chloride
Solution? (Formula weights: Na=23, Cl=35.5, NaCl=58.5).
0.009 x 1000 mL = 9 g NaCl
1 mole NaCl weighs 58.5 g
1/58.5g = x /9g
,
x = 0.154 mole = 154 millimoles
Osmolality:
What is the osmolality (number of milliosmoles) of 1 liter of 0.9% sodium chloride
solution? (Assume complete dissociation)
Na=23, Cl=35.5, NaCl=58.5, NaCl --> Na+ + Cl
# millimoles NaCl present per liter = 154 from previous problem
154 millimoles NaCl x 2 species (Na + Cl) = 308 mOsmol/liter
What is the osmolality of 10% CaCl2 solution? (Assume complete dissociation)
(Formula weights: Ca=40, Cl=35.5, CaCl2=111g/L)
10% CaCl2 = 100 g/1000 mL
100 / 111 g
=
x / 1 mole
x = 0.9 moles/liter = 900 millimoles
CaCl2 ----> Ca++ + 2 Cl = 3 species
900 millimoles CaCl2/L x 3 species = 2700 mOsmol/Lite
Stock Solutions:
A pharmacist is preparing an ophthalmic decongestant solution in batch form. Each
of three bottles will contain 15 mL. The preservative to be incorporated is 0.01%
benzalkonium chloride (BAK). The pharmacist has a stock solution containing 17%
BAK. How much of this stock solution would be required for the three bottles?
15 x 3
= 45 mL
45 x .0001
= .0045 g
0045/ x
=17/100
x
= 0.026mL
Specific Gravity in Weighing/Measuring:
A pharmacist receives a prescription for 120 mL of a 3% w/v Hydrochloric Acid
solution. The density of concentrated hydrochloric acid (37%) is 1.18 g/mL. How
many milliliters of the concentrated acid would be required for the Rx?
3% = .03
.03 x 120 mL = 3.6 g required
Volume =3.6 g/1.18 g/mL= 3.05 mL
37% = 0.37
, 3.05 mL /0.37= 8.24 mL
39
Mixing Products of Different Strengths:
A pharmacist receives an order for 120 g of a 0.1% corticosteroid ointment. On hand
are 1 oz of 0.1%, 2 oz of 0.15% and 2 ½ oz of 0.005%, all in the same ointment
base. If these three ointments are mixed together, how much additional
corticosteroid powder should be added to prepare the prescription? Assume the
quantity of corticosteroid added will be negligible compared to the 120 g total
weight.
120 x .001
=
120 mg needed
30 x 0.001
=
30 mg
15 x .0015
=
22.5 mg
75 x .00005
=
3.8 mg
-----Total
56.3 mg
120 mg - 56.3 mg = 63.7 mg
In what quantities could a 50% dextrose in water be mixed with a 5% dextrose in
water to obtain 900 mL of 15% dextrose in water?
50
10 ÷ 5 = 2
15
5
35 ÷ 5 = 7
-------
Total:
9 parts
(2/9)x 900 = 200 mL of D50W
(7/9)x 900 = 700 mL of D5W
------------900 mL Total Volume
Powders for Reconstitution:
The directions to constitute an amoxicillin suspension 250 mg/5 mL, 150 mL, state
that 111 mL of Purified Water are required. The physician has requested the product
be constituted at a concentration of 500 mg/5mL. How much Purified Water would
be required?
150 mL - 111 mL
= 39 mL occupied by powder
250 mg/5 mL
= 50 mg/mL
50 mg/mL x 150 mL
= 7.5 g of powder
7.5/0.5
= 15 doses
15 doses x 5 mL
= 75 mL volume
75 mL - 39 mL
= 36 mL required
40
Units to Weight Conversions:
A Rx order calls for 150,000 units of nystatin per gram of ointment with 60 grams to
be dispensed. How much nystatin would be weighed? (4400 USP Nystatin units/mg)
150,000 u/g x 60 g
= 9,000,000 units needed
9,000,000/4400 u/mg
= 2.045 g required
Shelf Life Estimates:
Shelf life estimates can be made using the equation:
t90 Orig
t90New = -------3∆T/10
where ∆T = change in temperature
3 is a reasonable estimate for the "Q" value,
based on energies of activation from the Arrhenius equation.
An antibiotic solution has a shelf-life of 96 hours when in a refrigerator. If it is
necessary that a patient use it in an ambulatory pump at approximate body
temperature (30oC) over 6 hours, would it still retain at least 90% of its original
potency during the entire period of administration?
t90 =96 /325/10
= 6.16 hours Ans. = yes
A prescription is received for an ophthalmic solution with a shelf-life of 4 hours at
room temperature. The preparation is to be administered in a physicians office at
12:00 noon the next day. Can it be prepared the evening before at about 8:00 pm and
still retain at least 90% of its shelf life if stored in a refrigerator?
t90 = 4 / 3-20/10 = 4 / 3-2 = 36 hours
Ans. Yes
A reconstituted antibiotic has a shelf-life at room temperature of 3 days. How long
would the preparation be good if stored in a refrigerator? (A reasonable estimate
based on (t90).
t90 = 3d / 3 2
= 3 X 9 = 27 days
Ophthalmic and Nasal Solutions-Sodium Chloride Equivalents:
How much sodium chloride is required to render the following Rx isotonic?
Rx
Lidocaine HCl
1%
(NaCl equiv. = 0.22)
Cocaine HCl
1%
(NaCl equiv. = 0.16)
41
Epinephrine Bitartrate
Sterile Water
qs
Sodium Chloride qs
50 x .01 = 0.5 x .22 =
50 x .01 = 0.5 x .16 =
50 x .001 = .05 x .18 =
0.1% (NaCl equiv. = 0.18)
50 mL
0.110
0.080
0.009
----0.199 g
The ingredients represent the equivalent of 0.199 g of NaCl.
50 x .009 = 0.45 g
0.45 - 0.199 = 0.251 g
NaCl to make 50 mL water isotonic
NaCl needed to add to this Rx to make it isotonic
Ophthalmic and Nasal Solutions-Buffer Solutions & pH:
Rx
Optimycin
NaCl
Phosphate Buffer pH 6.5 qs
1%
qs
100 mL
(Sorensen Modified Phosphate Buffer )
Acid Stock Solution (1/15 M)
Sodium Biphosphate, Anhy. 8.006 g
Purified Water qs
1000
42
Alkaline Stock Solution (1/15 M)
Sodium Phosphate, Anhy. 9.473 g
Purified Water qs
1000 mL
pH
5.9
6.2
6.5
6.6
6.8
7.0
7.2
7.4
7.7
8.0
mL of 1/15 M Sodium
Biphosphate Solution
90
80
70
60
50
40
30
20
10
5
mL of 1/15 M Sodium
Phosphate Solution
10
20
30
40
50
60
70
80
90
95
To prepare 100 mL of pH 6.5 phosphate buffer solution, use 70 mL of 1/15 Molar
Solution Biphosphate Solution and 30 mL of 1/15 Molar Sodium Phosphate
Solution.
43
EXPERIMENT 7
Preparation of Isotonic Buffered preserved Solution
Introduction :
Solutions having identical osmotic pressure are said to be isotonic . For fluids
to be in the humans , an isotonic solution is one having the same osmotic pressure as
the body fluids e.g. blood , tears , or other tissue fluids .
Tonicity is dependent upon the number of particles of substance in solution
regardless of the nature of the particles , whether they be ions , molecules or
aggregates of molecules . Thus , some substances do not dissociate on going into
solution but exist in solution as molecules . Examples of such un dissociated
substances are dextrose and sucrose . Others , such as sodium chloride and similar
salts , dissociate more or less completely into ions . It requires 0.9 g of Sodium
Chloride ( M.W. 58.45 ) per 100 c.c. to make an isotonic solution . while 9.2 g of
Sucrose ( M.W. 342.3 ) are needed to produce the same osmotic effect .It can be
seen that the dissociation of a substance exerts a marked effect on the osmotic
pressure produced while the molecular weight of the compound is relatively
unimportant .
Preparation of Isotonic Solutions :
In order to calculate the osmotic pressure of the fluid to be prepared , we use
one or more of the colligative properties of solutions . Of these , the direct
determination of freezing point or the determination of the vapor pressure of
solutions in relation to the vapor pressure of known solutions of sodium chloride are
the most commonly employed because of their accuracy and relative ease of
determination .
When using the freezing point-depression , the problem is to obtain a solution
which will have the same freezing point as blood or tears , or – 0.52 o C . Since , in
dilute solutions , the lowering of the freezing point and the increase in osmotic
pressure are directly proportional to the total number of particles in solution , it is
obvious that solutions which have the same freezing point will have the same
osmotic pressure .
Thus when we wish to convert a hypotonic solution to an isotonic solution , we add
sufficient particles , usually of sodium chloride or of dextrose , to lower the freezing
point to that of blood or lacrimal fluid .
44
Methods of Calculations :
Sodium Chloride Equivalent Method
A sodium chloride equivalent ( E ) may be defined as a factor which converts a
specific amount of solute to the amount of sodium chloride which will produce the
same osmotic effect . For example , the sodium chloride equivalent of boric acid is
0.55 this means that 1 g of boric acid in solution produces the same number of
particles as 0.55 g of sodium chloride , also that 10 gr. Of boric avid is equivalent to
5.5 grains of sodium chloride .
The method is based on the fact that molar lowering of freezing point is
proportional to the ratio of the freezing point depression produced by the solute
to its molar concentration .
L = ∆t / C
Where
L = Molar lowering of the freezing point
∆t = depression of freezing point produced by the solute ( o C )
C = Molar concentration of the solute
To calculate the sodium chloride equivalent (E) of a substance the following
equation is used :
E = L/M ( 58.45/3.4 )
Where E is the sodium chloride equivalent of a substance having molecular
weht M and molar freezing point depression L .
58.45 = M.W. of sodium chloride
3.5 = L value of chloride
Table I shows the values of the molecular weights ( M ) the molar freezing point
depression ( L) , and the sodium chloride equivalents ( E) of some substances of
pharmaceutical importance .
To calculate the sodium chloride the Sodium Chloride equivalent of Sodium Acid
Phosphate ( NaH2PO4H2O )
L = 3.2
M= 138.0
E= L/M ( 58.45 / 3.4 )
= 3.2 / 138.0 ( 53.45 / 3.4 ) = 0.40
45
To calculate the sodium chloride equivalent of sodium phosphate ( anhydrous )
( Na2HPO4)
L= 4.4
M=141.98
E= L/M ( 58.45/3.4 ) = (4.4 / 141.98) (58.45/3.4 ) = 0.53
Table I
Substance
Alcohol ,dehydrated
Antipyrine
Barbital Sodium
Benadryl hydrochloride
Caffeine
Dexrose.H2O
Ephedrin hydrochloride
Glycerine
Pilocarpine nitrate
Sodium acid phosphate
(NaH2PO4.H2O)
Sodium phosphate ,anhydrous
Sodium phosphate ,7 H2O
M
L
E
46.07
188.22
206.18
291.81
194.19
198.17
201.69
92.09
271.27
138.00
1.9
1.9
3.5
3.5
0.9
1.9
3.6
1.8
3.7
3.2
0.70
0.17
0.29
0.29
0.08
0.16
0.30
0.34
0.23
0.40
141.98
268.08
4.4
4.6
0.53
0.29
These values were taken from Martin’s “ Physical Pharmacy “ pg.255-256 .
Sorenson Buffer System
Stock solutions :
Sodium Biphosphate (NaH2PO4.H2O ) : 9.208 g/1000 ml .
Sodium phosphate (Na2HPO4 ) : 9.470 g/1000 ml .
Sample calculation for case # 1 . ( Refer Table II )
Q . 90 ml of SODIUM BIPHAOSPHATE Sock Solution
+ 10 ml of SODIUM PHOSPHATE Stock Solution
Result in pH of 5.91
What is the Sodium Chloride equivalent of the buffer ?
46
A . Amount of Sodium Biphosphate = ( 9.208 / 1000 ) x 90 = 0.8287 g
Amount of Sodium phosphate = [( 9.470 x10 )/1000] = 0.0947 g
Sodium Chloride equivalent (E) for Sodium Biphosphate = 0.40
( from example 1 or Tables )
Sodium Chloride equivalent ( E) for Sodium Phosphate = 0.53
( from example 2 or Tables )
1 g Sodium Biphosphate = 0.40 g of Sodium Chloride
0.8287 g of Sodium Biphosphate = 0.40/1 x 0.8287
= 0.3315 g of Sodium Chloride
1 g Sodium Biphosphate = 0.53 g of Sodium Chloride
0.0947 g Sodium Phosphate = ( 0.53 x 0.0947 ) / 1
= 0.0502 g of Sodium Chloride
Amount of Sodium Chloride required to make an isotonic solution = 0.90g / 100 ml
Amount of Sodium Chloride required to make an isotonic buffered
solution = 0.90 – ( 0.3315 + 0.0502 )
= 0.52
EXERCISES
Fill in the blanks in the table below before you come to the lab. Show all the
calculations.
TABLE II
#
Sodium
Biphosphate
Solution ( ml )
1
2
3
4
5
6
7
8
9
10
90
80
70
60
50
40
30
20
10
5
47
Sodium Phosphate
Solution ( ml )
10
20
30
40
50
60
70
80
90
95
Resulting pH
5.91
6.24
6.47
6.64
6.81
6.98
7.17
7.38
7.73
8.04
Sodium Chloride
Required to
make Isotonic
Solution
0.52
Procedure
In the following prescription:
Rx
Isotonic Pilocarpine Nitrate ( 0.5 % w/v ) Solution
Buffered at pH 7.38
Prepare 50 ml
Apply one drop to each eye as directed by the physician
1. Make 25 ml of Sorenson’s buffer (pH 7.38 ) by mixing the required amounts
of sodium biphosphate stock solution and sodium phosphate solution .
2. Weigh out pilocarpine nitrate and sodium chloride .Sodium chloride is used to
adjust isotonicity ; the sodium chloride equivalent ( E) of pilocarpine nitrate is
0.23 .
3. Dissolve the pilocarpine nitrate and sodium chloride in the buffer prepared in
1.
4. Adjust the volume to 50 ml with water .
5. Check the pH of the solution (pH paper or pH meter ).
6. Transfer to a 2 oz. Bottle and label .
Calculations :
1. From Table II figure out the composition of Sodium Bicarbonate and Sodium
Phosphate solutions which will provide the required pH .
2. Calculate the amount of sodium chloride equivalent of each ingredient . (This is
done by multiplying the amount of each ingredient by its sodium chloride
equivalent )
3. Add the equivalent amounts of sodium chloride .
4. Subtract the equivalent amount of sodium chloride from the value of an isotonic
sodium chloride solution ( 0.9 g /100 ml )
Quantities : required to fill the above prescription :
Pilocarpine nitrate
Sodium Bicarbonate Stock Solution
Sodium Phosphate Stock Solution
Sodium Chloride
Sterile Purified Water Q.S.
