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Eksipen Sediaan Farmasi

Apt. Nurfitriyana, M.Farm

Institut Sains & Teknologi Al-Kamal

Genap 2020/2021
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Pertemuan 4
Eksipien dalam Sediaan Cair
Types of Liquid Dosage Form (LDF)
• Solutions
- Aqueous solutions + Sugar Syrup
- Hydroalcoholic Elixir
- Aromatic alcoholic solutions Spirit
- Aromatic aqueous solutions Aromatic water
- Extracted liquids from crude products Tincture
• Emulsions
• Suspensions
Type of excipients
1. Solvents/Co-solvents
2. Buffering agents
3. Anti microbial preservatives
4. Anti oxidants
5. Sequestering agents
6. Wetting agents
7. Anti foaming agents
8. Thickening agents
9. Sweetening agents
10. Colouring agents
11. Flavouring agents
12. Humectant
1.Solvents/Co-Solvents
• Water is the solvent most widely used as a vehicle due to:
▫ Lack of toxicity, physiological compatibility, and good
solubilising power (high dielectric constant), but
Likely to cause instability of hydrolytically unstable drugs
Good vehicle for microbial growth

• Sorbitol, dextrose, etc. are often added as solubilisers, as

well as base sweeteners
▫ Similar pros and cons to water alone
• Water-miscible co-solvents are used to:
▫ Enhance solubility, taste, anti-microbial effectiveness or stability
▫ Reduce dose volume (e.g. oral, injections)
▫ Or, conversely, optimise insolubility (if taste of API is an issue)
▫ Examples: propylene glycol, glycerol, ethanol, low molecular
weight PEGs

• Water-immiscible co-solvents, e.g.

▫ Emulsions / microemulsions using fractionated coconut oils
 Some solvents for liquid preparations
A. Alcohol, Ethyl alcohol (ethanol)C2H5OH
1. Next to water, alcohol is the most useful solvent in pharmacy. It is used as
a primary solvent for many organic compounds.

2. It forms hydroalcoholic mixture with water that dissolves both alcohol-

soluble and water-soluble substances

3. Alcohol has been well recognized as a solvent and excipient in the

formulation of oral pharmaceutical products. Alcohol is often preferred
because of its miscibility with water and its ability to dissolve many
water-insoluble ingredients, including drug substances, flavorants, and
antimicrobial preservatives.

4. It is also used in liquid products as an antimicrobial preservative

alone or with parabens, benzoates, sorbates, and other agents.

5. Toxicity of ingested alcohol particularly for children. For OTC oral

products intended for children under 6 years of age, the recommended
alcohol content limit is 0.5%, for products intended for children 6 to 12
years old, the recommended limit is 5% and for children over 12 years and
adults, the recommended limit is 10%.
Diluted alcohol
- Is prepared by mixing equal volumes of alcohol and purified water (50%).
-Diluted alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and
preparations.

Alcohol, Rubbing (alcohol rubbing compound)

- It contains about 70% ethyl alcohol by volume.
-It is employed as a rubefacient externally and as soothing rub for bedridden patients, a
germicide for instruments
- As vehicle for topical preparation
-As skin cleanser before injection
Isopropyl rubbing alcohol
- It has the advantage over ethyl alcohol in that the commonly available product contains not
over 1% of water, while ethyl alcohol contains about 5% water, which often a disadvantages.
-Is about 70% by volume isopropyl alcohol, with or without colour additives, stabilizers and
perfume oils
- It is used externally as a rubefacient and soothing rub and for topical products
- The commercially available 91% isopropyl alcohol solution are commonly employed by
diabetic patients in preparing needles and syringes for hypodermic injections of insulin and for
disinfecting the skin.
• Glycerin, Glycerol
- It is a clear syrupy liquid with sweet taste
- It is miscible with water and alcohol
-As solvent it is comparable with alcohol, but because of
its viscosity, solutes are slowly soluble in it unless it is
rendered less viscous by heating.
-It is used as a stabilizer and as auxiliary solvent in
conjunction with water or alcohol.
- It has preservative qualities
- It is used in internal preparations
- It dissolves the fixed alkalies, a large number of salts
and vegetable acids, pepsin, tannin, some active
principals of plants, etc.
- It also dissolves gum, starch, etc.
• Propylene glycol
-A viscous liquid, miscible with water, with acetone and with chloroform in all
proportions.
-It is soluble in ether and will dissolve many essential oils but is immiscible with
fixed oils.
- It is a useful solvent with wide range of application
- It is substituted for glycerol in modern pharmaceutical preparations
- It is used for formulation of digoxin, diazepam, phenobarbital injection
- As diluent for ear drops

