LIQUID PREPARATIONS

Objectives:
• Discuss the advantages and
disadvantages of solutions
• Identify the sources of instability.
• Discuss the pharmaceutical considerations
of solutions
• Solutions, emulsions,
suspensions.
Prepared by dissolving the active ingredients
in an aq. solvent

Suspending the drug in an appropriate medium

or by incorporating the agent into one phase or
2 phase of an o/w system
 Advantages:
• Readily available for absorption
• Easier to swallow
• Homogenous
• Reduced gastric irritation caused by
certain solid doses from drugs
• Formulated for different routes
• Can be easily adjusted by dilution
 Disadvantages
• Less stable
• Susceptible to microbial contamination
• Unpleasant taste or odor are difficult to mask
• Bulky
• Less precise in dosage administration
• Suspension & emulsions have the added
drawback thoroughly shaken to allow accurate
dosing
 Sources of Instability of Liquid
Preparations
• pH
• Temperature
• Concentration of reactants
• Light or radiation
• Packaging components
 Considerations in the
Formulations of Liquids
1.SOLUBILITY 6.FLAVORS

2.STABILITY
7.COLORING AGENTS
3.PRESERVATIVE

4. SWEETENING AGENTS

5.VISCOSITY
8.APPEARANCE
 SOLUBILITY
• Can be increased by pH control or by the
addition of buffer – w/c will not affect the
stability of the product & organoleptic
characteristics
Co-solvents can be used

alcohol Glycerin PG

sorbitol
 STABILITY
• A solution must retain its clarity, color,
odor, taste and viscosity over its shelf life.
Consider the package and the effect of
the package

Stability of the active ingredient in the final

product
 PRESERVATIVE
Solution may become contaminated for a
number of reasons:
1.Raw materials used in the manufacture of
solutions are excellent growth media for
bacterial substances such as gums, dispersing
agents, sugars and flavors
2.Equipment, environment and personnel
contribute to product contamination.
PRESERVATIVE

3. Consumer use may result in the

introduction of microorganism.
 a preservative should be added to
the product
 Preservative should be:
1.effective against a wide spectrum of
microorganisms
2.stable for its shelf life
3.non toxic, non sensitizing
4.compatible with the ingredients in the
dosage form
5.free of taste and odor
 ACIDIC NEUTRAL MERCURIAL QUATERNARY
AMMONIUM
COMPOUNDS
PHENOL (0.2-0.5%) CHLOROBUTANOL THIOMEROSAL BENZALKONIUM
(0.5%) (0.001-0.1%) CHLORIDE (0.004-0.02%)

CHRLOROCRESOL BENZYL ALCOHOL PHENYL MERCURIC CETYLPYRIDINIUM

(.05-0.1%) (1.0%) ACETATE & NITRATE CHLORIDE (0.01-0.02%
(0.002-0,005)

O-PHENYL- A-PHENYL ETHYL NITROMERSOL

PHENOL (0.005- ALCOHOL (0.2- (0.001-0.1%
0.01% 1.0%)
ALKYL ESTERS OF
PARAHYDROXYBE
NZOIC ACID
(0.001-0.2%)
BENZOIC ACID and
SALTS (0.1-0.3%)

BORIC ACID (0.5-

1.0%)
SORBIC ACID
(0.05-0.2%)
Preservatives may be used alone or in combination to
prevent the growth of microorganisms.

Alcohols
Ethanol is useful as a preservative when it is used as a solvent.
It needs a relatively high concentration (> 10%) to be effective.
Propylene glycol also used as a solvent in oral solutions and
topical preparations. It can function as a preservative in the
range of 15 to 30%. It is not volatile like ethanol.

Acids
Benzoic acid and sorbic acid have low solubility in water.
They are used in a concentration range from 0.1 % to 0.5%.
Only the non-ionized form is effective and therefore its use is
restricted to preparations with a pH below 4.5 .
Esters
Parabens are esters (methyl, ethyl, propyl and butyl) of p-
hydroxybenzoic acid.
They are used widely in pharmaceutical products and are
effective and stable over a pH range of 4 to 8.
They are employed at concentrations up to about 0.2%.
Frequently 2 esters are used in combination in the same
preparation WHY?
- To achieve a higher total concentration
- To be active against a wider range of microorganisms.