48
-------------- g
-------------- ml
-------------- ml
-------------- ml
50 ml
EXPERIMENT 8
Compounding of Ophthalmic Liquids
Introduction
Ophthalmic solutions are sterile, free from foreign particles and especially
prepared for instillation into the eye. Ophthalmic suspensions are sterile liquid
preparations that contain solid particles in a suitable vehicle intended for instillation
into the eye.
Composition(s)
In addition to the active drugs, ophthalmic preparations contain a number of
excipients, including vehicles, buffers, preservatives, tonicity adjusting agents,
antioxidants and viscosity enhances. Important in the formulation process is the use
of ingredients that are nonirritating and compatible with the eyes.
Preparation Methods/Techniques
All work must be done in a clean-air environment, such as a laminar flow
hood, by qualified aseptic compounding pharmacists. The source of all the
ingredients must be the highest grade that can be reasonably obtained.
Solutions:
1. Accurately weigh/measure each of the ingredients.
2. Dissolve the ingredients in about 3/4 of the quantity of Sterile Water for
Injection and mix well.
3. Add sufficient Sterile Water for Injection to volume and mix well.
4. Determine the pH, clarity and other quality control factors from a sample
of the solution.
5. Filter through a sterile 0.2 micron filter into a sterile ophthalmic container.
6. Package and label.
7. If a large number are to be prepared, select a random sample to be checked
for sterility and to be assayed.
Suspensions:
1. Accurately weigh/measure each of the ingredients.
2. Mix the ingredients in about 3/4 of the quantity of Sterile Water for
Injection and mix well.
3. Add sufficient Sterile Water for Injection to volume and mix well.
4. Determine the pH, and other quality control factors from a sample of the
suspension.
5. Package in a suitable container for autoclaving.
6. Autoclave, cool and label.
7. If a large number are to be prepared, select a random sample to be checked
for sterility and to be assayed.
49
Or:
1. Accurately weigh/measure each of the ingredients.
2. Sterilize each of the ingredients by a suitable method.
3. Mix the ingredients in about 3/4 of the quantity of Sterile Water for
Injection and mix well.
4. Add sufficient Sterile Water for Injection to volume and mix well.
5. Determine the pH, and other quality control factors from a sample of the
suspension.
6. Package and label.
7. If a large number are to be prepared, select a random sample to be checked
for sterility and to be assayed.
Physicochemical Uniqueness of Common Ingredients
Considerations in preparing ophthalmic solutions involve clarity, tonicity,
pH/buffers, sterility, preservatives, antioxidants, viscosity enhancers, and proper
packaging.
Clarity-Ophthalmic solutions must be free from foreign particles, which is generally
accomplished by filtration. The filtration process also helps to achieve clarity of the
solution. Table 1 contains a list of usable clarifying agents.
Tonicity-Lacrimal fluid has an isotonicity value equivalent to that of a 0.9% sodium
chloride solution. However, the eye can tolerate a value as low as 0.6% and as high
as 1.8% sodium chloride equivalency. Some ophthalmic solutions will be hypertonic
by nature of the high concentration required of the drug substance. Others will be
hypotonic and will require the addition of a substance to attain the proper tonicity
range. Sodium chloride, boric acid and dextrose are commonly used. Three hundred
mOsm/L is ideal with 200-600 mOsm/L acceptable.
pH and Buffering-Ophthalmic solutions are ordinarily buffered at the pH of
maximum stability for the drug(s) they contain. The buffers are included to
minimize any change in pH during the storage life of the drug; this can result from
absorbed CO2 from the air or from hydroxyl ions from a glass container. Changes in
pH can affect the solubility and the stability of drugs, consequently, it is important to
minimize fluctuations in pH. The buffer system should be designed sufficient to
maintain the pH throughout the expected shelf-life of the product but with a low
buffer capacity so as soon as the ophthalmic solution is dropped into the eye, the
buffer system of the tears will rapidly bring the pH of the solution back to that of the
tears. This is accomplished by using as low a concentration of the buffers salts as
possible but still be effective. Generally a buffer capacity less than 0.05 is desired.
pH generally in the range of 4-8 is considered optimum.
50
Sterility-Ophthalmic solutions must be sterile. Sterility is best achieved through
sterile filtration using a sterile membrane filter of 0.45 or 0.2 micron pore size and
filtering into a sterile container. Other methods of sterilizing ingredients or
components of ophthalmics that can be used by compounding pharmacists include
dry heat, steam under pressure (autoclaving) and gas sterilization (ethylene oxide).
Preservation-Since most ophthalmic solutions/suspensions are prepared in multiple
use containers, they must be preserved. The selected preservative must be
compatible with the active drug as well as all the other excipients in the product.
Common preservatives for ophthalmic products are shown in Table 2.
Antioxidants may be required for selected active drug ingredients. Tables 3 contains
antioxidants that can be used in ophthalmic preparations.
Viscosity enhancers-An increase in the viscosity of ophthalmic products will result
in a longer residence time in the eye, providing a longer time for drug absorption and
effect. Numerous materials are used, among which methylcellulose is the most
common, generally in a concentration of about 0.25% if the 4000 cps grade is used.
If methylcellulose is autoclaved, it will come out of solution. However, it can be re
dispersed after cooling, especially if placed in a refrigerator. Hydroxypropyl
methylcellulose in the range of 0.5 to 1% is a good viscosity enhancer, while
polyvinyl alcohol 0.5 to 1.5% w/v is an alternative. Solution viscosity in the range of
25-50 cps is common. It is important that solution clarity be maintained with the use
of these viscosity enhancers. Suitable viscosity increasing additives are shown in
Table 4.
Packaging of ophthalmic solutions is appropriately done in sterile dropper bottles or
individual doses can be placed in sterile syringes, without needles.
Ophthalmic suspension particles must be of such a size that they do not irritate
and/or scratch the cornea, therefore a micronized form of the drug is required.
Ophthalmic suspensions must also be free from agglomeration or caking.
Incompatibilities
Zinc salts can form insoluble hydroxides at a pH above 6.4, so a Boric Acid
Solution vehicle may be selected. It also has a lower pH (about pH 5) and slight
buffering action.
Nitrates or salicylates are incompatible with solutions of benzalkonium Chloride,
therefore it should be replaced with 0.002% phenylmercuric nitrate.
Sodium chloride cannot be used to adjust the tonicity of silver nitrate solutions since
silver chloride would precipitate. Sodium nitrate should be used to adjust the tonicity
and phenylmercuric nitrate can be used as the preservative in this situation.
51
Storage/Labeling
Generally, ophthalmic preparations should be stored at either room or
refrigerated temperatures and should not be frozen.
Stability
Beyond-use dates for water-containing formulations is not later than 14 days,
when stored at refrigerated temperatures, for products prepared from ingredients in
solid form. If non aqueous liquids, the beyond-use recommendation is not later than
25% of the time remaining until the products expiration date or 6 months, whichever
is earlier. For all others, the recommended beyond-use recommendation is the
intended duration of therapy or 30 days, whichever is earlier. These beyond-use
recommendations can be extended if there is supporting valid scientific stability
information, as explained in the General Compounding Chapter of the United States
Pharmacopoeia 23/National Formulary 18.
Example Vehicles
Isotonic Sodium Chloride Solution:
Sodium Chloride USP
Benzalkonium Chloride
Sterile Water for Injection
0.9 g
1:10,000
qs 100 mL
Boric Acid Solution:
Boric Acid USP
Benzalkonium Chloride
Sterile Water for Injection
1.9 g
1:10,000
qs 100 mL
Rx Artificial Tears:
Polyvinyl alcohol
Povidone
Chlorobutanol
0.9% Sodium chloride solution
1.5%
0.5%
0.5%
qs
Instructions:
1. Calculate the quantity of each ingredient for the total amount to be prepared.
2. Accurately weigh or measure each ingredient.
3. Dissolve all ingredients in the sterile 0.9% sodium chloride solution.
4. Filter through a 0.2 micron filter into a sterile ophthalmic container.
5. Package and label.
52
Table 1:
Wetting/clarifying agents used for ophthalmic preparations.
Agent
Polysorbate 20
Polysorbate 80
Usual Concentration (%)
1%
1%
Table 2:
Common preservatives used in ophthalmic products.
Preservative Name:
Usual
Concentration:
Concentration
Range:
Chlorobutanol
Maximum
Concentr Incompatibilities:
ation:
0.5%
soaps
anionic materials
salicylates
nitrates
Quaternary
Ammonium
Compounds:
Benzalkonium
chloride
Benzethonium
chloride
Organic Mercurials:
Phenylmercuric
acetate
Phenylmercuric
nitrate
Thimerosal
Parahydroxybenzoates
0.01%
0.004-0.02%
0.013%
0.01%
Certain halides
with
phenylmercuric
acetate.
0.001-0.01%
0.004%
0.004%
0.01%
0.1%
Adsorption by
macromolecules.
The maximum levels are listed by the FDA Advisory Review Panel on OTC
Ophthalmic Drug Products (1979) for direct contact with the eye tissues and not for
ocular devices such as contact lens products.
53
Table 3:
Antioxidants used for ophthalmic preparations.
Antioxidant
Ethylenediaminetetraacetic acid
Sodium bisulfite
Sodium metabisulfite
Thiourea
Usual Concentration (%)
0.1%
0.1%
0.1%
0.1%
Table 4:
Viscosity increasing agents for ophthalmic preparations.
Agent
Hydroxyethylcellulose
Hydroxypropyl methylcellulose
Methylcellulose
Polyvinyl alcohol
Polyvinylpyrrolidone
54
Usual Concentration (%)
0.8
1.0%
2.0%
1.4%
1.7%
1. Buffers and Buffer Capacity
 Using dibasic potassium phosphate (K2HPO4) and monobasic potassium
phosphate (KH2PO4), prepare 500 ml of a buffer solution at pH 7.4 with a
buffer capacity of 0.05.
 Using a pH meter, measure the pH of 100 ml of the solution.
 Titrate 100 ml of the solution with 1 N NaOH until the pH increases by one
unit and determine whether the buffer capacity is as calculated. Note that the
exact normality of the NaOH solution may vary with available stock solutions;
note and record the exact normality of the reagent you use in the experiment.
 Calculate the buffer capacity as:
∆B= gram equivalent of strong acid/base to change pH of 1 liter of buffer
solution
∆pH= the pH change caused by the addition of strong acid/base
Calculations:
MW K2HPO4 _________________
MW KH2PO4 _________________
Ka ________________
pKa _______________
K2HPO4 = __________ g
KH2PO4 = __________ g
Data and Results:
Measured beginning pH _______
Volume of ____N NaOH added to 100 ml to change pH by 1 unit = _________
Eq NaOH added _______
Measured buffer capacity _______
55
2. Isotonicity and Sterility
Use the NaCl equivalent method and appropriate compounding techniques to
prepare the following sterile, isotonic ophthalmic solution.
Rx
Procaine HCl
1.5 %
Benzalkonium chloride 1:10,000
Boric Acid q.s.
Aqua. dest. q.s. ad
60 ml
M.Ft. Sterile, isotonic solution
Sig. gtts ii o.u. t.i.d.
Procaine HCl _______________________ g (E = ___________ )
Benzalkonium chloride _______________ g (E = ___________ )
Boric Acid _________________________ g (E = ___________ )
Benzalkonium chloride 1:1,000 solution needed __________________ ml
Calculations:
Compounding Procedure:
Therapeutic use: ___________________________________
Measured osmolality ________________________________ (mmol/Kg)
56
EXPERIMENT 9
3. Isotonicity and pH Adjustment
A. Prepare the following prescription.
Rx
Ampicillin Sodium
Sodium chloride q.s.
30 mg/ml
M.Ft. 15 ml of sterile, buffered, isotonic solution at pH 6.6
Sig. gtts ii o.u. t.i.d.
Ampicillin sodium ______________________ g (E = _____________)
Sodium chloride _______________________ g
Monobasic sodium phosphate, anhydrous (NaH2PO4) 0.0667 M solution
needed ____________ ml
Dibasic sodium phosphate, anhydrous (Na2HPO4) 0.0667 M solution
needed _______________ ml
Calculations:
Compounding Procedure:
Therapeutic use: ___________________________
Measured osmolality _____________________ (mmol/Kg)
B. Make calculations to prepare the following prescription as a buffered isotonic
solution at pH = 5.9. Describe how you would prepare the solution using 500
mg/vial Vancomycin Sulfate powder for injection (when reconstituted with 9.7 ml
sterile water for injection makes a 50 mg/ml solution), Sodium Chloride 30%
(concentrate) for injection, and stock solutions of 0.0667 M NaH2PO4and 0.0667 M
Na2HPO4. Do not prepare.
Rx
Vancomycin sulfate 30 mg/ml
Sodium chloride q.s.
Monobasic sodium phosphate q.s.
Dibasic sodium phosphate q.s.
M.Ft. 15 ml of sterile, buffered, isotonic solution at pH 5.9
Sig. gtts ii o.u. t.i.d.
Vancomycin sulfate ________________________ mg (E = __________)
57
Monobasic sodium phosphate, anhydrous (NaH2PO4) 0.0667 M solution needed
__________________ ml
Dibasic sodium phosphate, anhydrous (Na2HPO4) 0.0667 M solution needed
__________________ ml
Sodium chloride (30%) concentrate needed _____________ ml
Calculations:
Compounding Procedure:
Therapeutic use: ____________________________
Label _____________________________
58
PART 4
IV ADMIXTURE
59
Introduction
a. Attitude:
Number one rule: always think of the patient.
A well thought out training program for aseptic technique should focus on
safety and accuracy.
Safety: a.) The finished product should be free of contamination (particles,
bacteria, extraneous material). b.) The solution should be clear -- all
medications should be completely dissolved. c.) All compounding materials
should be checked for expiration date, outer integrity, etc. Accuracy:
Guidelines must be set up to ensure the right drug, right dose, and right
concentration. This includes using the appropriate syringe size to measure
out fluid volumes in order to minimize errors. Another example would be
to require that all syringes be drawn back to the original amount of each
individual dose and placed next to the admixture to facilitate checking by
the pharmacist. If a filter needle was required, it should also be present.
b. Dangers of poor aseptic technique:
Patients who are receiving intravenous therapy tend to be the most critical.
Every precaution must be taken to avoid contamination. The IV route is the
most dangerous route of administration because it bypasses all of the body's
natural barriers. An improperly prepared solution when administered can
have very serious consequences: infections, emboli, occlusions and
even.........
Guidelines for Sterile Compounding
Pharmacists have been providing sterile compounding services in institutions
for decades. These services have provided parenteral therapies, infusion services,
and complex infusion administration devices and supplies. However, in the past two
decades, compounding sterile formulations and providing administration services
has expanded beyond the institution. These additional areas include home care
agencies, infusion service agencies, outpatient clinics, and community pharmacies.
