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Types of additives in parenteral formulation
Aims of additives usage
Requirements of substances as additives in parenteral
Solubilizing agents
Substances to increase tonicity
Other additives

Types of additives in parenteral formulation

1. Preservatives
2. Buffer
3. Antioxidants
4. Solubilizing agents
5. Isotonic substances
6. Other additives (local anesthetic,
vasoconstrictor, stabilizer, inert gas,
complexing agents, chelating agents,

The aims of excipients addition in parenteral

To increase or maintain the solubility of active
ingredients (as solubilizers)
To increase or maintain the stability of product (such
as buffer, antioxidants, chelating agents)
To ensure safety and sterility (preservatives)
To reduce pain and irritation during the injection
(isotonic agents)
To control or extend the release of drug (polimer)

Requirements of additives usage in

parenteral formultion:

Non toxic in the given amount

Do not disturb therapeutic effect of
Do not disturb the identification and
quantification of drug level

Preservatives are used to maintain the
sterility of multiple dosage form of drug
solution products.
Requirements of preservatives as
additives in parenteral formulation:
Able to prevent the growth of bacteria and
kill the contaminating microbes
Compatible with drug even for long duration
of storage
Stable at sterilization process
Non toxic at the given amount
Small absorption ability to the rubber
Do not interfere the identification of drug
Can be dissolved in the used vehicle

Example of preservatives used in parenteral


Phenol 0.5%

- Benzalconium chloride 0.01%

Cresol 0.3%
- Benzethonium fuoride 0.01%
Chlorcresol 0.1%
- Benzil alcohol
1-2 %
Chlorbutanol 0.5% - methyl p-hydroxy benzoat 0.1-0.2%
Phenylmercury(II) nitrate - propyl p-hidroxy benzoat
Thimerosal 0.01% - butyl p-hydroxy


Combination of methyl p-hydroxybenzoat 0.18 % dan propyl
p-hydroxybenzoat 0,02%

The parenteral formulation that should not

be added with preservatives

dose volume more than 15 mL.

The route administration by intra
cardiac, intraartery, intra thecal, intra
cysterna, and peridural.

Incompatibility of preservatives

Benzyl alcohol immiscible with Chloramphenicol sodium

metylcellulose and nonionic surfactant
(polisorbate 80)
Phenyl mercury salt incompatible with halogen,
penicillin, sodium metabisulphite, aluminium and other
metal, amonia and its salt, amino acid, sulphuric
compound, rubber,
disodium edetate and sodium
Precipitate in acid solution.
Unstable at pH < 7.
Can not miscible with aluminium and other metal, silver
sodium chloride, lecithin, phenyl mercury
compound, amonium quartener, protein, sodium meta
bisulphite, EDTA compound.
Absorb rubber and certain plastic from closure

Benzalkonium chloride can not miscible with:

-anionic surfactant and detergens
- high concentration of surfactant
- citric, nitrate, permanganate, calcium chloride, salisylic,
silver salt, tartrate, boric acid 5%, hydroxide alkaline,
carbonate, etc.

Cannot miscible with silver nitrate and sodium sulphide


Hydrolised to chloride acid at neutral pH or above. Used

in solution with buffer at pH 5-5.5.

Loss of activity due to poliethylene or rubber surface

absorption from closure.
Inactivated by polysorbate 80, CMC
Paraben and phenol immiscible with nitrofuranthoin,
amphothericin B dan erytromicin


Buffer system is needed for : parenteral

formulations which are sensitive to the
pH changes, such as antibiotics
(penicillin, streptomycin,tetracyclin),
polipeptide (insulin, vasopresin)
The used buffer capacity usually is low (do
not change pH of body fuid at the time of
injection), but strong enough to prevent

the pH changes during storage and


Buffer capacity : measurement of resistance
from pH changes of a solution.
Example: Acetate, Citrate , phosphate,
amino acid (Polipeptide)
Reason for buffer addition:

Reduce tissue damage and pain at the

time of injection

Increase therapeutic effect of certain


Increase chemical stability of drugs

Factors that affect pH of injectable drug

Product degradation
Container and closure effecr (release of
alkaline from glass cotainer, or from rubber
Gas diffusion through closure
Example of buffer : Sodium citrate, sodium
phosphate, sodium acetate, sodium
succinate, hystidine, Tris (hydroxymethyl)
aminomethane, etc.