Quaternary Ammonium Compounds

Benzalkonium chloride is used at a relatively low
concentration 0.002 to 0.02%.
This class of compounds has an optimal activity over the pH
range of 4 to 10 and is quite stable at most temperatures.
Because of the cationic nature of this type of preservative it is
incompatible with many anionic compounds.
 SWEETENING AGENTS
• Sucrose is the most widely used
sweetening agent.
Advantages: Colourless, highly water
soluble, stable over a wide pH range (4-8),
increase the viscosity, masks both salty
and bitter taste, has soothing effect on
throat.
• Polyhydric alcohols (sorbitol, mannitol
and glycerol) possess sweetening power
and can be used for diabetic preparations.
• Saccharin. Used to supplement sugars
and polyols as sweeteners
• Approx 250 to 500 x as sweet as sugar
• Have a bitter aftertaste if not properly used in
the formula.
• Aspartame. A synthetic sweetener that is
200 times sweeter than sucrose and no
aftertaste
 VISCOSITY-ENHANCING
AGENTS
• Used to improve palatability and ease of
pourability
• Can be achieved by increasing the sugar
concentration or incorporating viscosity
controlling agents
• Polyvinylpyrrolidone (PVC)
• Cellulosic derivatives (methyl cellulose, CMC)
 FLAVORS
Mask unpleasant taste or odour
 Enable the easy identification of the
product.
 Natural products: fruit juices, aromatic oil
(peppermint, lemon)
 Artificial perfumes are cheaper, more
readily available and more stable than
natural products.
 FLAVORS
• Fruit flavors
• Disguise acid or sour taste
• Butterscotch, liquorice, cinnamon
• Effective w/ salty taste
• Salty taste, chocolate, anise and fruit
flavor
• Mask bitter taste
• Chloroform, menthol
• Mild local anesthetic, and soothing effect
• Flavor enhacing agents like citric acid,
Flavors may be
chemically
unstable because
of oxidation,
reduction, or
hydrolysis and
stability may be
affected
 COLORING AGENTS
• To mask unpleasant appearance or
increase the acceptability of the
preparation to the patient
• Acceptability may be enhanced by
inclusion of a color that is closely
associated with the flavor.
 Requirements for dyes:
• Non toxic
• Non irritant
• Compatible with the active and other
ingredients of the preparation
• Solubility
• Stability and compatibility
 3 categories:
1. Mineral pigments
 Iron oxide – used in solid pharmaceutical
dosage form and preparation for external use
 Low solubility in liquids
2. Natural colorants
 Anthocyanins, carotenoids, chlorophylls,
xantophylls, riboflavin, saffron and caramel
 Used for oily or fatty products
3. Synthetic organic dyes
3. Synthetic Organic dyes
Commonly known as “coal tar” dyes
Preferred to natural colorants because they
provide a wider range of bright and stable
colors
 APPEARANCE
• Overall – depends on the color and clarity
• Purification step is required to achieve
maximum clarity
• “polishing” – removal of particulate matter
may be accomplished by:
1. Settling and subsequent decantation
2. Centrifugation
3. Filtration – practical method when large
volume are involved
RAW MATERIALS