Pharmacists are also providing patient and caregiver assessments, education, and
skills, and are taking the responsibility for coordinating patient care through an
interdisciplinary team.
Pharmacists will compound a wide variety of sterile formulations in these different
settings. These formulations will include products administered by injection (IV, IM,
SQ, ID, intrathecal, epidural) or via inhalation, intranasal, or ophthalmic routes of
administration. Sterile formulations for either institutional or home care use have a
number of special requirements such as:
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





sterility
particulate material
pyrogen-free
stability
pH
osmotic pressure
Sterility is the freedom from bacteria and other microorganisms. Formulations must
be sterile, which is not a relative term; an item is either sterile or not sterile.
If the sterile formulation is a solution, it must be free of all visible particulate
material. Particulate materials refer to the mobile, undissolved substances
unintentionally present in parenrtal products. Examples of such material are
cellulose, glass, rubber cores from vials, cloth or cotton fibers, metal, plastic, rust,
diatoms, and dandruff. Sterile suspensions and ointments may have particulate
material, but these are usually the active drug or an ingredient, not contaminants.
Particles measuring 50 microns or larger can be detected by visual inspection.
Specialized equipment is needed to detect particles less than 50 microns in size. The
USP 24/NF19 Section <788> sets limits on the number and size of particulate that
are permissible in parentral formulations. For large volume parenterals, the limit is
not more than 12 particles/ml that are equal to or larger than 10 microns, and not
more than 2 particles/ml that are equal to or larger than 25 microns. For small
volume parenterals, the limit is 3000 particles/container that are equal to or larger
than 10 microns, and not more than 300/container that are equal to or larger than 25
microns.
The potential sources of particular material are:
1. The product itself
2. Manufacturing and such variables as the environment, equipment, and
personnel
3. The packaging components
4. The administration sets and devices used to administer the product
5. The manipulations and environment of the product at the time of
administration.
Sterile formulations must be pyrogen-free. Pyrogens are metabolic by-products
of living microorganisms. So if pyrogens are detected in a sterile product, that means
that bacteria have proliferated somewhere along during the formulation process. In
humans, pyrogens cause significant discomfort but are rarely fatal. Symptoms
include fever and chills, cutaneous vasoconstriction, increased arterial blood
pressure, increased heart workload, pupillary dilation, piloerection, decreased
respiration, nausea and malaise, severe diarrhea, or pain in the back and legs.
61
The stability of drugs in sterile formulations is an important consideration. In
institutional settings, most admixtures are prepared hours in advance of when they
are to be administered, and are generally utilized within a short period or time. In
home health care settings, admixtures are prepared days in advance of when they are
to be administered, and are generally utilized over longer periods of time compared
to the clinical setting. Therefore, the stability of a particular drug in a particular
sterile formulation must be known.
Physiological pH is about 7.4, and an effort should be made to provide sterile
formulations that do not vary significantly from that normal pH. Of course, there are
situations in which this becomes a secondary consideration because acidic or
alkaline solutions may be needed to solubilize drugs or used as a therapeutic
treatment themselves.
Osmotic pressure is a characteristic of any solution that results from the number
of dissolved particles in the solution. Blood has an osmolarity of approximately 300
milliosmoles per litter (mOsmol/L), and ideally any sterile solution would be
formulated to have the same osmolarity. The most commonly used large volume
parenteral solutions have osmolarities similar to that of blood; for example, 0.9%
sodium chloride solution (308 mOsmol/L) and 5% dextrose solution (252
mOsmol/L).
Intravenous solutions that have larger osmolarity values (hypertonic) or smaller
osmolarity values (hypotonic) may cause damage to red blood cells, pain, and tissue
irritation. However, there are some therapeutic situations where it may be necessary
to administer hypertonic or hypotonic solutions. In these cases, the solutions are
usually given slowly through large veins to minimize the reactions.
During the early 1990s, guidelines were issued by NABP, ASHP, and the USP
regarding the compounding of sterile products. These recommendations were an
effort to provide assistance to pharmacists and technicians responsible for preparing
sterile products. However, none of these recommendations has been uniformly
adopted and accepted which has resulted in inconsistent practice conditions.
The NABP Model Rules for Sterile Pharmaceuticals are the most general guidelines
and do not address some of the key features found in other guidelines. However,
they enumerate the basic considerations in sterile compounding.
 Policy and procedure manuals for compounding, dispensing, and
delivering sterile products should be established and periodically reviewed.
These records should be part of a documented, ongoing quality assurance
program.
 Pharmacists and supportive personnel should be trained and adhere to
hygienic and aseptic techniques
62
 Sufficient reference materials about sterile products should be available
 Drugs and supplies should be stored, labeled, and disposed of properly
 Sterile compounding should be done in an area separate from other
activities
 Procedures should be established for assigning beyond-use dates that
exceed the manufacturer labeled expiration dates
Equipment, Supplies, and Devices:

Laminar flow hoods (horizontal and vertical)
Laminar flow hoods are used to control airborne contamination of sterile
products during their extemporaneous preparation. Room air is filtered through a
high efficiency particulate air (HEPA) filter removing 99.97% of all particles 0.3
microns or larger. Parallel air streams bathe the work area with a velocity sufficient
to provide the area free of particles and microorganisms. The direction of airflow
may be horizontal or vertical. Horizontal flow hoods are most commonly used, with
the more costly vertical flow hoods being reserved for agents that may produce an
environmental hazard (e.g. cytotoxic agents, radioactive agents, antimicrobial
agents).
Horizontal Flow Hood
Vertical Flow Hood
Laminar flow hoods used in sterile compounding must be Class 100 (less than
100 particles of 0.05 micron size per cubic foot).
63
Laminar flow hoods are effective only when properly used. Interruption of the air
flow will interfere with the effectiveness of the hood. Downstream contamination
occurs when any object comes between the HEPA filter and the sterile product,
interrupting the parallel flow and creating dead space. Cross-stream contamination
may occur due to rapid movements of the operator in the hood. Backward
contamination may be caused by turbulence created by objects being placed in the
hood, by fast traffic passing the hood, or by coughing, sneezing, etc. by the operator.
It should be remembered that the hood does not produce sterilization, but merely
prevents contaminants from settling onto the surface of the sterile product. Any
movement of greater velocity and different direction than that of the hood's air flow
will create a turbulence that reduces the hood's effectiveness. Working at a smooth,
steady pace at least 6 inches into the hood may minimize contamination.

Filtration and Filters:
Filtration is used to remove particles from solutions. These particles might be
particulate matter or they may be microorganisms. Filtration is not a "terminal
sterilization" procedure as are steam (moist heat), dry heat, ionized radiation, or gas
sterilization. Filtration will sterilize the product, but after filtration, the sterile
product is then aseptically combined with its packaging. Filtration is used for
materials that are chemically or physically unstable if sterilized by heat, gas, or
radiation.
There are two types of filters, depth filters and membrane filters.
Depth filters are seldom used for sterilization. They are constructed of randomly
oriented fibers or particles (e.g., diatomaceous earth, porcelain, asbestos) that have
been pressed, wound, or otherwise bonded together to form a tortuous pathway for
flow. The microorganisms are either entrapped in the path or adsorbed to the filter
material. The random structure of material inside the filter creates fluid flow
64
pathways that can vary from extremely narrow to very wide. Filter materials can also
break off or come loose during filtration and appear in the filtrate.
Depth filters are rigid enough to filter a solution being pulled into a syringe.
They can also be used to filter a solution being pushed out of a syringe. But the same
filter cannot be used to draw up and then expel a solution. A new needle is required
before pushing the solution out of the syringe. If the solution is expelled through the
original filter needle, the solution will be re-contaminated.
Screen filters have a continuous uniform structure that consists of fixed size
pores. Particles that are larger than the pore openings cannot pass through the filter
and are retained on the surface of the filter. The amount of material retained by a
screen filter is limited by the surface area of the filter. Screen filter pore sizes can be
predetermined and precisely controlled during manufacturing.
The most common screen filter used in compounding is called a "membrane
filter." In terms of structure, membrane filters are thin microporous sheets made
from a variety of plastics. Membrane filters must have a nominal pore size of 0.22
microns or less if they are to be used for sterilization. However, membrane filters are
available in a wide range of pore sizes from 0.11 to 10 microns.
Membrane filters are intended to filter a solution only as it is expelled from a
syringe. If a solution is to be drawn into a syringe and then filtered through a
membrane filter, use the following procedure:
1.
2.
3.
4.
5.
6.
7.
A regular needle (or a depth filter needle) is attached to the syringe.
The solution is pulled into the syringe.
Air bubbles are removed from the syringe.
The needle is removed from the syringe.
A membrane filter unit is then attached to the syringe.
A regular needle is placed on the needle end of the filter.
Air is eliminated from the filter chamber by holding the syringe in a vertical
position so that the needle is pointing upward. Air must be expelled before the
filter becomes wet; otherwise, the air will not pass through the filter.
8. Once air has been expelled, pressure should be slowly and continuously
applied to push the solutions through the filter.
Membrane filters also eliminate the risk of air embolism. Once a membrane
filter is wet, air cannot pass through it unless the "bubble point pressure" of the filter
is exceeded. "Bubble point pressure" for a 0.22 micron membrane filter is
approximately 55 psi, a pressure that will not occur during parenteral administration.
So any air that enters the administration set will be stopped at the filter surface and
not allowed to enter the patient's body.
65
The same bubble point pressure is used in another way. After a filter is used, the
integrity of the filter can be determined if the wetted filter is exposed to a high
pressure. If the filter is intact, the appearance of bubbles on the filter surface should
occur when the pressure is about 50 - 55 psi. However, if the filter integrity has been
compromised, the bubble point pressure will be much lower.
Membrane filters are often packaged in a round plastic holder which can
easily be attached to the end of syringes. Some filters are attached to administration
sets and serve as "final filters" and filter the solution immediately before it enter the
patient's vein. Some administration sets have filters already built into the set. Filters
can also be placed inside of needles; these are called "filter needles." Double ended
filter needles which is a simple unit that has a filter between two needles. This
allows solution transfer directly from one container to another container and
eliminates the need of using a syringe to transfer the solution. Filters are also
supplied as single membrane units to be used in specialized filtration apparatus.
Several things must be considered when selecting a membrane filter:
Hydrophilic filters are easily wetted and are used for aqueous solutions.
Hydrophobic filters repel water but allow solvents such as alcohol and air to pass. So
these filters would be used to sterilize solutions containing alcohol or isopropyl
alcohol, or as air filters. Other considerations include the volume capacity of the
filter, how much pressure can be applied to the filter without damaging its integrity,
and what is the filter's compatibility or adsorption profile for the material being
filtered.
The material to be filtered also requires some considerations. Viscous oils can be
filtered, but it is a time consuming process. Heating the oil will reduce its viscosity
and make filtration easier. Some powders can also be filtration sterilized by first
dissolving the powder in a solvent, filtering the resultant solution, and then
evaporating the solvent under aseptic conditions.
Consideration must also be given to the sterilization of containers, closures,
and apparatus. A non-sterile surface that comes in contact with a sterilized product
will render the product non-sterile. These contact surfaces must also be pyrogenfree. The temperatures and times necessary for depyrogenation are substantially
greater than those for sterility. It will probably be necessary to depyrogenate
containers, closures, and apparatus separately from the formulation and then
aseptically combine them.
66
Types of Parentral Solution
Large Volume Parenteral (LVP) Solutions
Parenteral solutions are packaged as large volume parenteral (LVP) solutions
and small volume parenteral (SVP) solutions. LVP solutions are typically bags or
bottles containing larger volumes of intravenous solutions. Common uses of LVP
solutions without additives include: 1) correction of electrolyte and fluid balance
disturbances; 2) nutrition; and 3) vehicle for administering other drugs.
Large volume parenteral solutions are packaged in containers holding 100 ml or
more. There are three types of containers: glass bottle with an air vent tube, glass
bottle without an air vent tube, and plastic bags.
Plastic bags have advantages over glass bottles: they do not break; they weigh
less; they take up less storage space, and they take up much less disposal space.
However, some drugs adsorb to the plastic. Also, some drugs and solutions leach a
plasticizer out of the plastic; the plasticizer is included to keep the plastic pliable.
There are now newer plastics that minimize some of these problems.
Plastic bags are available in different sizes. The most common sizes are 250, 500,
and 1,000 ml. The top of the bag has a flap with a hole in it to hang the bag on an
administration pole. Graduation marks are on the front of the bag to indicate the
volume of solution used. They are marked at 25 ml to 100 ml intervals depending on
the overall size of the bag. The plastic bag system collapses as the solution is
administered so a vacuum is not created inside the bag.
At one end of the bag are two ports of about the same length. One is the
administration set port and the other is the medication port. The administration
set port has a plastic cover on it to maintain the sterility of the bag; the cover is
easily removed. Solution will not drip out of the bag through this port because of a
plastic diaphragm about ½ inch inside the port. When the spike of the administration
set is inserted into the port, the diaphragm is punctured, and the solution will flow
out of the bag into the administration set. This inner diaphragm cannot be resealed
once it is punctured. The medication port is also covered by a protective rubber tip.
Drugs are added to the solution through this port using a needle and syringe. There is
an inner plastic diaphragm about ½ inch inside the port, just like the administration
set port. This inner diaphragm is also not self-sealing when punctured by a needle,
but the protective rubber tip prevents solutions from leaking from the bag once the
diaphragm is punctured.
Because of the advantages of plastic bags, glass LVP solution bottles are not
often used. The major advantage of glass bottles is to administer drugs that are
incompatible with plastic bags. Glass intravenous bottles are packaged with a
vacuum, sealed with a solid rubber closure, and the closure is held in place by an
67
aluminum band. Graduation marks are along the sides of the bottle and are usually
spaced every 20 ml to 50 ml. The solution bottle is hung on an administration pole in
an inverted position using the aluminum or plastic band on the bottom of the bottle.
Solutions in either the plastic bag or glass bottle flow from the containers to the
patient through an administration set. But for solutions to flow out of a glass
container, air must be able to enter the container to relieve the vacuum as the
solution leaves. Some bottles have air tubes built into the rubber closure for this
purpose. Some bottles do not, in which case an administration set with a filtered
airway in the spike must be used.
Many different LVP solutions are commercially available. Four solutions are
commonly used either as primary fluids (infused at 2 - 3 ml per minute) or as the
base of an admixture solution. The solutions are sodium chloride solution, dextrose
solution, Ringer's solution, and Lactated Ringer's solution. Various combinations of
different strengths of sodium chloride and dextrose solutions are also available, i.e.,
5% dextrose and 0.45% sodium chloride, or 5% dextrose and 0.2% sodium chloride.
Small Volume Parenteral Solutions
Small volume parenteral (SVP) solutions are usually 100 ml or less and are
packaged in different ways depending on the intended use. If the SVP is a liquid that
is used primarily to deliver medications, it is packaged in a small plastic bag called a
minibag of 50 - 100 ml (minibags look like small plastic LVP bags). SVPs can also
be packaged as ampules, vials, and prefilled syringes. Liquid drugs are supplied in
prefilled syringes, heat-sealed ampules, or in vials sealed with a rubber closure.