Function: to maintain easily oxidized drug, such as
adrenaline, chlorpromazine, morphine,
apomorphine, ascorbic acid, etc.
Example of antioxidants:
Antioxidants for aqueous injectable drug:
- Ascorbic acid 0,02-0,1%
- sodium bisulphite, sodium metabisulphite 0.10.15%
- sodium formaldehyde sulphocylate 0,1-0,15%
- Thio urea 0,005%
Acting as reducing agent.


Antioxidant for oleagineous injectable drug

- Propyl gallat 0,005-0,15%
- Tocopherol 0,05-0,5%,

Antioxidant (Blocking agent)

-Ascorbic acid ester ( 0.01-0,05%)
- citric acid (0,005-0,01%)
- Phosporic acid (0,05-0,01%)
- Tartaric acid (0,01-0,02%)

Chelating agent
Function: forming complex with metals like Cu,Fe,
and Zn which catalyze oxidation of drug molecule.
Source of metal contamination:
- The impurity of drug
- Solvent (such as water), container and rubber
- Processing equipments
Example of chelating agents:
Edetic acid 0.1% , Disodium edetate 0.1%,
Calcium disodium edetate 0.1% , Citric acid 0.32.0%, tartaric acid, sodium citrate,
Ethylenediaminetetraacetic acid (EDTA).

Characteristic of ideal antioxidants/

chelating agents:

Effective at non toxic concentration, low


Stable and effective at the used condition

(wide range of pH and temperature)

Dissolved at desired concentration

Compatible with varies of drug and other


No odor, taste and non irritate

No colour in the original form and

oxidized from

Relative low in cost

Solubilizing agents
Basic approach of parenteral drug
1. Salt formation
2. pH adjustment
3. The usage of Co-solvents
4. The usage of Surfactant
5. Complexation agents
6. Transform the formula from solution to
dispersed system, oil solution or more
complex formulation such as
microemulsion or liposome.

1.Co solvents
Ethanol 1-50 % ,
Glycerine 1-50 %,
PEG(300 & 400) and PG 1-50 %,
Polysorbate 20, 40, 80,
Povidone, sorbitan monopalmitate , dimetilasetamida,
Cremophor El
Polyoxyethylene sorbitan monooleate (Tween 80)
Sorbitan monooleate
Polyoxyethylene sorbitan monolaurate (Tween 20)
Polyoxyethylenepolyoxypropylene copolymers

Solubilizing agent

1. Co-solvents: are used for barbiturate drugs,

antihistamine, cardiac glycoside.
Organic solvents also can prevent the hydrolysis
of the drugs.
Sorbitol had been reported to increase the
degradation rate of penicillin in neutral aqueous
Propylene glycol will increase the antimicrobial
activity of parabens with the presence of nonionic
surfactant and inhibit the interaction of methyl
paraben and polysorbate.

2. Surfactants
Polyoxythylene sorbitan monooleate (Tween 80)
Polyoxyethylene sorbitan monolaurate (Tween 20)
Polyoxyethylenepolyoxypropylene copolymers
3. Complexing agents
Sulfobutylether-b-cyclodextrin (Captisol1)
Amino acids (arginine, lysine, histidine)

Example of complexing agents to increase solublity:

a. The addition of sodium benzoate to increase
the solubility of caffeine in Caffeine Sodium
Benzoate Injection
b. The addition of excessive ethylene diamine in
Aminophylline Injection to mantain the solubility
of theophylline.
c.The addition of calcium d-saccharate or
lactobisacconate, glucoheptonate, and laevulinate
in Calcium Gluconate Injection to prevent the
crystalization of calcium gluconate.
The added calcium salts are not more than 5%
from calcium gluconate itself.

Substances that increasing tonicity

Sodium chloride
Osmosis : process in which 2 solutions are placed in each
side of semipermeable membrane, the solvent will move
pass through the membrane from low concentration
solution to high concentration solution in order to
equilibrate concentration. The pressure that responsible
for the movement is called osmotic pressure.
Isoosmotic : two solutions that have same osmotic

Solution that has same osmotic pressure

with certain body fuid is called isotonic with
the spesific body fuid.
0,9% of NaCl solution is isotonic with body
Solution with lower osmotic pressure than
body fuid or 0,9% of NaCl solution is called
Solution with higher osmotic pressure than
body fuid or 0,9% of NaCl solution is called

Effects of hypotonic solution on red

blood cells:
Causing the cell to swelling rapidly until
burst, releasing the inside components
This damage is permanent, and very
harmful if the bursted cells are too many
(large volume is given)

The hypotonic solution is made isotonic by

adding substances that can increase the
tonicity, such as NaCl, dextrose , KCl,
sodium citrate, sodium nitrate, potassium
Nitrate , sorbitol, mannitol, etc.