• Polyethyleneglycol, PEG 400

- It is miscible with water, acetone, alcohol and other glycols.
-It dissolves many water-soluble organic compounds as well as certain water
insoluble substances such as acetylsalicylic acid and theophyllin.
- Is used as a solvent in topical solution
- Used as co-solvent with alcohol and water
- Can be used for extraction processes
- In the formulation of veterinary solutions
Role of co-solvency
Weak electrolytes and non-polar molecules frequently have
poor water solubility
Their solubility usually can be increased by the addition of a
water- miscible solvent in
which the drug has good solubility.
This process is known as co-solvency, and the
solvents used in combination to
increase the solubility of the solute are known as
co- solvent
Co-solvents are employed not only to affect solubility
of the
drug, but also to improve the solubility of volatile
constituents used to impart a desirable flavor and odour to
the product.
 Types of pharmaceutical water
• Purified water,
• USP Water for
injection
• Aromatic water

Physiological compatibility
Lack of toxicity
Possesses a high dielectric
constant
ensuring the dissolution of a wide range of
ionizable materials
Lack of selectivity
• Water is used both as vehicle and as a solvent for the
desired flavoring or medicinal ingredients.
• Advantages: Tasteless, odourless, lack of
pharmacological activity, neutral and very cheap

• Tap Water
• It is not permitted to use tap water for the dispensing of
pharmaceutical dosage forms due to its possible bacterial
contamination and the presence of dissolved salts that
destroy the active ingredients or enhance their
decomposition.

• Freshly Boiled and Cooled Water

• Boiling is seldom used to destroy vegetative bacteria. But,
on storage for long time spores may yield vegetative
microorganism.
• Purified Water
• Must be used for most pharmaceutical operations and in all
the tests and assays.
• Such water is prepared by distillation, deionization
(ion exchange method) or reverse osmosis.
• "Hard" waters are those that contain the Ca and Mg
cations.
• “Alkaline" waters are those that contain bicarbonates as
the major impurity.
• Ultraviolet energy, heat or filtration (Millipore filtration) can be
used to remove or kill the microorganisms present in the
water.

• Water for injection

• Must be used for the formulation of parental solutions.
• It is obtained by sterilizing pyrogen-free distilled water.
 Aromatic Waters
• Aromatic waters (medicated waters) are clear, saturated aqueous
solution of volatile oils or other aromatic or volatile substances.
• They are used principally as flavored or perfumed vehicles.
• Volatile oils solutions represent an incompatibility problem of
salting out. This occurs after the incorporation of a very soluble
salt in their solution.
• Aromatic water will deteriorate with time therefore:
- should be made in small quantities
-protected from intense light and excessive heat by storing in air
tight, light resistant containers.
- If they become cloudy or otherwise deteriorate; they should be
discarded. Deterioration may be due to volatilization,
decomposition or mould growth.
The strengths of pharmaceutical preparations are usually expressed in terms of
percent strength, although for very dilute preparations, expressions of ratio strength
may be used.