Powdered drugs are supplied in vials and must be constituted (dissolved in a suitable
liquid) before being added to any solution. SVPs packaged as ampules, vials, or
prefilled syringes are typically added to a minibag or a LVP but they may also serve
as the final container. The term admixture is used to denote a solution where such an
additive has been added to a minibag or LVP.
Ready-to-mix systems consist of a specially designed minibag with an adapter for
attaching a drug vial. The admixing akes place just prior to administration. The
major advantages of ready-to-mix systems include a significant reduction in waste
and lower potential for medication error because the drug vial remains attached to
the minibag and can be rechecked as needed. However, the systems do cost more,
and there is the potential that the system will not be properly activated so that the
patient receives only the diluent or a partial dose of drug.
68
Administration Set
The basic method to administer a LVP solution is to use an administration set. The
set contains a spiked plastic device to pierce a port on the IV container. This
connects to a sight or drip chamber that may be used to set the flow rate, the rate
ordered by the physician at which the solution is to be administered to the patient
(generally measured in ml/hour). A clamp pinching the tubing also regulates flow.
The line then leads to a rubber injection port to which a needle may be attached or to
an infusion pump which will control the flow rate.
Heparin Lock
In some instances, a patient may not have a primary LVP solution, yet must receive
piggyback medications. This is done through a heparin lock, which is a short piece
of tubing attached to a needle or intravenous catheter. When the tubing is not being
used for the piggyback, heparin is used to fill the tubing. This drug prevents blood
from clotting in the tube.
69
Other Devices
Infusion pumps, syringe pumps, and ambulatory pumps are devices used to
administer LVP solutions and control flow rates. Administration sets are threaded
through infusion pumps, and the pumps control gravity flow. Syringe pumps expel
solutions from a syringe into an administration set such as a heparin lock. An
ambulatory pump is about the size of a hand. It allows patients to have some
freedom of movement compared to being restricted to an infusion pump attached to
an adminstration pole. Infusion pumps have made the infusion process much more
accurate and easier to administer and have been a major factor in the growth of home
infusion.
PROCESS VALIDATION
In a general sense, validation is any mechanism that will establish a high
degree of assurance that specific processes are achieving their objective. Its ultimate
goal is to produce products that consistently meet predetermined specifications and
quality attributes. Consistent quality (and improvement if possible) is a "must" for
the health and well-being of the patient and should be an on-going process.
Several types of "quality control" can be developed for sterile compounding.
Media Fills
The Validation subsection of Section <1206> of the USP 24/NF19 describes
an evaluation procedure commonly referred to as "media fills." The evaluation
involves an operator manipulating microbial growth media (usually soybean casein
digest medium) according to a prescribed validation procedure. The procedure
requires multiple aseptic transfers to multiple containers. It is recommended that the
validation procedure by done at peak periods of fatigue, stress, and pacing demands
(e.g., immediately after normal production activity).
The premise behind media fills is that the growth medium will support the growth of
the contaminating microbe, and this growth can be detected. The other requirement
of the validation is that the media must be manipulated using the same aseptic
techniques actually being evaluated.
It is important to note that this validation is not intended to be a one time
evaluation. The USP 24/NF19 recommends that competent operators be challenged
quarterly. Other references suggest that 40 validation sample should be prepared for
each 800 admixtures prepared, or that 10 validation samples be prepared each
month. Regardless of the frequency, a competent sterile compounder will need to be
evaluated on a regular and on-going basis.
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Other Methods
 A process validation might involve sending formulations to contract
analytical laboratories for testing. Analysis of drug content, sterility, and
pyrogenicity can be routinely done using randomly selected samples.
 Process validation could be observing and testing formulation variables
such as color, clarity, uniformity of dispersion, odor, consistency, pH,
specific gravity, etc.
 The validation could also be documenting adherence to formulation
records, policies and procedures, SOPs using compounding records, or
techniques or procedures. Some example forms for Home Infusion
Pharmacies have been published.
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PROCESS VALIDATION FOR TPN PREPARATION IN LOCAL
HOSPITALS IN UAE
Title of Policy and Procedure: General Cleaning of the I.V room
Policy:
The I.V Room must remain a clean room at all times, with routine cleanings
and inspections.
Procedure:
1. No one is to enter the I.V Room except the pharmacists who are preparing the
formulae.
2. No one should open the door of the I.V Room during mixing in order not to
disrupt the airflow.
3. No eating, drinking, smoking or any activities what so ever allowed in the I.V
Room except intravenous medication preparation.
4. Garbage has to be removed from trash containers outside of the I.V room once it
is full or at least daily.
5. Vacuuming or mopping of floor must be done daily when mixing is at a
standstill.
6. Daily scrubbing of the sink, floors and shelves must be done with detergents.
7. The sink must remain dry at all times.
8. The temperature of the room must remain within standards of 22 degrees Celsius
at all times.
9. The walls are to be scrubbed whenever necessary and on a periodical basis.
10. The environmental services staff daily must sign the daily cleaning log sheet.
11. The refrigerator must remain free of anything except sealed medications, and its
temperature maintained between 2-8degree Celsius.
12. The refrig4erator temperature log sheet is to be completed weekly.
72
Title of Policy and Procedure: Personal hygiene in the I.V room
Policy:
Hygiene is absolutely essential for prevention and control of infections and is a
procedure that must be practiced faithfully by all hospital personnel. For the I.V
Room, it is mandatory to follow procedure to ensure the cleanest environment
possible.
Procedure:
A. Attire in the I.V Room
1. The I.V Room pharmacist is to dress in theater scrubs if possible,
otherwise a sterile gown is to be used on top of clothing and closed
properly so street clothes are exposed. The hair must be covered with
hair caps upon entry, and a mask must be used during the preparations
in the hood.
2. After hand washing, sterile gloves should be used during preparations
3. Clean shoes should be used or shoe covers whenever possible.
B. Hand washing
1. Hands must be washed before beginning any work in the
sterile preparation area and upon each re-entry into the
area. All jewelry and other accessories need to be removed
from hands up the elbows.
2. Wet your hands with water.
3. Spread a film of bacteriostatic agent over the entire surface
of the hand.
4. Wash thoroughly using a rotary motion and friction over
the entire hands, between fingers and nails and well up the
wrists for 30seconds to one minute.
5. Rinse Thoroughly
6. Dry hands well by patting or blotting with paper towel
7. Turn off the faucet with a paper towel when the faucet is
hand controlled.
8. A bacteriostatic agent maybe used between hand washing.
9. Apply generous amounts of the bacteriostatic fluid to the
hands rubbing between digits, Allow to dry, then continue
mixing.
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C. Maintaining Sterility
1. The Pharmacist preparing should not scratch their face or
hand or any uncovered areas.
2. Talking, coughing, sneezing should be kept to a minimum.
If that pharmacist is ill with an infection, another pharmacist
should mix instead if possible; otherwise clean procedures are of even
greater importance.
3. If a product is spilled on the gloves, they should be
changed immediately.
4. If there is a wound, mixing is only possible if the wound is
dry and fully covered.
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Title of Policy and Procedure: Guidelines for working in the laminar flow hood
Policy:
While workings in the hood a set of points should be kept in mind in order to ensure
that work is done under sterile conditions.
Procedure:
1. Work well inside the hood at least six inches away from the outer edge.
2. Avoid nervous gestures and mannerisms (scratching etc).
3. Do not block the air stream to the exposed sterile needle with your
hands or fingers.
4. Hands should not be placed between the Hepa filter and when
transferring derices.
5. Plac4e the needle top facing the filter not away.
6. When drawing medicines, work horizontally holding the syringe in one
hand and the bottle/vial/ampoule in the other.
7. Place the finished needle on the side of the bottle to the right.
8. Select the size and quantity of additives, diluents, syringes etc. to be
used for the admixture.
9. Check them for expiration date or any discoloration that would render
them unfit for use.
10. External surfaces of items need to be cleaned by an alcohol swab.
11. Place the syringes, ampoules, vials on either or both sides of your
majo5r site of activity this will minimize movement.
12. A pharmacist other than the one preparing the mixture must check all
preparations. The check should be through; looking for correct
ingredients, concentrations, quantities, expiration dates, compatibility,
techniques and the final solution.
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Title of Policy and Procedure: Documentation of TPN formulae
Policy:
All TPN formulae must be prescribed on the approved forms, entered into the
nurse’s kardex and then labeled accordingly.
Procedure:
1.Any total Parenteral Nutrition formula needs to be prescribed on the approved
prescription TPN form.
2. All the ingredients to be mixed must be written with concentrations and volumes.
The prescribing doctor must sign and stamp the form. The nurse must also sign the
prescription form.
3.A copy remains in the file and one copy for the I.V Room. The form is used for
preparation and is then filed.
4.Any changes made to the original prescription should be initialed by the
prescribing doctor.
5. A prescription for TPN to be given should be in the Kardex for the nurses to
follow.
6.The Prepared TPN bag is labeled with the exact ingredients wadded to the bag,
including volume, concentration or strength accordingly.
7.The bags are labeled with an expiration date, to be kept in the refrigerator label,
and to be protected form light written on it.
Title Of Policy Procedure: Sterilizing the Laminar Flow Hood
Policy:
The Laminar flow Hood provides a sterile air space for mixing the medications.
Sterilization techniques must be used to ensure this sterile environment is
maintained.
Procedure:
1. The laminar flow hood is maintained and inspected according to its
manual. Specific guidelines are available to ensure its safe and effective
use.
2. The hospital engineer must inspect the hood filters monthly and sign the
log sheet. If the filters do not meet standards, they must be changed.
Both the hepa filter and pre-filters should be changed every 3-4months
of use.
76
3. The hood must run for 30 minutes in order to ensure sterile airflow.
After that it is sterilized and may be used for medication preparation.
4. The hood is wiped down with alcohol in order to prepare it for use.
Gauze is used to wipe the hood with alcohol, starting closest to the filter
and moving away. This wiping down effect is in the direction of the
airflow from the hood, therefore not obstructing the sterile airflow. All
4 surfaces should be wiped down, as well as the rod. Do Not Wipe The
Filter Panel.
5. This wipe down procedure is done every time the hood is switched on
(30minutes later) and before the hood is switched off for the day. This
wipe down is also performed periodically during preparations, and
every time a product is spilled on the hood’s surface.
6. If the hood is left without use for some time or if it is found to be
unusually dirty, it is to be cleaned with an appropriate soap using
distilled water for dilution and gauze for the scrubbing.
77
Title of the Policy and Procedure: Storage Conditions of I.V room items
Policy:
The items needed for the preparation of total parenteral nutrition formulae are to be
stored under hygienic conditions and at appropriate temperature and light control.
The compounded formulae need to be stored under refrigeration until they are
administered to be the patient, and protected from light at all times.
Procedure:
1. The items needed for the preparation of total parenteral nutrition vary
tremendously, and may require different storage conditions. Hence,
each item needs to be inspected for storage requirements carefully.
2. All items need to be stored in a cool, dry place.
3. All items needs to be stored in a clean and dust free area, in order not to
jeopardize their sterility.
4. Any item that needs to be protected from light or kept under
refrigeration, should be stored as such at all times.
5. The compounded formulae are stored in the refrigerator until they are
dispensed to the wards.
6. The compounded formulae should be stored for a maximum of 12 hours
before being administered to the patient.
Calculate the following for 5 prescriptions:
1.The volume of electrolytes to be added to the bag as prescribed
2.The maximum electrolyte concentration that can be used per patient weight
3.The maximum volume per patient weight and age.
4. The calories requirements based on the patient’s diagnosis
5. The calories provided by the prescription.
6. The ratio of calories from nonfat to fat source in the prescription.
7. The rate of infusion based on total volume so that it runs for 24 hours.
mMoles= milliquivalents(mEq)
Valence of the ion
Na=1 valence
K=1
Mg=2
Ca=2
PO4=3
Cl=1
78
SO4=2
Acetate=1
Gluconate=2
Meq. Wt= gm/valence
1000
1mEq Na=23mg
1mEq k=39mg
1mEq Ca=20mg
1mEgMg=12mg
1mEq Cl=35.5mg
Normal Saline is 0.9% sodium chloride=0.9gm of NaCl/100ml of solution
Concentration in mmol/liter = 10 x concentration in mg/ 100ml
Molecular weight
Calculations Workshop:
Solve the following Calculation:
1. Doctor order 30gms of dextrose, we only have 50% dextrose in stock.
How many mls of 50% dextrose will we need?
2. We have amino acids 5% order for 70gms total. How many mls of the aminoacid
5% are needed?
3. Convert these: 10mMoles KCl = --------------------mEq KCl
20m Moles Ca = ---------------------mEq Ca
30mEq Kphos = ---------mEq K and ----mEq Phos
20mEq Mg = ----------------------------mMoles Mg
4. If the doctor orders 10 mMoles/Liter of Na, How many mMoles will be in
2500ml bag?
5. Same order as above, how many mls of 30% (5mEq/1ml) NaCl will be needed
for the 2500ml bag?
6. Doctor prescribes TPN total volume 1750ml, to be infused over 24 hours.
What is the rate of infusion (ml/ Hour)?
7. Mg SO4 ordered to be added to TPN at 10mEq/Liter. The magnesium we have is
an MgSO4 50% 4mEq/ml 10 ml vial. The total volume for the TPN bag is 2500ml.
How many mls of MgSO4 should be added to the 2500ml bag?
79
8. If the TPN is ordered to run at 100ml/hour, and the total volume is
2000ml.
How long will the TPN run for? If it is started at 1200 noon on Monday, what time
will it finish?
9. Order for 50mEq of Kphos, 20mEq of NaCl to be added to the final volume
of TPN. What is the final content in the TPN of Potassium, Phosphate, Sodium and
Chloride?
10. Same order as above, can Ca Gluconate be added to this mixture?
How much?
80
Examples of TPN Prescription Prepared For Adults :
Example 1
Patient name—No Body-----------------------------File No. 1850xx
Age----45------------------Diagnosis------head injury------------------------------Wt.
Kg.
Ideal Wt.
70
Date----7/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:81
10
500
25
1000
20
500
150
40
10
10
10
2000
80
24
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
Example 2
Patient name—No Bady-----------------------------File No. 1850xx
Age----50------------------Diagnosis-----# Facial Bone------------------------------Wt.
Kg.
Ideal Wt.
70
Date----7/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:-
82
10
50
25
1000
20
500
50
20
19
20
10
10
10
200
80
24
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
Example 3
Patient name—No Bady-----------------------------File No. 1850xx
Age----45------------------Diagnosis------CRF------------------------------Wt.
Kg.
Ideal Wt.
75
Date----8/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:-
83
10
500
50
500
20
500
100
30
1 amp.