Effects of hypertonic solution to the red

blood cells:
A. Solution for intravenous injection
The cells will shrink, the cell wall is seen
crenulation and this damage is temporary,
it will be normal again if the pressure is
equal at the cell wall. Therefore if it is
injected to the blood fow, it should be
slowly whereby the solution will be diluted
rapidly by the blood circulation.

B. Solution for subcutaneous injection

Isotonicity is not very important because it

is injected to the lipid tissue, not to the
blood fow system.

C. Solution for intramuscular injection

in water should be slightly
hypertonic to increase the absorption.
Solution for long acting purpose (slow
absorption), such as suspension in water
should be isotonic, hypertonic vehicle will
increase the absorption.

D. Solution for intracutaneous injection

Diagnostic dosage forms should be isotonic
because non isotonic solution will give the
wrong reaction.
E. Solution for intra thecal injection
Solution for this route of administration
should be isotonic. The volume of
cerebrospinal liquid is only about 60-80 mL,
therefore small volume of non isotonic
solution will damage the osmotic pressure
and resulting vomiting and other effects.

There are 6 methods to calculte tonicity of

injectable solution:
1. Molecular concentration 4. Freezing point
2. Ionic concentration
5. Sodium chloride
3. Dissociation factor
6. Graphical

1. Molecular Concentration
It is based on the Vant Hoff assumption that the law of
osmotic pressure is equal to the law of gas from Charles
and Boyle,
= ---- RT or
= cRT
dimana : = osmotic pressure
c = molarity,
n = mole
R = gas constant
v = volume (L)
T = absolute temperature
If one mole unionized substance is dissolved in 22,4 L of
water at temperature of 0C ( 273 K ), it will give an
osmotic pressure as much as:

1 x 0,0821 x 273
-------------------- = 1 Atm
Therefore, solution with molarity of 1 mole/L will give
osmotic pressure as much as:
1 x 0,0821 x 273
-------------------- = 22,4 Atm
Blood plasma and eye tear are known to have osmotic
pressure around
6.7 Atm, then the bias molarity can be calculated as:
--------- = 0.3 mole/liter

Therefore, an isotonic solution has molarity as much as:

0.3 M or W= 0.3 M.
Anhydrate glucose (MW=180) has isotonic solution at:
0.3 x 180 = 54 gram/liter
= 5.4 %
For the ionized substances the formula used as follow:
0.3 x M
W = ----------N
W= concentration in gram/liter
M= molecular weight of substance
N= ion number for each molecule of substance
1. Sodium chloride is ionized become 2 ions, MW= 58, the
isotonic solution is:

0.3 x 58
----------= 8.7 gram/liter = 0,87 % ~ 0.9%
2. R/ Sodium chloride
0.12% MW = 58
Glucose anhydrate
qs MW = 180
The needed glucose anhydrate is calculated as follow:
a. Find the molarity of sodium chloride
1.2 x 2
--------- = 0.04 mole/l
b. Find the neede glucose anhydrate molarity to get
isotonic solution:
= 0.3 0.04 mole/l
= 0.26 mole/l
c. The percentage of anhydrate glucose to get isotonic
solution is:
0.26 x 180 = 46.8 gram/l
= 4.68%

2. Ionic concentration
It has been known that the normal composition of blood is
as follow:
Cation: Na+
142 m Eq/l
327 mg%
5 m Eq/l
20 mg%
5 m Eq/l
10 mg%
3 m Eq/l
4 mg%
155 m Eq/l
361 mg%
Anion: HCO3CI
SO4organic acid

27 m Eq/l 165 mg%

103 m Eq/l 366 mg%
2 m Eq/l
10 mg%
1 m Eq/l
5 mg%
6 m Eq/l
16 m Eq/l 7100 mg%
155 m Eq/l
7646 mg%

Therefore the total ions number in normal blood = 310 m Eq/l.