• Percentage (%)
• % w/v (e.g., 1%w/v =1g constituent in 100 mL
• %v/v (e.g., 1%v/v = 1mL constituent in 100 mL
preparation)
• % w/w (e.g.,1%w/w=1
preparation) g constituent in 100 g
preparation)
• Ratio strength
• weight in volume (e.g., 1:1000 w/v= 1g constituent in 1000
mL preparation)
• volume in volume (e.g., 1:1000 v/v = 1ml constituent in
1000 mL preparation)
• weight in weight (e.g., 1:1000 w/w = 1 g constituent in 1000
g preparation)
 2. Buffering Agents
• Can be necessary to maintain pH of the formulation to:
▫ Ensure physiological compatibility
▫ Maintaining/optimising chemical stability
▫ Maintaining/optimising anti-microbial
effectiveness
▫ Optimise solubility (or insolubility if taste is an
issue)
 But, optimum pH for chemical stability, preservative
effectiveness and solubility (or insolubility) may not be
the same
 Compromises need to be made
• Ex: carbonates, citrates, phosphate, lactates,
gluconates, tartarates, borates (external). Its
presence in solution resists any changes in pH
upon dilution or addition of small quantities of
acid or base. The usual buffering agents used in
oral liquid preparations are acetate and
phosphate buffer. The buffer increase
 3. Anti-microbial Preservatives
a. Preservatives are used in multi-use cosmetic/pharmaceutical
products (including paediatric formulations)
▫ Prevents an increased risk of contamination and proliferation by opportunistic
microbes (from excipients or introduced externally), that would result in
potential health issues
▫ Avoid use wherever possible, especially in products aimed at younger
paediatric patients
e.g. not required for sterile, single-dose products (as recommended for
neonates)
b. Ideally targeted for microbial cells - showing no toxicity/irritancy
towards mammalian cells
▫ Challenge is that the active groups involved are usually harmful to all living
tissue
c. There are a limited number of approved preservatives available for multi-
use oral products, and options are even more limited for other routes of
administration
▫ Should not use in parenteral infusions
▫ Must avoid access to cerebrospinal fluid and retro-ocular administration
d. This restricted number can be further reduced by consideration of
factors such as levels required (dose), pH-solubility profiles, API &
excipient incompatibilities, adsorption, irritancy and toxicity.
Choice of Preservative
The preservative selected should have the following
properties :
• It should be effective against a wide range of
microorganisms.
• It should be compatible with other ingredients of the
formulation.
• It should be soluble in aqueous phase when used in
emulsions.
• It should be nontoxic.
• It should be free from odour and taste.
• It should preserve the preparations and remain stable
for the shelf life of the product.
• No singly preservative possesses all the qualities
therefore it becomes necessary to use a combination of
preservatives to prevent the growth of
microorganisms. The most commonly used
preservatives are as follows:
Examples:
1. Benzoic acid and sodium benzoate 0.1 to 0.2%.
2. Salicylic acid 0.1%.
3. Phenol 0.2 to 0.5%.
4. Chlorocresol 0.05 to 0.1%.
5. Alcohol 15 t 20%.
6. Chlorbutanol 0.5%.
7. Phenylmercuric nitrate 0.002 to 0.005%.
8. Sorbic cid and its salts 0.05 to 0.2%.
9. Benzalkonium chloride 0.004 to 0.02 %.
10.Methyl paraben and propyl paraben 0.1% to 0.2%.
 4. Anti-Oxidants
• Used to control oxidation of:
▫ API
▫ Preservative, e.g. potassium sorbate
▫ Vehicle, e.g. oils or fats susceptible to β-oxidation
(rancidification)
▫ Colourants (ageing discolouration)

• Sacrificial (more oxidisable than API, preservative, etc).

Levels will reduce with time…. need to be monitored by
specific assay
▫ Light exposure and metal ion impurities can accelerate
oxidative degradation and hence depletion of antioxidant

• Need to assess regulatory acceptability (differs in

different countries)
• Efficacy can be affected by:
▫ Compatibility with other excipients
▫ Partitioning into micelles (from surfactants)
▫ Adsorption onto surfaces (container, thickening
agent and suspended particles)
▫ Incompatibilities, e.g. with metal ions
Examples:
5. Sequestering/Chelating agents
Chelating agent excipients are used in chelation therapy
to detoxify poisonous metal agents such as mercury [Hg],
arsenic [As], and lead [Pb] by converting them to a
chemically inert form that can be excreted without further
interaction with the body.