1 amp.
1 amp.
1650
24
Central
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
Example 4
Patient name—No Bady-----------------------------File No. 1850xx
Age----36------------------Diagnosis------Pancreatitis------------------------------Wt.
Kg.
Ideal Wt.
70
Date----8/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:-
84
10
500
25
1000
20
500
100
40
10
10
10
80
24
Central
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
Example 5
Patient name—No Bady-----------------------------File No. 1850xx
Age----47------------------Diagnosis------Pancreatitis------------------------------Wt.
Kg.
Ideal Wt.
65
Date----9/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:-
85
10
750
25
1250
2000
80
24
Peripheral
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
Example 6
Patient name—No Bady-----------------------------File No. 1850xx
Age----39------------------Diagnosis------Pancreatitis------------------------------Wt.
Kg.
Ideal Wt.
70
Date----7/5/01-------------------------------------
Protein
Amino Acid
Volume
Glucose
Dextrose
Volume
Fat
Lipid
Volume
Sodium Chloride
Potassium Chloride
Calcium Gluconate
Magnesium Sulphate
Potassium Phosphate
Other
Other
Trace elements
Water Soluble Vitamins
Fat Soluble Vitamins
Regular Insulin
Iron
Heparin
Total Volume
Rate of infusion
Duration of Infusion
Central Line or
Peripheral Line
Doctor’s Signature
Nurse’s Signature
Time Received
Time Infusion Started
Medications:-
86
3
5
500
10
1000
80
10
10
1500
60
24
Peripheral
G
%
ml
G
%
ml
G
%
ml
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
mM/24hrs
ml
ml
ml
U
mg
U
ml
ml/hour
hour
APPENDIX
Goal:
To familiarize students with the differences in nutritional requirements between
adults and children with respect to fluids, electrolytes, calories, carbohydrates,
proteins, fats and trace elements.
Introduction:
Adequate nutrition for the proper growth and development of a child requires
individualization. The amount and type of fluid, calories, electrolytes, and trace
elements are all based on age, weight, nutritional status, and disease state.
I. The total daily fluid requirement of any patient is equal to the normal daily
maintenance fluids plus replacement of any fluid deficit plus replacement of any
significant abnormal ongoing losses. Two methods to calculate normal
maintenance fluids are described below. Normal maintenance fluids provide
replacement for normal body functions and for normal losses (for example,
insensible water loss, urine output and stool losses). Other factors that may increase
the patient's total daily fluid requirements need to be replaced in addition to the
normal daily maintenance fluids.
Total daily fluid requirement = Normal Maintenance Fluids + Deficit + Ongoing
Abnormal Losses
Total daily fluid requirements may be increased by:
1) increases in insensible water losses due to such factors as fever,
hyperventilation, phototherapy, radiant warming, skin breakdown, burns, etc.
2) initial deficits of fluid i.e., dehydration
3) significant ongoing abnormal losses such as diarrhea, vomiting, nasogastric
tube losses, high output renal failure, etc.
A. Daily maintenance fluid requirements (i.e., normal maintenance fluids) are
those required to maintain normal homeostasis for a 24 hour period. Surface area
and body weight are two common methods used for the calculation of maintenance
fluids in pediatric patients.
NOTE: Premature infants will have greater daily maintenance fluid requirements
then those shown here due to their larger surface area to body weight ratio and
thinner skin, both of which significantly increase their insensible water losses from
the skin. In fact, preterm infants < 750 grams often require 200 - 250 ml/kg/day to
prevent dehydration. Due to their highly specialized needs, calculation of fluid
87
requirements for premature neonates will be considered beyond the scope of this
lecture.
1. Daily maintenance fluid requirements calculated by body surface area: For
pediatric patients, the amount of daily maintenance fluid required is in the range of
1500 - 1800 ml/m2/day. Usually 1500 ml/m2/day is used. The surface area method is
usually used in children > 10 kilograms because a precise measurement of surface
area is often difficult in smaller infants.
2. Daily maintenance fluid requirements calculated by body weight
Weight
< 2.5 kg
2.5 - 10 kg
11 - 20 kg
> 20 kg
Daily maintenance fluid requirements
120 ml/kg/day.
100 ml/kg/day.
1000 ml plus 50 ml/kg for every kg over 10 kg.
1500 ml plus 20 ml/kg for every kg over 20 kg.
EXAMPLES:
Weight:
8 kg :
15 kg :
27 kg :
Maintenance fluid
100 ml/kg/day = 800 ml/day
1000 ml + (50 ml/kg * 5) = 1000 + 250 = 1250 ml/day
1500 ml + (20 ml/kg * 7) = 1500 + 140 = 1640 ml/day
3. Factors which may increase insensible water loss will increase daily fluid
requirements.
a. Estimates of additional insensible water loss (e.g., fever) can be calculated as a
percent increase of normal maintenance fluids (e.g. for fever, increase daily fluid by
12% of normal maintenance for every degree Centigrade over 37 degrees).
b. Neonates who receive phototherapy require 20 ml/kg/day additional fluid due to
increased insensible water loss.
B. Fluid deficit is calculated by clinical assessment of dehydration.
Clinical Signs
Thirst
Mild
slight
alert,
Behavior
restless
Mucous membrane normal
Tears
present
88
Degree of
dehydration
Moderate
moderate
irritable to touch,
may be lethargic
dry
+/-
Severe
intense
hyperirritable to lethargic,
may be comatose
very dry
absent
Eyes
Skin elasticity
(pinch retracts)
Skin color
Anterior fontanelle
Weight loss
Fluid deficit
normal
immedi
ately
normal
normal
3-5%
30-50
ml/kg
sunken
grossly sunken
slowly
very slowly > 2 seconds
pale
sunken
8 - 10 %
mottled or gray
very sunken
12 - 15 %
80-100 ml/kg
120-150 ml/kg
NOTE: If the pediatric patient is hemodynamically stable, 1/2 of the fluid
deficit is replaced over the first 8 hours, and the second 1/2 of the fluid deficit
is replaced over the next 16 hours.
C. Ongoing losses also need to be replaced. Estimates of sensible fluid losses can
usually be easily measured (e.g., NG tube losses, vomiting, etc).
D. Fluid restriction: As in adults, the amount of daily fluids administered to a
pediatric patient may need to be restricted. Situations which require fluid restriction
include patients with cerebral edema, congestive heart failure, renal failure, SIADH,
patent ductus arteriosus, and certain pulmonary disorders. Fluid restriction may be
calculated 1) as a percent of maintenance fluids (e.g., 2/3 or 3/4 maintenance) or 2)
as insensible loss (300 - 400 ml/m2) plus urine output.
II. Pediatric Total Parenteral Nutrition (TPN)
A. The indications for TPN in children are similar to the indications in adults, i.e.,
if the G.I. tract cannot be used as a route of administration for nutrition, then
parenteral nutrition may be indicated. One big difference vs adults is that due to
fewer body stores and a higher caloric daily requirement, children are started on
hyperalimentation sooner than adults. Generally, the smaller or younger the child is,
the sooner (s)he needs appropriate nutritional intake. Indications:
1. Congenital or acquired anomalies if the G.I. tract: gastroschisis, bowel
fistulas, intestinal obstruction, atresias, short gut syndrome.
NOTE: "Short gut syndrome" or "short bowel syndrome" is a condition which
is present after a significant amount of intestine has been surgically removed.
Often these patients are dependent upon lifetime parenteral nutrition.
2. Chronic or recurrent diarrhea: malabsorption syndrome, inflammatory
bowel disease.
89
3. Malnutrition (i.e. TPN as a supplement in certain diseases in which
adequate caloric intake is not being achieved via the oral route: cystic fibrosis,
cancer, anorexia nervosa, hypermetabolic states, e.g., burns).
4. Patient who are NPO (or who will be NPO) for sufficient periods of time to
cause a significant decrease in caloric intake (e.g., post-operative patients).
B. Pediatric Parenteral Nutrition Practice Guidelines (from the American
Society for Parenteral and Enteral Nutrition1):
1. Patients who are candidates for parenteral nutrition support are those
requiring nonvolitional feeding who are either already malnourished or are at
risk of developing malnutrition.
2. Peripheral parenteral nutrition should be used to provide partial or total
nutrition for up to 2 weeks in patients who cannot ingest or absorb oral or
enterally delivered nutrients, or when central vein parenteral nutrition is not
feasible.
3. Peripheral parenteral nutrition may be used for short-term (less than 2
weeks) maintenance, supplemental nutrition, or repletion nutrition support in
some older infants and children who are not fluid restricted.
4. Central intravenous nutrition support should be used in patients who do not
tolerate enteral nutrition support or in whom peripheral access is limited,
parenteral support will last longer than 2 weeks, nutrient needs cannot be met
by peripheral parenteral nutrition, or fluid restriction is required.
C. Monitoring: In order to assure that TPN is meeting the nutritional goals, growth
parameters (i.e., weight, height, head circumference) need to be assessed
periodically. Monitoring of specific laboratory parameters assures adequate intake
and decreases the complications of TPN. (See required reading: Table 108.11,
Suggested monitoring schedule during pediatric TPN)
D. Fluid Calculations
1. Initial: The actual volume of TPN (hyperalimentation plus intralipid) to be
given is calculated by subtracting the volume of the patient's other necessary
fluids (e.g., continuous dopamine infusions, arterial lines, etc.) from the total
daily fluid requirement. In patients who are not fluid restricted, who do not
90
have fluid deficits or ongoing abnormal losses, and who do not receive other
fluids, TPN is usually started at normal daily maintenance fluids.
2. Advancement of TPN fluid: In order to provide an adequate amount of
calories for normal growth and development, the daily total fluid volume will
need to exceed the daily normal maintenance fluid requirements.
a. Precautions: Congestive heart failure can easily be produced in a
pediatric patient, if fluids are advanced too rapidly or too much fluid is
given per day. Daily fluids should be increased according to the
following guidelines and patients need to be monitored for
signs/symptoms of fluid overload, edema, and CHF.
b. For infants < 10 kg the initial daily fluid volume may be increased (if
tolerated) by 10 ml/kg/day until the desired caloric intake is achieved.
The maximum amount of fluid (if tolerated) is 200 ml/kg/day.
c. For infants > 10 kg, the initial daily fluid volume may be increased
by 10% of the initial volume per day (if tolerated) until the desired
caloric intake is achieved. The maximum amount of fluid (if tolerated)
is 4000 ml/m2/day).
E. Caloric Requirements: The goal of TPN is to provide adequate calories and
nutrients for proper growth and development of the child. Proper growth of the child
is determined by maintenance of the child's respective growth percentile for age and
gender. For example, if an infant is 75th percentile for height and weight at age 3
months, then the goal is to maintain the 75th percentile for height and weight at
older ages (i.e. as the child gets older, (s)he should be following the 75th percentile
growth curves).
1. Caloric requirements per kg are greater in infants compared to
children and adults. Children also require more calories per Kg
than adults. These increases in caloric requirements are due to
increases in cellular growth and physical activity, as well as an
increased heat loss (due to the larger surface area per body weight
seen in infants and children vs adults).
TPN caloric requirements2
91
AGE (yrs)
Kcal/kg/day
0-1
1-7
7 - 12
90 - 120
75 - 90
60 - 75
2. Factors that increase caloric requirements: Similar to adults,
certain factors will increase daily caloric requirements in children.
FACTOR
INCREASE IN CALORIC NEED2
Fever
10 - 12 % for each degree > 37o C
Cardiac failure
Major surgery
Burns
Severe sepsis
Long term growth failure
15 - 25 %
20 - 30 %
up to 100 %
40 - 50 %
50 - 100 %
NOTE: Infants with protein calorie malnutrition may require 150 - 175
Kcal/kg/day for growth.
F. Carbohydrates: As in adults, pediatric patients are NOT started on TPN with the
highest amount of dextrose required to give adequate calories. Carbohydrates are
started at a lower amount and advanced in a stepwise fashion to allow an appropriate
response of the pancreas. This stepwise advancement allows the pancreas to adjust
to the higher amounts of dextrose given by secreting larger amounts of endogenous
insulin. Hyperglycemia, glucosuria and osmotic diuresis are thus prevented. (NOTE:
Dextrose = 3.4 Kcal/gram)
1. Carbohydrate intake must be calculated for newborns and the very low birth
weight premature infant in terms of gm/kg/day or mg/kg/min.
a. Preterm infants < 1 kg
1. Initial: 3 - 5 mg/kg/minute (Homeostasis)
2. Advance by: 0.5 - 1 mg/kg/minute per day
b. Term newborns and older infants
1. Initial: 7 - 8 mg/kg/minute
2. Advance by: 2 - 4 mg/kg/minute per day
c. Infants: Usual maximum rate of infusion: 18 - 20 mg/kg/minute
d. Children: Usually require 6 - 9 mg/kg/minute
92
2. Practical guidelines: Recommendations according to percent dextrose:
Serum and urine glucose must be monitored as some patients may not tolerate
these increases. These patients (usually preterm infants) will require other
percent concentrations of dextrose, e.g., 6%, 7% etc.
Patient Age Group
Initial concentration
Advance by
Premature infants
Newborn infants
5 % Dextrose
Older infants
5 % Dextrose
2.5 % Dextrose
every
other day
2.5 % Dextrose per
day
5 % Dextrose per
day
Children
Teenagers
5 % Dextrose
Adults
NOTE: Premature and newborn infants are more likely to become
hypoglycemic if the dextrose solution is suddenly discontinued. Serum
dextrose must be monitored if TPN discontinued. Excess carbohydrates (in
comparison to protein and fats) may result in fatty infiltrates of the liver and
an increase in pCO2 on blood gas.
3. Maximum dextrose concentrations for infants and children
a. Peripheral: 10%. Concentrations above 10% are associated with an
increase in phlebitis and a decreased duration of use of the peripheral
line. The peripheral use of 12.5% dextrose containing TPN is
discouraged however, 12.5% dextrose containing TPN is sometimes
used in patients who require higher calories or who are fluid restricted.
Close supervision of the IV site then becomes mandatory (e.g., direct
nursing care, ICU care).
b. Central: 20 - 25 %. The rapid dilution of TPN solutions with the
larger quantities of blood in central veins, allows for solutions with
higher final osmolalities to be used centrally (i.e., higher concentrations
of dextrose). Typically, dextrose concentrations up to 20 % are used
centrally. TPN with 25 % dextrose is usually reserved for severely
malnourished patients. Occasionally, concentrations greater than 25%
(i.e. 30 - 35 %) have been used in older infants and children who are
severely fluid restricted.
93
G. Protein Requirements: Pediatric patients require a greater amount of protein per
kilogram per day compared to adults. Again, this is due to their increased growth
rates.3
Age group
Premature neonates and infants
Greater than 1 year of age
Adolescents & adults
Daily amount of parenteral protein to
promote nitrogen retention
2.5 - 3 grams/kg/day
1.5 - 2 grams/kg/day
1 - 1.5 grams/kg/day
1. Initiation and Advancement: Similar to carbohydrates, pediatric patients
are NOT started at the daily amount of protein to promote nitrogen retention.