Then an electrolyte solution is isotonic if has ion number equal
to 310 m Eq/l
1. Sodium chloride solution MW = 58 isotonic if has ions as
much as 310 m Eq/l, consist of Na ion equal to 155 m Eq/l
dan CI ion equal to155 m Eq/l, therefore the percentage of
isotonic sodium chloride solution is 155 x 58 = 8990 mg/l =
0,899 % ~ 0.9%
2. R /
40 m Eq
40 m Eq
m.f. inj ad 1000 ml
Available ions equal to 80 m Eq/l
Required ions = 310 80
= 230 m Eq/l
The required ions consist of 115 mEq Na ion dan 115 mEq CI
Therefore the required sodium chloride is 115 x 58 = 6670 mg

3. Dissociation factor
It was introduced by Nicolo, which then used in
Netherland Pharmacopoeia Fourth Edition.
Three factors used in this method are:
1. Concentration of substance in solution ( gram/L )
2. Molecular weight of substance
3. Dissociation level of substance which approach the true

For undissociated substance = 1

For weak acid and weak base = 1,5

For strong acid, strong base and salt = 1,8

From the above factors it can be derived the serum isotonic
as example:

NaCI,dissociation level =1,8 isotonic concentration = 9

gram/l ; BM = 58.
1,8 x 9
Serum isotonic factor = ----------- = 0,28

Glucose anhydrate, dissociation level =1; isotonic

concentration =

1 x 50,5
Serum isotonic factor = ------------- = 0,28
From the above examples, generally it can be concluded
that a solution is isotonic if has the following equation:
------x a + ------- x b + ------------------------- = 0,28
To calculate the additional substances to be added to get
isotonic solution (h), it can be used the following equation:
h= ------- 0,28 ----- x a + ------ x b
= MW of the dissolved substances
= Concentration of the dissolved substnaces in
= MW of additional substance
fh, fA, fB
= dissociation level

R/ Glucose
MW = 180
Potassium chloride 0.5
MW = 74,5
Sodium chloride
MW = 58
m.f. inj. ad
100 ml
h = ------ 0,28 ------ x 5 + ------ x 20
= 1,549 gram/l
= 0,155 gram/100 ml

4. Freezing point depletion

This method is based on the fact that freezing point of a
solutio is depended on the amount of dissolved
Therefore, the freezing point of a solution can be used to
measure how concentrate a solution. More concentrate
a solution, then it has lower freezing point.
The freesing poin of plasma and tear = - 0,52C, then a
solution is isotonic if it has same freezing point as
plasma and tear (- 0,52C). The equation to calculate
the amount of added substances to get isotonic solution
is stated below:
0,52 - a
W = ----------------b
W = Amount of the additional substances in gram/ 100 ml
a = Freezing point of the dissolved substance in water
b = Freezing point of the 1% additional susbtance in

R/ Procaine HCI 1,5
Sodium chloride
m.f. inj. Ad 100 ml

FP = -0,122
FP = -0,576

0,52 (0,122 x 1,5)

W = ----------------------- = 0,585 gram/100 ml

5. Sodium chloride equivalence

Sodium chloride equivalence is an amount of NaCI that give
equal osmotic effect with one gram of dissolved
There are two method to get the equivalence number/
value of sodium chloride:
1. The dividing result of freezing point of substance with
freezing point of NaCI at the same concentration
1 % Vitamin C
= - 0,105C
1 % NaCI = - 0,576C
Therefore the sodium chloride equivalence of Vitamin C is
----------- = 0,18
This method is based on the fact that molal freezing point
equal to the freezing point of dissolved substance in
molal concentration

Wells gave the following equation:

L = ---C
L = Molal freezing point depletion
t= Freezing point depletion due to the dissolved
c = Molal concentration of dissolved substance
Because substances with the same ion tend to show the
same molal freezing point depletion. Wells grouping
these compounds based on the ion type and gave the
average L value, which can be used to calculate sodium
choride equivalence value (E).

Penggolongan harga L rata-rata menurut Wells

Jenis 1 A : L = 1,9
Non elektrolit ; bahan tidak terdisosiasi dalam larutan,
Contoh :
sukrosa, dekstrosa, kamper
Jenis 1 B : L = 2,0
Elektrolit lemah ; bahan hanya sedikit yang terdisosiasi dalam
larutan. Contoh: asam borat, asam sitrat, epedrin basa
Jenis 2 A : L = 2,0
Elektrolit di- valent ; bahan dalam larutan terdisosiasi dalam 2
ion, keduanya bermartabat 2. Contoh; Magnesium sulfat, Zink
sulfat Kupri sulfat
Jenis 2 B : L = 3,4
Elektrolit Uni-Univalent ; bahan dimana dalam larutan
dalam 3 ion, kation bermartabat 2, anion bermartabat 2. Contoh:
NaCI, KCI, AgNO, Efedrin HCI, Pilokarpin HCI