Chelating agents inhibits auto oxidations by metal

ions Metal ions are a catalyst to auto oxidation

process
Examples:
6. Wetting Agents
• To aid ‘wetting’ and dispersion of a
hydrophobic API, preservative or antioxidant
▫ Reduce interfacial tension between solid and liquid during
manufacture or reconstitution of a suspension
▫ Not all are suitable for oral administration

• Examples include:
▫ Surface active agents, e.g.
 Oral: polysorbates (Tweens), sorbitan esters (Spans)
 Parenteral: polysorbates, poloxamers, lecithin
 External: sodium lauryl sulphate
….but these can cause excessive foaming (see anti-foaming
agents) and can lead to deflocculation and undesirable
physical instability (sedimentation) if levels too high

▫ Hydrophilic colloids that coat hydrophobic particles, e.g.

bentonite, tragacanth, alginates, cellulose derivatives. Also
used as suspending agents, these can encourage
deflocculation if levels are too low.
 7. Anti-Foaming Agents
• The formation of foams during manufacturing processes or
when reconstituting liquid dosage forms can be
undesirable and disruptive.

• Anti-foaming agents are effective at discouraging the

formation of stable foams by lowering surface tension
and cohesive binding of the liquid phase.

• A typical example is Simethicone (polydimethylsiloxane-

silicon dioxide), which is used at levels of 1-50ppm.

 Of course, a foam is also a very valid dosage form option for

certain situations, e.g. for topical administration and in
wound dressings.

In addition, wet granulation using a foam rather than

aqueous granulation fluid is gaining popularity.
8. Thickening Agents
• Suspension stabilisers: prevent settling/sedimentation
(particularly if a wetting agent present)

• They usually modify viscosity and are often thixotropic (where

viscosity is dependent on applied shear and exhibits ‘shear
thinning’)
 Easily poured when shaken
Must permit accurate dosing with chosen method (e.g.
graduated syringe, spoon)
Quickly reforms ‘gel-like’ structure
They can impact on flocculation at low levels

• Work by entrapment of solid particles, e.g. API, in a viscous or even

• ‘gel-like’ structure
• ▫ Can be either water-soluble, e.g.
methylcellulose or hydroxyethylcellulose
• ▫ Or water-insoluble, e.g. microcrystalline
cellulose
Example:
• semi-synthetic: thickening agents-methyl
cellulose, carboxy methyl cellulose,
hydroxypropyl cellulose, synthetic polymers and
gelatin. Sodium carboxy methyl cellulose
(3.5%) is used in injectable suspensions.
• Clays: hydrated aluminium silicate or
magnesium silicate
• Non-ionic: sorbitol, glycerin, sugar or
polycthylene glycols
 9.Sweetening Agents
• Natural sweeteners
▫ Sucrose; soluble in water (vehicle), colourless, stable (pH 4-8),
increases viscosity; Arguably the best taste/mouthfeel overall
but cariogenic & calorific → avoid in paediatrics?
▫ Sorbitol (non-cariogenic, non-calorific - appropriate for
paediatric formulations), but lower sweetness intensity than
sucrose (so you need more) & can cause diarrhoea

• Artificial sweeteners
▫ Regulatory review required – often restricted territories
▫ Much more intense sweeteners compared with sucrose
▫ As a consequence the levels are much lower (<0.2%) but still need to
refer to WHO Acceptable Daily Intakes (ADIs)
▫ Can impart a bitter or metallic after-taste (hence used in combination with
natural sweeteners), e.g.
Saccharin, and it’s salts
Aspartame
Acesulfame –K
Sucralose – excellent sweetness, non-cariogenic, low calorie,
wide & growing regulatory acceptability but relatively
expensive
 10. Flavouring Agents
• Supplement and complement a sweetening agent
▫ Ensures patient compliance (especially in paediatric formulations – a big
issue)
▫ Can be natural, e.g. peppermint, lemon oils,
▫ Or artificial e.g. butterscotch, ‘tutti-frutti’ flavour
▫ Instability can be an issue – combinations can be used to cover intended
product shelf-life
• Taste appreciation is not globally consistent…
▫ Genetic element: one person’s acceptable taste is another’s unacceptable
taste
▫ Territorial (cultural?) differences in preference; e.g. US vs. Japan vs. Europe
▫ Affected by age (paediatric perception and preferences are different from
adult)
▫ Can be affected by certain disease states, e.g. during cancer chemotherapy
• Regulatory acceptability of flavours needs to be checked
▫ Different sources, different compositions, different flavour, e.g. there are >30
different “strawberry flavours”!
▫ Usually complex of composition (so refer to internationally recognised
standards)
 11. Colouring agents