Again, patients are started on lower amounts of protein and advanced in a
stepwise fashion.
a. Neonates: Start with 0.5 - 1 gram/kg/day of protein and advance daily
by 0.5 gm/kg/day.
b. Older infants and children: Start with 1 gram/kg/day and advance
daily by 0.5 - 1 gm/kg/day.
Neonates receiving standard adult amino acid formulations were found to
have elevated plasma concentrations of methionine, phenylalanine and glycine
as well as decreased concentrations of tyrosine, cysteine and taurine compared
to normal breast fed infants. Two amino acid formulations have been designed
to meet the special amino acid requirements in neonates and young infants.
TrophamineR and Aminosyn-PFR contain less methionine, phenylalanine and
glycine than adult formulations. Both also contain taurine, tyrosine, and
histidine. L- Cysteine HCL must be added at the time of TPN preparation due
to its instability in solution for prolonged periods.
NOTE: When using TrophamineR, 40 mg of cysteine HCL is added to the
TPN for every one gram of protein. Since cysteine HCL comes as a HCL salt,
one mmol of acetate or lactate is added to the TPN for every mmol (160 mg)
of cysteine HCL. This acetate or lactate is added to balance the HCL load and
prevent a metabolic acidosis which can be produced in premature and young
infants. (Remember that bicarbonate results from acetate and lactate via the
Kreb's cycle.)
Studies have shown that neonates receiving TPN utilizing TrophamineR had
"normal" amino acid patterns i.e., patterns that were similar to breast fed
infants. Significantly greater weight gain and nitrogen balance were seen in
infants were given Trophamine compared to adult amino acid formulations.
94
Further studies in neonates comparing Aminosyn-PFR and TrophamineR are
needed.
4. Nonprotein calorie to gram nitrogen ratio: If an improper amount of
nonprotein calorie to gram nitrogen ratio is given to a patient, (s)he will utilize
proteins as a caloric source rather than for anabolic processes (i.e, as building
blocks for cell growth). The optimal nonprotein calorie to gram nitrogen ratio
in pediatric patients is not well defined. In the past, a nonprotein calorie to
gram nitrogen ratio of 150 -200: 1 was suggested for adults. However, it is
now realized that the ideal nonprotein calorie to gram nitrogen ratio differs
with age and severity of illness. For critically ill infants and children, a
nonprotein calorie to gram nitrogen ratio of 240 - 350: 1 has been suggested
for proper utilization of amino acids. Remember:
Grams of protein / 6.25 = nitrogen content in grams
5. Caloric density: 4 Kcal/gram. Since it is not optimal to use protein as a
caloric source, the protein caloric content of hyperalimentation fluids is
generally not calculated.
H. Lipids: Lipids are administered as part of TPN to prevent or reverse an essential
fatty acid deficiency and to provide a concentrated iso-osmotic source of calories.
1. Essential fatty acid deficiency:
a. Both linoleic acid and linolenic acid are thought to be essential.
b. The premature infant may develop biochemical evidence of essential
fatty acid deficiency in as little as 2 days, due to limited fat stores.
c. Provision of 2 - 4 % of the required total daily calories as IV fat
emulsion or approximately 0.5 - 1 gram/kg/day will prevent clinical
signs and symptoms of essential fatty acid deficiency.
d. Signs of essential fatty acid deficiency include reduced growth,
decreased platelets, impaired wound healing, dry scaly skin and sparse
hair.
e. Biochemical evidence of essential fatty acid deficiency includes a
triene:tetraene ratio greater than 0.4.
2. Lipid Metabolism:
a. Importance of Vitamin E: Lipid metabolism results in lipid
peroxidation and free radical formation. Free radicals can damage cell
membranes if Vitamin E is deficient. (Vitamin E acts as a free radical
95
scavenger.) Lipid emulsions do contain a small amount of Vitamin E,
however, supplementation with MVI is recommended, especially in
infants. In order to prevent peroxidative injury, a vitamin E :
polyunsaturated fatty acid (PUFA) ratio of > 0.6 mg/g is needed.
b. Decreased lipoprotein lipase activity: Lipoprotein lipase hydrolyzes fat
particles to free fatty acids and monoglycerides. Both premature and term
newborns have low lipoprotein lipase activity compared to adults. This results
in a reduced lipid clearance rate. Hypertriglyceridemia / hyperlipidemia (fat
intolerance) occurs when the rate of infusion of the fat emulsion exceeds the
plasma lipid clearance rate. Premature infants, small for gestational age
infants (regardless of gestational age) and nutritionally depleted older children
are at risk for hypertriglyceridemia. Due to decreased fat clearance, lipid
infusions for these patients should be administered over 24 hours.
NOTE: In infants and children, IntralipidR is typically infused over 18 24 hours.
c. Decreased metabolism of glycerol and free fatty acids:
Plasma lipid clearance is also decreased in neonates due to their
decreased metabolism of free fatty acids and glycerol. Carnitine
facilitates the transport of free fatty acids across the mitochondrial
membranes to the site of fat oxidation. Premature neonates and
newborns have limited carnitine stores which can decrease the proper
utilization of free fatty acids.
3. Lipid emulsion dosing guidelines 2,3
Initial dose
Advance by
Maximum dose
Premature or SGA Full term or AGA
Older children
0.5 gm/kg/day
1 gm/kg/day
0.25 gm/kg/day or 0.5 gm/kg/day
every other day
3 gm/kg/day
3 - 4 gm/kg/day
1 gm/kg/day
0.5 gm/kg/day
2 - 3 gm/kg/day
4. Serum triglycerides should be monitored before every (or every other)
increase in lipid emulsion, especially in premature infants and routinely
thereafter. If triglyceride levels are less than 200 mg/dl the patient can be
maintained on her/his present dose.3
5. Caloric Content: Fats are usually considered to contain 9 kcal/gram. Due
to emulsifying agents and other additives, IntralipidR 10% = 1.1 kcal/ml and
IntralipidR 20% = 2 kcal/ml. Usually 25 - 40 percent of the total calories are
provided by lipids but no more than 60 percent of total calories should be
provided by lipids.
96
6. Hypersensitivity reactions including allergic reactions, fever, chills,
shivering, cyanosis, flushing, nausea, vomiting, headache, dizziness, or chest
and back pain have been reported due to the egg phospholipids which are used
to emulsify fat emulsions. Patients should be monitored for these immediate
adverse reactions.
7. Controversies
a. Hyperbilirubinemia: Free fatty acids, which displace bilirubin from
albumin binding sites, may cause an increase in the concentration of
unconjugated bilirubin and increase the risk of kernicterus. Decreased
amounts of fat emulsion (0.5 - 1 gm/kg/day i.e., just enough to prevent
essential fatty acid deficiency) are usually given to neonates with
elevated bilirubin concentrations. These decreased amount of lipids are
usually given when total bilirubin concentrations are greater than onehalf that required for exchange transfusion.
b. Pulmonary compromise: In patients with pulmonary compromise,
lipid emulsions may decrease pulmonary diffusion capacity with a
resultant decrease in PO2. These effects were observed when large
amounts of fat emulsion were administered over short periods of time.
The risk is decreased if lipids are infused over 24 hrs.
c. Heparin stimulates the release of lipoprotein lipase and has been
postulated to be effective in reducing serum triglyceride concentrations
in neonates receiving lipid emulsions. Further studies are needed before
routine use of heparin can be recommended.
NOTE: Heparin is routinely used in TPN at a final concentration of 1
unit/ml to decrease thrombus formation at the central catheter tip, and
to increase the duration of patency of peripheral hyperalimentation
lines. (see required text reading)
I. Electrolytes and minerals
1. Requirements: Unless the patient has an electrolyte abnormality, start with
the recommended daily amount and adjust according to serum chemistries.
Element
Sodium
Potassium
Chloride
Magnesium
Calcium Gluconate
Phosphorus
97
Daily requirement
(infants and children)
2 - 4 mEq/kg
2 - 3 mEq/kg
2 - 3 mEq/kg
0.25 - 0.5 mEq/kg
100 - 500 mg/kg
1 - 2 mmol/kg
Comments:
Sodium: Premature neonates may require higher daily amounts.
Magnesium: Do not routinely add magnesium in the TPN for infants whose
mothers have received therapeutic dose of magnesium (i.e. for tocolysis or
prophylaxis against eclampsia). Check magnesium serum concentration first.
Magnesium may be added if serum magnesium is not elevated.
Calcium Gluconate: Usually, the higher amounts listed are needed in
premature newborns and neonates (300 - 500 mg/kg/day), while the lower
amounts are recommended for older infants (200 mg/kg/day) and toddlers
(100 mg/kg/day). Older children may require only 1 - 2 grams per day of
calcium gluconate.
Phosphorous: Older infants and children will require less phosphorous (0.5
mmol/kg/day) than premature infants and newborns (up to 2 mmol/kg/day).
Potassium phosphate = 0.68 mmol phosphate per mEq
Sodium phosphate = 0.75 mmol phosphate per mEq
2. Calcium and Phosphate Compatibility
Since premature newborns, neonates, and young infants require a greater
amount of calcium and phosphorus compared to adults, calcium / phosphate
compatibility in hyperalimentation fluid is an important issue. Many times the
amount of calcium and phosphorous that these patients require is greater than
the solubility and calcium-phosphate can precipitate.
Many factors effect the solubility of calcium with phosphate in
hyperalimentation solutions. Specific texts (e.g., Trissel's Handbook on
Injectable Drugs) and solubility curves4 are utilized to determine if the amount
of calcium and phosphate ordered in a hyperalimentation will precipitate.
2. Calcium and Phosphate Compatibility Factors which effect calcium and
phosphorous solubility include:
a. Concentration of calcium and phosphorous
b. Salt form of calcium
c. Concentration of amino acids
d. Type of amino acid solution
e. Concentration od dextrose
98
f. Addition of cysteine (effects pH)
J. Vitamin requirements
1. MVI PediatricR provides the American Medical Association Nutrition
Advisory Group (AMA-NAG) requirements for infants greater than 10 kg
until 11 yrs of age. (See table 7 below) 5
2. Unlike the adult MVIR product, the pediatric product contains Vitamin K.
3. FDA recommendations for MVI PediatricR:
Infants < 1 kg
30 % of a vial (1.5 ml)
Infants 1 - 3 kg
65 % of a vial (3.25 ml)
Infants > 3 kg - 11 yrs
100% of a vial (5 ml)
4. In premature infants, the above FDA recommendations may not be
adequate for certain vitamins (vitamin A and E) and may result in higher
serum concentrations of water soluble vitamins (e.g., ascorbic acid).
99
K. Trace elements requirements: 6
1. Trace elements should be given to premature infants upon initiation of TPN
and to term neonates and infants who will receive TPN for > 2 weeks.
2. Copper, zinc, chromium, and manganese available as combination
products: EXAMPLES: Trace element content per 1 ml:
PTE-4
Pedtrace
Neotrace
Zinc
1 mg
0.5 mg
1.5 mg
Copper
0.1 mg
0.1 mg
0.1 mg
Manganese
25 mcg
25 mcg
25 mcg
Chromium
1 mcg
0.85 mcg
0.85 mcg
The usual dose of these products is 0.2 ml/kg/day. Please note the big
difference in zinc concentrations in these products. Neotrace has the highest
amount of zinc and (just as the name implies) is intended for use in neonates.
PTE-4 and Pedtrace have less zinc than neotrace and are intended for use in
infants and children whose zinc requirements are less than neonates. If PTE-4
or Pedtrace is used in neonates, additional zinc must be given in order for
the neonate to receive the total daily recommended amount. Children > 40 50 Kg should use the adult trace element formulations (e.g., Multitrace).
3. Selenium 2 - 3 mcg/kg/day up to daily maximum of 30 - 40 mcg also needs
to be added to the TPN.
4. Iodine
a. Absorbed from topical povidone iodine solution or ointment, so no
need to add to TPN.
b. Thyroid profile monitoring recommended for long term TPN.
5. Iron
a. IV iron dextran is recommended for infants > 2 months of age
receiving TPN for > 1 month. Preterm infants < 2 months of age may
experience hemolysis after given IV iron dextran.
b. If iron is added to the hyperalimentation daily (controversial) the
dose is 0.1 - 0.2 mg/kg/day.
100
c. For monthly IV replacements of iron: calculate iron needs by the
following equation and administer the dose over 3 days. (Maximum
daily dose = 25 mg).
Body weight (pounds) x (100 - % Hgb) x 0.3 = mg of elemental iron
6. Disease states which alter trace element requirements:
a. Increased losses: In diarrhea states or excess G.I. fistula losses extra
zinc may be needed.
b. Decreased elimination:
1. Cholestasis (obstructive jaundice):
Eliminate copper and manganese from TPN
2. Renal failure:
Eliminate Cr and Se from TPN
NOTE: Some clinicians may eliminate Zn or decrease the daily
amount.
L. Complications associated with TPN include infectious, mechanical, metabolic
and other problems such as cholestasis and rickets: (see Table 9-27) 6. For further
discussion of the cns of TPN see requred reading text.
1. Infection: The most common organisms to cause sepsis in TPN patients are
Staphylococcus epidermidis and Staph aureus. Other common bacteria
include: Streptococcus, gram-negative organisms and Candida. Catheter site
infections also occur.
2. Mechanical: One of the many mechanical problems with central TPN is
thrombus formation. Urokinase (5,000 units/ml) may be used in children to
lyse clots in catheters. When using urokinase to lyse a catheter thrombus, it is
important to "treat the clot and not the patient" i.e., urokinase should NOT be
injected past the catheter into the patient. The internal volume (ml) of the
patient's central catheter must be known and only that same amount of
urokinase used. Also, after allowing the urokinase to sit in the catheter and
dissolve the clot, the urokinase should be withdrawn from the catheter. It
should not be administered systemically to the patient. NOTE: The amount of
urokinase that is used in adults to clear a catheter can have systemic effects in
small infants if inadvertently administered through the catheter and not drawn
back as required.
101
3. TPN cholestasis can occur in pediatric patients, usually after about 2 weeks
of TPN. Premature infants and those receiving > 2.5 gm/kg/day of protein
have a higher incidence of liver dysfunction. Other factors which may
increase the incidence of TPN cholestasis include: sepsis, fasting (being
NPO), and calorie overload. Discontinuation of TPN will usually reverse
liver dysfunction. If TPN cannot be discontinued, TPN cholestasis may be
managed by the following:
a. Give the appropriate type and amino acids and reduce the amino acid
load.
b. Give the appropriate amount of calories (i.e. give an adequate but not
an excessive amount).
c. Cyclic hyperalimentation (i.e., cycling the patient off of
hyperalimentation for part of the day): Pediatric precautions: Infants
more often than older children and adolescents may not be able to
tolerate infusion periods less than 12 hours/day. Intolerance is usually
due to inability to handle the higher ml/hr rates of fluid volume or
nutrients that are given over the shorter period of time (i.e., the total
daily amount of fluid and nutrients may be given over < 24 hours time,
this results in a higher ml/hour rate).
d. Stimulate the gut with minimal enteral feeds.