Type of 3 A : L = 4,3
Uni-divalent electrolytes; substances that in solution are dissociated
into 3 ions, 1 equivalence cation and 2 equivalence anion.
Example: sodium carbonate, sodium phosphate (NaHPO4), Atropine
Type of 3 B : L = 4,8
Di-univalent electrolytes; substances that in solution are dissociated
into 3 ions, 2 equivalence cation and 1 equivalence anion.
Example: Calcium chloride, zinc chloride, magnesium chloride
Type of 4 A : L = 5,2
Uni-trivalent electrolytes; substances that in solution are dissociated
into 3 ions, 1 equvalence cation, and 3 equivalence anion.
Example: Sodium citrate
Type of 4 B : L = 6,0
Tri-univalent electrolytes; substances that in solution are dissociated
into 3 ions, 3 equivalence cations and 1 equivalence anion.
Example: AICI, FeCI.

Type of 5 : L = 7,6
Example : Tetra borate, Sodium borate, potassium borate
To calculate the equivalence of sodium chloride, we can use
the following equation:
L (58,45)
E = --------atau E = 17 ----M (3,44)
E = equivalence of NaCl,
M= molecular weight of substance
L = the molal freezing point
58.45 = BM NaCI ; 3.44 = L NaCI
KCI, L = 3.4
and BM = 74.55
The sodium chloride equivalence is:
17 -------- = 0.78

Example to calculate tonicity:

R / Ephedrine HCI
E = 0.28
E = 0.18
E = 0.16
ad 6o ml
1. 1.2 gram x 0.28
= 0.34 gram
0.3 gram x 0,18
= 0.05 gram
0.39 gram
2. Isotonic solution of NaCl = 0.9 gram/100 ml
= 0.54 gram/60 ml
3. NaCI that is required to get isotonic solution = 0.54
0.39 = 0.15 gram
4. For dextrose:
0.15 : 0.16 = 0.94 gram

6. Graphical method
This method was introduced by Rasmussen and Jerslev
(1955), then stated in International Pharmacopoeia
supplement (1959) and also in First Edition of
Indonesian Pharmacopoeia.
Example of graph:

The Indonesian Pharmacopoiea gives procedure to use

the method:
1. Hypotonic solution contains one substance, the
addition of 100 mL of NaCl can be read directly on the
suitable ordinate at the axis
2. Hypotonic solution contains more than one substance
(n), the following equation can be used:
- required NaCI = amount of NaCl for the mixture of n
substance (gram/ 100ml) minus with (n-1) x 0.9
- Percentage of NaCI = percentage of NaCI (n-1) x
0.9 %

1. Surfactant , is used in parenteral
suspension as:
- Wetting agent for powder to be
suspended due to the uniform distribution
of drug is required to get appropiate dose.
- To prevent caking which very difficult to be
dispersed (difficult to get at the time to be

Reason of surfactant addition:

To increase the solubility of drug by micellization

To increase the stability of drug by trapping in

micelle structure

To prevent agregation causing by interfacial

interaction liquid-air or liquid-solid, example:
formula contains protein (polisorbate 80)

Example of other surfactant:

poloxamer 188 (polioksietilen-polioksipropilen

copolimer ) sorbitan trioleate, Suspending agent
( Na CMC, polivinilpirolidon, polieten glikol,
propilen glikol)

2. Inert Gas
The other method to increase the stability
of oxidation sensitive drug is replacing the
air in the solution with nitrogen or
carbondioxide gas. The water used as
solvent is boiled to reduce the dissolved

3. Anesthetic
The injection of acidic drug can give painful
feeling at the site of injection. To reduce the
pain, it can be added the anesthetic
substance, example:
Benzyl alcohol 1.5-2 % ( Luminal injection)
Novocaine ( Vitamin B complex injection)
(Penicillin injection)

b. Vasoconstrictor
example: ephineprine 1: 100000 in lidocaine
HCL injection to prolong local effect of the drug

c. Stabilizer
Example: - Calcium salts (Calsium
gluconate injection)
- CO2 gas in Na bicarbonate injection
- Theophylline in Mersalyl injection
(organic acid complex contain mercury )
- 1 % lecithine in phytonadion