Colouring agents may be defined as the substances used to

impart colour to foods, drugs and cosmetics to increase their
organoleptic properties. In pharmaceutical preparations
they may be used to increase their acceptability by the
patients, to give warning, or to produce standard
preparations.

• The examples of mineral colours are ferric oxide (yellow and red), carbon black,
titanium dioxide and ultramarine.
• Only the permitted colours are used in food and pharmaceutical preparations.
Caramel or burnt sugar, an artificial colour is used to produce brown colour in
cough syrups. elixirs and other oral liquid preparation.
Certified color additives are classified according to
their approved use: (a) FD&C color additives,
which may be used in foods, drugs, and cosmetics;
(b) D&C color additives, some of which are
approved for use in drugs, some in cosmetics, and
some in medical devices; and (c) external D&C
color additives, the use of which is restricted to
external parts of the body, not including the lips
or any other body surface covered by mucous
membrane
12. Humectants
• Hygroscopic excipients used at ~5% in aqueous
suspensions and emulsions for external application.
• Their function is to retard evaporation of aqueous
vehicle of dosage form:
▫ To prevent drying of the product after application to the
skin
▫ To prevent drying of product from the container after first
opening
▫ To prevent cap-locking caused by condensation onto neck
of container-closure of a container after first opening
• Examples include:
▫ propylene glycol
▫ glycerol
▫ PEG
General philosophy regarding excipients for
liquid dosage forms
• Choose the appropriate dosage form for the target
population(s)
• Avoid health hazards – apply a benefit vs. risk balance
assessment:
▫ Minimum age of target population
▫ Maximum duration of therapy
▫ Double-check age-related safety of “established” (adult dosage form?)
excipients
▫ Novel excipients need comprehensive safety testing
• Justify inclusion and minimise number of excipients and
quantity to be
used:
▫ Especially
younger age
groups
▫ Choose dosage
forms that achieve
this
▫ Not for aesthetic
or cosmetic
purposes
▫ Avoid sugar for
long-term use
Overview thoughts for paediatric dosage forms

So…..

 A quite wide range of excipients and dosage

forms needs to be considered

Key considerations for paediatric formulations are

to
minimize the use of excipients, understand the
limitations of those types of excipient that can and
are used and be able to justify their use at the dose
levels involved.
Solvents/Preservatives
• Propylene Glycol Toxicity

▫Propylene glycol (PG) is a general solvent with anti-

microbial properties used in a wide range of
pharmaceutical preparations including oral liquids,
topicals and parenteral preparations

▫However, it’s use in large volumes in children is

very much discouraged:
 PG has been associated with cardiovascular, hepatic, respiratory and
CNS adverse events, especially in neonates where the biological
half- life is prolonged (~17h) compared with adults (5h).
 I.V. parenterals containing PG must be infused slowly
 PG also has a laxative action at high oral doses through high
osmotic pressure effects.
 Solvents
• Ethanol Toxicity
▫ Widely used as a co-solvent to aid solubility
▫ In US, maximum permitted quantities in OTC products:
 <0.5% for children under 6-years
 <5% for children 6-12-years
 <10% for children over 12-years
▫ Acute (overdose) or chronic (long-term use) toxicity is possible
▫ May cause adverse symptoms of intoxication, lethargy, stupor, coma, respiratory
depression and cardiovascular collapse
• Peanut Oil Toxicity
▫ Peanut oil is used as a food additive and as a solvent in intra-muscular injections
▫ It has been suggested that the use of peanut oil in childhood (infant formula and
topical preparations) can lead to later episodes of hypersensitivity, and therefore
should be discontinued
Sweeteners
• Saccharin
▫ Restricted regulatory acceptability
▫ Poor aftertaste
▫ Hypersensitivity reactions; mainly dermatologic
▫ Paediatrics with allergy to sulphonamides should avoid saccharin