M. Heparin: As previously mentioned, heparin 1 unit per ml (final volume) of
hyperalimentation solution is often used in the pediatric population, both in central
and peripheral TPN. Therapeutic doses of heparin may be approached with
extremely high hyperalimentation rates or with frequent heparin flushes.
(Maintenance doses of heparin are considered to be 10 - 25 units/kg per hour.)
Therefore, a reduction from the usual 1 unit/ml of heparin in the hyperal to 0.5
units/ml may be needed especially in small infants requiring larger volumes of fluid.
102
Goal:
To familiarize students with the differences in nutritional requirements between
adults and children with respect to fluids, electrolytes, calories, carbohydrates,
proteins, fats and trace elements.
Introduction:
Adequate nutrition for the proper growth and development of a child requires
individualization. The amount and type of fluid, calories, electrolytes, and trace
elements are all based on age, weight, nutritional status, and disease state.
I. The total daily fluid requirement of any patient is equal to the normal daily
maintenance fluids plus replacement of any fluid deficit plus replacement of any
significant abnormal ongoing losses. Two methods to calculate normal
maintenance fluids are described below. Normal maintenance fluids provide
replacement for normal body functions and for normal losses (for example,
insensible water loss, urine output and stool losses). Other factors that may increase
the patient's total daily fluid requirements need to be replaced in addition to the
normal daily maintenance fluids.
Total daily fluid requirement = Normal Maintenance Fluids + Deficit + Ongoing
Abnormal Losses
Total daily fluid requirements may be increased by:
4) increases in insensible water losses due to such factors as fever,
hyperventilation, phototherapy, radiant warming, skin breakdown, burns, etc.
5) initial deficits of fluid i.e., dehydration
6) significant ongoing abnormal losses such as diarrhea, vomiting, nasogastric
tube losses, high output renal failure, etc.
A. Daily maintenance fluid requirements (i.e., normal maintenance fluids) are
those required to maintain normal homeostasis for a 24 hour period. Surface area
and body weight are two common methods used for the calculation of maintenance
fluids in pediatric patients.
NOTE: Premature infants will have greater daily maintenance fluid requirements
then those shown here due to their larger surface area to body weight ratio and
thinner skin, both of which significantly increase their insensible water losses from
the skin. In fact, preterm infants < 750 grams often require 200 - 250 ml/kg/day to
prevent dehydration. Due to their highly specialized needs, calculation of fluid
requirements for premature neonates will be considered beyond the scope of this
lecture.
103
1. Daily maintenance fluid requirements calculated by body surface area: For
pediatric patients, the amount of daily maintenance fluid required is in the range of
1500 - 1800 ml/m2/day. Usually 1500 ml/m2/day is used. The surface area method is
usually used in children > 10 kilograms because a precise measurement of surface
area is often difficult in smaller infants.
2. Daily maintenance fluid requirements calculated by body weight
Weight
< 2.5 kg
2.5 - 10 kg
11 - 20 kg
> 20 kg
Daily maintenance fluid requirements
120 ml/kg/day.
100 ml/kg/day.
1000 ml plus 50 ml/kg for every kg over 10 kg.
1500 ml plus 20 ml/kg for every kg over 20 kg.
EXAMPLES:
Weight:
8 kg :
15 kg :
27 kg :
Maintenance fluid
100 ml/kg/day = 800 ml/day
1000 ml + (50 ml/kg * 5) = 1000 + 250 = 1250 ml/day
1500 ml + (20 ml/kg * 7) = 1500 + 140 = 1640 ml/day
3. Factors which may increase insensible water loss will increase daily fluid
requirements.
a. Estimates of additional insensible water loss (e.g., fever) can be calculated as a
percent increase of normal maintenance fluids (e.g. for fever, increase daily fluid by
12% of normal maintenance for every degree Centigrade over 37 degrees).
b. Neonates who receive phototherapy require 20 ml/kg/day additional fluid due to
increased insensible water loss.
B. Fluid deficit is calculated by clinical assessment of dehydration.
Clinical Signs
Thirst
Mild
slight
alert,
Behavior
restless
Mucous membrane normal
Tears
present
Eyes
normal
Skin elasticity
immedi
(pinch retracts)
ately
104
Degree of
dehydration
Moderate
moderate
irritable to touch,
may be lethargic
dry
+/sunken
Severe
intense
hyperirritable to lethargic,
may be comatose
very dry
absent
grossly sunken
slowly
very slowly > 2 seconds
Skin color
normal
Anterior fontanelle normal
Weight loss
3-5%
30-50
Fluid deficit
ml/kg
pale
sunken
8 - 10 %
mottled or gray
very sunken
12 - 15 %
80-100 ml/kg
120-150 ml/kg
NOTE: If the pediatric patient is hemodynamically stable, 1/2 of the fluid
deficit is replaced over the first 8 hours, and the second 1/2 of the fluid deficit
is replaced over the next 16 hours.
C. Ongoing losses also need to be replaced. Estimates of sensible fluid losses can
usually be easily measured (e.g., NG tube losses, vomiting, etc).
D. Fluid restriction: As in adults, the amount of daily fluids administered to a
pediatric patient may need to be restricted. Situations which require fluid restriction
include patients with cerebral edema, congestive heart failure, renal failure, SIADH,
patent ductus arteriosus, and certain pulmonary disorders. Fluid restriction may be
calculated 1) as a percent of maintenance fluids (e.g., 2/3 or 3/4 maintenance) or 2)
as insensible loss (300 - 400 ml/m2) plus urine output.
II. Pediatric Total Parenteral Nutrition (TPN)
A. The indications for TPN in children are similar to the indications in adults, i.e.,
if the G.I. tract cannot be used as a route of administration for nutrition, then
parenteral nutrition may be indicated. One big difference vs adults is that due to
fewer body stores and a higher caloric daily requirement, children are started on
hyperalimentation sooner than adults. Generally, the smaller or younger the child is,
the sooner (s)he needs appropriate nutritional intake. Indications:
1. Congenital or acquired anomalies if the G.I. tract: gastroschisis, bowel
fistulas, intestinal obstruction, atresias, short gut syndrome.
NOTE: "Short gut syndrome" or "short bowel syndrome" is a condition which
is present after a significant amount of intestine has been surgically removed.
Often these patients are dependent upon lifetime parenteral nutrition.
2. Chronic or recurrent diarrhea: malabsorption syndrome, inflammatory
bowel disease.
105
3. Malnutrition (i.e. TPN as a supplement in certain diseases in which
adequate caloric intake is not being achieved via the oral route: cystic fibrosis,
cancer, anorexia nervosa, hypermetabolic states, e.g., burns).
4. Patient who are NPO (or who will be NPO) for sufficient periods of time to
cause a significant decrease in caloric intake (e.g., post-operative patients).
B. Pediatric Parenteral Nutrition Practice Guidelines (from the American
Society for Parenteral and Enteral Nutrition1):
1. Patients who are candidates for parenteral nutrition support are those
requiring nonvolitional feeding who are either already malnourished or are at
risk of developing malnutrition.
2. Peripheral parenteral nutrition should be used to provide partial or total
nutrition for up to 2 weeks in patients who cannot ingest or absorb oral or
enterally delivered nutrients, or when central vein parenteral nutrition is not
feasible.
3. Peripheral parenteral nutrition may be used for short-term (less than 2
weeks) maintenance, supplemental nutrition, or repletion nutrition support in
some older infants and children who are not fluid restricted.
4. Central intravenous nutrition support should be used in patients who do not
tolerate enteral nutrition support or in whom peripheral access is limited,
parenteral support will last longer than 2 weeks, nutrient needs cannot be met
by peripheral parenteral nutrition, or fluid restriction is required.
C. Monitoring: In order to assure that TPN is meeting the nutritional goals, growth
parameters (i.e., weight, height, head circumference) need to be assessed
periodically. Monitoring of specific laboratory parameters assures adequate intake
and decreases the complications of TPN. (See required reading: Table 108.11,
Suggested monitoring schedule during pediatric TPN)
D. Fluid Calculations
1. Initial: The actual volume of TPN (hyperalimentation plus intralipid) to be
given is calculated by subtracting the volume of the patient's other necessary
fluids (e.g., continuous dopamine infusions, arterial lines, etc.) from the total
daily fluid requirement. In patients who are not fluid restricted, who do not
have fluid deficits or ongoing abnormal losses, and who do not receive other
fluids, TPN is usually started at normal daily maintenance fluids.
106
2. Advancement of TPN fluid: In order to provide an adequate amount of
calories for normal growth and development, the daily total fluid volume will
need to exceed the daily normal maintenance fluid requirements.
a. Precautions: Congestive heart failure can easily be produced in a
pediatric patient, if fluids are advanced too rapidly or too much fluid is
given per day. Daily fluids should be increased according to the
following guidelines and patients need to be monitored for
signs/symptoms of fluid overload, edema, and CHF.
b. For infants < 10 kg the initial daily fluid volume may be increased (if
tolerated) by 10 ml/kg/day until the desired caloric intake is achieved.
The maximum amount of fluid (if tolerated) is 200 ml/kg/day.
c. For infants > 10 kg, the initial daily fluid volume may be increased
by 10% of the initial volume per day (if tolerated) until the desired
caloric intake is achieved. The maximum amount of fluid (if tolerated)
is 4000 ml/m2/day).
E. Caloric Requirements: The goal of TPN is to provide adequate calories and
nutrients for proper growth and development of the child. Proper growth of the child
is determined by maintenance of the child's respective growth percentile for age and
gender. For example, if an infant is 75th percentile for height and weight at age 3
months, then the goal is to maintain the 75th percentile for height and weight at
older ages (i.e. as the child gets older, (s)he should be following the 75th percentile
growth curves).
2. Caloric requirements per kg are greater in infants compared to
children and adults. Children also require more calories per Kg
than adults. These increases in caloric requirements are due to
increases in cellular growth and physical activity, as well as an
increased heat loss (due to the larger surface area per body weight
seen in infants and children vs adults).
TPN caloric requirements2
107
AGE (yrs)
Kcal/kg/day
0-1
1-7
7 - 12
90 - 120
75 - 90
60 - 75
2. Factors that increase caloric requirements: Similar to adults,
certain factors will increase daily caloric requirements in children.
FACTOR
INCREASE IN CALORIC NEED2
Fever
10 - 12 % for each degree > 37o C
Cardiac failure
Major surgery
Burns
Severe sepsis
Long term growth failure
15 - 25 %
20 - 30 %
up to 100 %
40 - 50 %
50 - 100 %
NOTE: Infants with protein calorie malnutrition may require 150 - 175
Kcal/kg/day for growth.
F. Carbohydrates: As in adults, pediatric patients are NOT started on TPN with the
highest amount of dextrose required to give adequate calories. Carbohydrates are
started at a lower amount and advanced in a stepwise fashion to allow an appropriate
response of the pancreas. This stepwise advancement allows the pancreas to adjust
to the higher amounts of dextrose given by secreting larger amounts of endogenous
insulin. Hyperglycemia, glucosuria and osmotic diuresis are thus prevented. (NOTE:
Dextrose = 3.4 Kcal/gram)
1. Carbohydrate intake must be calculated for newborns and the very low birth
weight premature infant in terms of gm/kg/day or mg/kg/min.
a. Preterm infants < 1 kg
1. Initial: 3 - 5 mg/kg/minute (Homeostasis)
2. Advance by: 0.5 - 1 mg/kg/minute per day
b. Term newborns and older infants
1. Initial: 7 - 8 mg/kg/minute
2. Advance by: 2 - 4 mg/kg/minute per day
c. Infants: Usual maximum rate of infusion: 18 - 20 mg/kg/minute
d. Children: Usually require 6 - 9 mg/kg/minute
108
2. Practical guidelines: Recommendations according to percent dextrose:
Serum and urine glucose must be monitored as some patients may not tolerate
these increases. These patients (usually preterm infants) will require other
percent concentrations of dextrose, e.g., 6%, 7% etc.
Patient Age Group
Initial concentration
Advance by
Premature infants
Newborn infants
5 % Dextrose
Older infants
5 % Dextrose
2.5 % Dextrose
every
other day
2.5 % Dextrose per
day
5 % Dextrose per
day
Children
Teenagers
5 % Dextrose
Adults
NOTE: Premature and newborn infants are more likely to become
hypoglycemic if the dextrose solution is suddenly discontinued. Serum
dextrose must be monitored if TPN discontinued. Excess carbohydrates (in
comparison to protein and fats) may result in fatty infiltrates of the liver and
an increase in pCO2 on blood gas.
3. Maximum dextrose concentrations for infants and children
a. Peripheral: 10%. Concentrations above 10% are associated with an
increase in phlebitis and a decreased duration of use of the peripheral
line. The peripheral use of 12.5% dextrose containing TPN is
discouraged however, 12.5% dextrose containing TPN is sometimes
used in patients who require higher calories or who are fluid restricted.
Close supervision of the IV site then becomes mandatory (e.g., direct
nursing care, ICU care).
b. Central: 20 - 25 %. The rapid dilution of TPN solutions with the
larger quantities of blood in central veins, allows for solutions with
higher final osmolalities to be used centrally (i.e., higher concentrations
of dextrose). Typically, dextrose concentrations up to 20 % are used
centrally. TPN with 25 % dextrose is usually reserved for severely
malnourished patients. Occasionally, concentrations greater than 25%
(i.e. 30 - 35 %) have been used in older infants and children who are
severely fluid restricted.
G. Protein Requirements: Pediatric patients require a greater amount of protein per
kilogram per day compared to adults. Again, this is due to their increased growth
rates.3
109
Age group
Premature neonates and infants
Greater than 1 year of age
Adolescents & adults
Daily amount of parenteral protein to
promote nitrogen retention
2.5 - 3 grams/kg/day
1.5 - 2 grams/kg/day
1 - 1.5 grams/kg/day
1. Initiation and Advancement: Similar to carbohydrates, pediatric patients
are NOT started at the daily amount of protein to promote nitrogen retention.
Again, patients are started on lower amounts of protein and advanced in a
stepwise fashion.
a. Neonates: Start with 0.5 - 1 gram/kg/day of protein and advance daily
by 0.5 gm/kg/day.
b. Older infants and children: Start with 1 gram/kg/day and advance
daily by 0.5 - 1 gm/kg/day.
Neonates receiving standard adult amino acid formulations were found to
have elevated plasma concentrations of methionine, phenylalanine and glycine
as well as decreased concentrations of tyrosine, cysteine and taurine compared
to normal breast fed infants. Two amino acid formulations have been designed
to meet the special amino acid requirements in neonates and young infants.