• Aspartame Toxicity
▫ Source of phenylalanine – possibly an issue for phenylketoneurics
▫ Aspartame has been blamed for hyperactivity in children but as yet
unproven

• Sorbitol
▫ Can induce diarrhoea
Solvents/Solvent sweeteners
• Need for oral liquid preparations (that
children typically find easier to swallow) often
necessitates:
▫ Taste-masking; which often relies on sweeteners
▫ Addition of co-solvents to improve drug solubility …if a solution is wanted
(elegance/mouth feel vs. taste)

• Most commonly used solvent sweeteners are

▫ Propylene glycol
▫ Glycerine (Glycerol)
Anti-microbial Preservatives
• Benzyl Alcohol toxicity in neonates

▫ Widely used as a preservative in cosmetics, foods and pharmaceuticals

(including injectables and oral liquids)

▫ Toxic syndrome observed in neonates – it was attributed to the practice

of “flushing out” umbilical catheters with solutions containing benzyl
alcohol (BA), because of trace levels of benzaldehyde that were present

▫ Dilution of nebulisation solutions with BA-preserved saline led to

severe respiratory complications and even death in neonates.
Attributed to accumulation of BA due to an immature metabolic
capability.

 Only dilute inhaled solutions with non-preserved, sterile

diluents
Anti-microbial Preservatives
• Sodium Benzoate toxicity
▫ Widely used as a preservative in cosmetics, foods and pharmaceuticals
(including injectables and oral liquids)
▫ Injectable combinations of Na Benzoate and Caffeine should not be
used in neonates; found to elicit non-immunological contact
reactions, including urticaria and atopic dermatitis
▫ Limitation on dosing of NA benzoate to neonates - ≤10mg/kg/day –
due to immature metabolic capability
• Thimerosal toxicity
▫ Formerly widely used as a preservative in cosmetics, in soft contact lens
solutions and pharmaceuticals (primarily vaccines)
▫ Being phased out from most paediatric vaccines as better options
emerge
▫ Possible links with toxicity in paediatric vaccines, e.g. linked with
childhood autism but not proven
Diluents/Fillers
• Lactose toxicity (immature metabolism)
▫ Lactose occurs widely in dairy products and is used in infant feed formulae.

▫ In pharmaceutical preparations it is widely used as a diluent in tablets and

capsules, in lyophilised powders, as a sweetener in liquid formulations
and as a carrier in dry powder inhalation products.

▫ Lactose intolerance occurs when there is a deficiency in the intestinal

enzyme lactase, leading to GIT build-up of lactose. There is then the risk of
abdominal bloating and cramps.

▫ Lactase is normally present at high levels at birth, declining rapidly in early

childhood (4-8 years) . Hypolactasia (malabsorption of lactose) can thus
occur at an early age and, furthermore, this varies among different ethic
groups.

▫ Significant lactose intolerance can also occur in adults but this is rare.
“E number” Additives
(Colourants, preservatives, stabilisers, anti-
oxidants, etc.)
• Current high profile concerns...

▫ Some opinion that additives in processed foods are linked to children's

allergies.

▫ Particular attention has been paid to infants and children's products

because their immature organs are less efficient at removing such toxins
from their systems.

▫ Certain combinations of the following artificial food colours: sunset yellow

(E110), quinoline yellow (E104), carmoisine (E122), allura red (E129),
tartrazine (E102) and ponceau 4R (E124) have been linked to a negative
effect on children’s behaviour.
 48

TERIMAKASIH