TrophamineR and Aminosyn-PFR contain less methionine, phenylalanine and
glycine than adult formulations. Both also contain taurine, tyrosine, and
histidine. L- Cysteine HCL must be added at the time of TPN preparation due
to its instability in solution for prolonged periods.
NOTE: When using TrophamineR, 40 mg of cysteine HCL is added to the
TPN for every one gram of protein. Since cysteine HCL comes as a HCL salt,
one mmol of acetate or lactate is added to the TPN for every mmol (160 mg)
of cysteine HCL. This acetate or lactate is added to balance the HCL load and
prevent a metabolic acidosis which can be produced in premature and young
infants. (Remember that bicarbonate results from acetate and lactate via the
Kreb's cycle.)
Studies have shown that neonates receiving TPN utilizing TrophamineR had
"normal" amino acid patterns i.e., patterns that were similar to breast fed
infants. Significantly greater weight gain and nitrogen balance were seen in
infants were given Trophamine compared to adult amino acid formulations.
Further studies in neonates comparing Aminosyn-PFR and TrophamineR are
needed.
4. Nonprotein calorie to gram nitrogen ratio: If an improper amount of
nonprotein calorie to gram nitrogen ratio is given to a patient, (s)he will utilize
proteins as a caloric source rather than for anabolic processes (i.e, as building
110
blocks for cell growth). The optimal nonprotein calorie to gram nitrogen ratio
in pediatric patients is not well defined. In the past, a nonprotein calorie to
gram nitrogen ratio of 150 -200: 1 was suggested for adults. However, it is
now realized that the ideal nonprotein calorie to gram nitrogen ratio differs
with age and severity of illness. For critically ill infants and children, a
nonprotein calorie to gram nitrogen ratio of 240 - 350: 1 has been suggested
for proper utilization of amino acids. Remember:
Grams of protein / 6.25 = nitrogen content in grams
5. Caloric density: 4 Kcal/gram. Since it is not optimal to use protein as a
caloric source, the protein caloric content of hyperalimentation fluids is
generally not calculated.
H. Lipids: Lipids are administered as part of TPN to prevent or reverse an essential
fatty acid deficiency and to provide a concentrated iso-osmotic source of calories.
1. Essential fatty acid deficiency:
a. Both linoleic acid and linolenic acid are thought to be essential.
b. The premature infant may develop biochemical evidence of essential
fatty acid deficiency in as little as 2 days, due to limited fat stores.
c. Provision of 2 - 4 % of the required total daily calories as IV fat
emulsion or approximately 0.5 - 1 gram/kg/day will prevent clinical
signs and symptoms of essential fatty acid deficiency.
d. Signs of essential fatty acid deficiency include reduced growth,
decreased platelets, impaired wound healing, dry scaly skin and sparse
hair.
e. Biochemical evidence of essential fatty acid deficiency includes a
triene:tetraene ratio greater than 0.4.
2. Lipid Metabolism:
a. Importance of Vitamin E: Lipid metabolism results in lipid
peroxidation and free radical formation. Free radicals can damage cell
membranes if Vitamin E is deficient. (Vitamin E acts as a free radical
scavenger.) Lipid emulsions do contain a small amount of Vitamin E,
however, supplementation with MVI is recommended, especially in
infants. In order to prevent peroxidative injury, a vitamin E :
polyunsaturated fatty acid (PUFA) ratio of > 0.6 mg/g is needed.
111
b. Decreased lipoprotein lipase activity: Lipoprotein lipase hydrolyzes fat
particles to free fatty acids and monoglycerides. Both premature and term
newborns have low lipoprotein lipase activity compared to adults. This results
in a reduced lipid clearance rate. Hypertriglyceridemia / hyperlipidemia (fat
intolerance) occurs when the rate of infusion of the fat emulsion exceeds the
plasma lipid clearance rate. Premature infants, small for gestational age
infants (regardless of gestational age) and nutritionally depleted older children
are at risk for hypertriglyceridemia. Due to decreased fat clearance, lipid
infusions for these patients should be administered over 24 hours.
NOTE: In infants and children, IntralipidR is typically infused over 18 24 hours.
c. Decreased metabolism of glycerol and free fatty acids:
Plasma lipid clearance is also decreased in neonates due to their
decreased metabolism of free fatty acids and glycerol. Carnitine
facilitates the transport of free fatty acids across the mitochondrial
membranes to the site of fat oxidation. Premature neonates and
newborns have limited carnitine stores which can decrease the proper
utilization of free fatty acids.
3. Lipid emulsion dosing guidelines 2,3
Initial dose
Advance by
Maximum dose
Premature or SGA Full term or AGA
Older children
0.5 gm/kg/day
1 gm/kg/day
0.25 gm/kg/day or 0.5 gm/kg/day
every other day
3 gm/kg/day
3 - 4 gm/kg/day
1 gm/kg/day
0.5 gm/kg/day
2 - 3 gm/kg/day
4. Serum triglycerides should be monitored before every (or every other)
increase in lipid emulsion, especially in premature infants and routinely
thereafter. If triglyceride levels are less than 200 mg/dl the patient can be
maintained on her/his present dose.3
5. Caloric Content: Fats are usually considered to contain 9 kcal/gram. Due
to emulsifying agents and other additives, IntralipidR 10% = 1.1 kcal/ml and
IntralipidR 20% = 2 kcal/ml. Usually 25 - 40 percent of the total calories are
provided by lipids but no more than 60 percent of total calories should be
provided by lipids.
6. Hypersensitivity reactions including allergic reactions, fever, chills,
shivering, cyanosis, flushing, nausea, vomiting, headache, dizziness, or chest
and back pain have been reported due to the egg phospholipids which are used
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to emulsify fat emulsions. Patients should be monitored for these immediate
adverse reactions.
7. Controversies
a. Hyperbilirubinemia: Free fatty acids, which displace bilirubin from
albumin binding sites, may cause an increase in the concentration of
unconjugated bilirubin and increase the risk of kernicterus. Decreased
amounts of fat emulsion (0.5 - 1 gm/kg/day i.e., just enough to prevent
essential fatty acid deficiency) are usually given to neonates with
elevated bilirubin concentrations. These decreased amount of lipids are
usually given when total bilirubin concentrations are greater than onehalf that required for exchange transfusion.
b. Pulmonary compromise: In patients with pulmonary compromise,
lipid emulsions may decrease pulmonary diffusion capacity with a
resultant decrease in PO2. These effects were observed when large
amounts of fat emulsion were administered over short periods of time.
The risk is decreased if lipids are infused over 24 hrs.
c. Heparin stimulates the release of lipoprotein lipase and has been
postulated to be effective in reducing serum triglyceride concentrations
in neonates receiving lipid emulsions. Further studies are needed before
routine use of heparin can be recommended.
NOTE: Heparin is routinely used in TPN at a final concentration of 1
unit/ml to decrease thrombus formation at the central catheter tip, and
to increase the duration of patency of peripheral hyperalimentation
lines. (see required text reading)
I. Electrolytes and minerals
1. Requirements: Unless the patient has an electrolyte abnormality, start with
the recommended daily amount and adjust according to serum chemistries.
Element
Sodium
Potassium
Chloride
Magnesium
Calcium Gluconate
Phosphorus
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Daily requirement
(infants and children)
2 - 4 mEq/kg
2 - 3 mEq/kg
2 - 3 mEq/kg
0.25 - 0.5 mEq/kg
100 - 500 mg/kg
1 - 2 mmol/kg
Comments:
Sodium: Premature neonates may require higher daily amounts.
Magnesium: Do not routinely add magnesium in the TPN for infants whose
mothers have received therapeutic dose of magnesium (i.e. for tocolysis or
prophylaxis against eclampsia). Check magnesium serum concentration first.
Magnesium may be added if serum magnesium is not elevated.
Calcium Gluconate: Usually, the higher amounts listed are needed in
premature newborns and neonates (300 - 500 mg/kg/day), while the lower
amounts are recommended for older infants (200 mg/kg/day) and toddlers
(100 mg/kg/day). Older children may require only 1 - 2 grams per day of
calcium gluconate.
Phosphorous: Older infants and children will require less phosphorous (0.5
mmol/kg/day) than premature infants and newborns (up to 2 mmol/kg/day).
Potassium phosphate = 0.68 mmol phosphate per mEq
Sodium phosphate = 0.75 mmol phosphate per mEq
2. Calcium and Phosphate Compatibility
Since premature newborns, neonates, and young infants require a greater
amount of calcium and phosphorus compared to adults, calcium / phosphate
compatibility in hyperalimentation fluid is an important issue. Many times the
amount of calcium and phosphorous that these patients require is greater than
the solubility and calcium-phosphate can precipitate.
Many factors effect the solubility of calcium with phosphate in
hyperalimentation solutions. Specific texts (e.g., Trissel's Handbook on
Injectable Drugs) and solubility curves4 are utilized to determine if the amount
of calcium and phosphate ordered in a hyperalimentation will precipitate.
2. Calcium and Phosphate Compatibility Factors which effect calcium and
phosphorous solubility include:
a. Concentration of calcium and phosphorous
b. Salt form of calcium
c. Concentration of amino acids
d. Type of amino acid solution
e. Concentration od dextrose
f. Addition of cysteine (effects pH)
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J. Vitamin requirements
1. MVI PediatricR provides the American Medical Association Nutrition
Advisory Group (AMA-NAG) requirements for infants greater than 10 kg
until 11 yrs of age. (See table 7 below) 5
2. Unlike the adult MVIR product, the pediatric product contains Vitamin K.
3. FDA recommendations for MVI PediatricR:
Infants < 1 kg
30 % of a vial (1.5 ml)
Infants 1 - 3 kg
65 % of a vial (3.25 ml)
Infants > 3 kg - 11 yrs
100% of a vial (5 ml)
4. In premature infants, the above FDA recommendations may not be
adequate for certain vitamins (vitamin A and E) and may result in higher
serum concentrations of water soluble vitamins (e.g., ascorbic acid).
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K. Trace elements requirements: 6
1. Trace elements should be given to premature infants upon initiation of TPN
and to term neonates and infants who will receive TPN for > 2 weeks.
2. Copper, zinc, chromium, and manganese available as combination
products: EXAMPLES: Trace element content per 1 ml:
PTE-4
Pedtrace
Neotrace
Zinc
1 mg
0.5 mg
1.5 mg
Copper
0.1 mg
0.1 mg
0.1 mg
Manganese
25 mcg
25 mcg
25 mcg
Chromium
1 mcg
0.85 mcg
0.85 mcg
The usual dose of these products is 0.2 ml/kg/day. Please note the big
difference in zinc concentrations in these products. Neotrace has the highest
amount of zinc and (just as the name implies) is intended for use in neonates.
PTE-4 and Pedtrace have less zinc than neotrace and are intended for use in
infants and children whose zinc requirements are less than neonates. If PTE-4
or Pedtrace is used in neonates, additional zinc must be given in order for
the neonate to receive the total daily recommended amount. Children > 40 50 Kg should use the adult trace element formulations (e.g., Multitrace).
3. Selenium 2 - 3 mcg/kg/day up to daily maximum of 30 - 40 mcg also needs
to be added to the TPN.
4. Iodine
a. Absorbed from topical povidone iodine solution or ointment, so no
need to add to TPN.
b. Thyroid profile monitoring recommended for long term TPN.
5. Iron
a. IV iron dextran is recommended for infants > 2 months of age
receiving TPN for > 1 month. Preterm infants < 2 months of age may
experience hemolysis after given IV iron dextran.
b. If iron is added to the hyperalimentation daily (controversial) the
dose is 0.1 - 0.2 mg/kg/day.
c. For monthly IV replacements of iron: calculate iron needs by the
following equation and administer the dose over 3 days. (Maximum
daily dose = 25 mg).
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Body weight (pounds) x (100 - % Hgb) x 0.3 = mg of elemental iron
6. Disease states which alter trace element requirements:
a. Increased losses: In diarrhea states or excess G.I. fistula losses extra
zinc may be needed.
b. Decreased elimination:
1. Cholestasis (obstructive jaundice):
Eliminate copper and manganese from TPN
2. Renal failure:
Eliminate Cr and Se from TPN
NOTE: Some clinicians may eliminate Zn or decrease the daily
amount.
L. Complications associated with TPN include infectious, mechanical, metabolic
and other problems such as cholestasis and rickets: (see Table 9-27) 6. For further
discussion of the cns of TPN see requred reading text.
1. Infection: The most common organisms to cause sepsis in TPN patients are
Staphylococcus epidermidis and Staph aureus. Other common bacteria
include: Streptococcus, gram-negative organisms and Candida. Catheter site
infections also occur.
2. Mechanical: One of the many mechanical problems with central TPN is
thrombus formation. Urokinase (5,000 units/ml) may be used in children to
lyse clots in catheters. When using urokinase to lyse a catheter thrombus, it is
important to "treat the clot and not the patient" i.e., urokinase should NOT be
injected past the catheter into the patient. The internal volume (ml) of the
patient's central catheter must be known and only that same amount of
urokinase used. Also, after allowing the urokinase to sit in the catheter and
dissolve the clot, the urokinase should be withdrawn from the catheter. It
should not be administered systemically to the patient. NOTE: The amount of
urokinase that is used in adults to clear a catheter can have systemic effects in
small infants if inadvertently administered through the catheter and not drawn
back as required.
3. TPN cholestasis can occur in pediatric patients, usually after about 2 weeks
of TPN. Premature infants and those receiving > 2.5 gm/kg/day of protein
have a higher incidence of liver dysfunction. Other factors which may
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increase the incidence of TPN cholestasis include: sepsis, fasting (being
NPO), and calorie overload. Discontinuation of TPN will usually reverse
liver dysfunction. If TPN cannot be discontinued, TPN cholestasis may be
managed by the following:
a. Give the appropriate type and amino acids and reduce the amino acid
load.
b. Give the appropriate amount of calories (i.e. give an adequate but not
an excessive amount).
c. Cyclic hyperalimentation (i.e., cycling the patient off of
hyperalimentation for part of the day): Pediatric precautions: Infants
more often than older children and adolescents may not be able to
tolerate infusion periods less than 12 hours/day. Intolerance is usually
due to inability to handle the higher ml/hr rates of fluid volume or
nutrients that are given over the shorter period of time (i.e., the total
daily amount of fluid and nutrients may be given over < 24 hours time,
this results in a higher ml/hour rate).
d. Stimulate the gut with minimal enteral feeds.
M. Heparin: As previously mentioned, heparin 1 unit per ml (final volume) of
hyperalimentation solution is often used in the pediatric population, both in central
and peripheral TPN. Therapeutic doses of heparin may be approached with
extremely high hyperalimentation rates or with frequent heparin flushes.
(Maintenance doses of heparin are considered to be 10 - 25 units/kg per hour.)
Therefore, a reduction from the usual 1 unit/ml of heparin in the hyperal to 0.5
units/ml may be needed especially in small infants requiring larger volumes of fluid.
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