COMPOUNDING PROCEDURE
MANUFACTURING
CONSIDERATIONS

PACKAGING
EQUIPMENT
 Raw Materials
• Should conform to specification which
should assure identity, purity, uniformity
and freedom from excessive microbial
contamination.
• Incoming raw materials – should be
impounded and thoroughly tested before
they are release
• Water is most important constituent as a
vehicle
WATER
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 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.
 Techniques employed for
purification of water
• Reverse osmosis
• Purification
• UV sterilization
• Membrane filtration
 EQUIPMENT
• Mixing tanks equipped with a means of
agitation, measuring devices and filtration
system, sterilization
COMPOUNDING PROCEDURE
1. Dilute solutions, prepared from rapidly
dissolving materials, are simply prepared
by charging the solute to the solvent and
agitating until the solution is homogenous
2. Solutes present in small concentrations,
particularly dyes and colored materials
should be predissolved prior to mixing
with the main batch.
3. Measuring the right volume of liquid
 PACKAGING
• The specific method used for filling a
pharmaceutical liquid varies greatly
depending on the characteristic of a liquid
(viscosity, surface tension, foam producing
qualities and compatibility with the
materials used in the construction of the
filling machine.
 Three basic filling methods

1. Gravimetric
2. Volumetric
3. Constant level
 Gravimetric method
• Limited to large containers or to highly
viscous products.
 Volumetric method
• Accomplished by the pumping of a liquid
at a constant pressure through an orifice
of constant size
 Constant level filling
• Uses the containers as the means of
controlling the fill of each unit.
Common problem encountered in
filling liquids

Excessive foam
Foaming during the filling operation
often can be decreased by filling
equipment that minimizes product
turbulence, closed system filling to limit
the introduction of air or gases

Addition of defoaming device

SOLUTIONS
• Homogenous mixture prepared by
dissolving a solid, liquid, or gas in
another liquid
Classification of Solutions According to
Vehicle

(a) Aqueous solutions

(b) Non-aqueous solutions

Aqueous Solutions

Aqueous solutions are homogeneous mixtures

that are prepared by dissolving a solid, liquid or
gas in an aqueous medium (vehicle).

Vehicle: This may be water, aromatic water or

extracts.
 Pharmaceutical Solutions

Aqueous Sweet &/or Viscid Nonaqueous

1. Douches 1. Syrups 1. Elixirs

2. Enemas 2. Honeys 2. Spirits
3. Gargles 3. Mucilages 3. Collodions
4. Mouthwashes 4. Jellies 4. Glycerins
5. Nasal washes 5. Liniments
6. Juices 6. Oleo Vitamin
7. Sprays
8. Otic solutions
9. Inhalations
Douches
Douche is an aqueous solution, which is directed against a
part or into a cavity of the body.
It functions as a cleansing or antiseptic agent.
Eye douches are used to remove foreign particles and
discharges from the eyes. It is directed gently at an oblique
angle and is allowed to run from the inner to the outer
corner of the eye.
Douches most frequently dispensed in the form of a
powder with directions for dissolving in a specified quantity
of water.
Enemas
 These preparations are rectal injections employed to:
 evacuate the bowel (evacuation enemas),
 influence the general system by absorption
(retention enemas) e.g. nutritive, sedative or
stimulating properties
 affect locally the site of disease (e.g. anthelmintic
property)
 they may contain radiopaque substances for
roentgenographic examination of the lower bowel.
 Retention enemas are used in small quantities (about
30ml) and are thus called retention microenema.
 Gargles
• Aq solutions frequently containing
antiseptics, antibiotics or anesthetics used
for treating the pharynx and nasopharynx
by forcing air from the lungs through the
gargle that is held in the throat.
 Mouthwashes
• Aq. solutions often in concentrated form
containing one or more active ingredients
and excipients.
• Used by swishing the liquid in the oral
cavity. Used for 2 purpose: therapeutic
cosmetic
These include Syrups, Honeys, Mucilages, and
Jellies. All of these preparations are viscous
liquids or semisolids. The sweetness and viscid
appearance are given by sugars, polyols, or
polysaccharides (gums).
SYRUPS
Syrups are concentrated solutions of sugar such as sucrose in
water or other aqueous liquid.

simple syrup: when water is used alone for making syrup.

medicated syrup: when the aqueous preparation contains
some added medicinal substance
flavored syrup: which contains aromatic or pleasantly
flavored substances and is intended to be
used as a vehicle or flavor for prescriptions
HONEYS
Are thick liquid preparations. At one time, before sugar
was available, honey was used as a base, instead of
syrup.

MUCILAGES
The official mucilages are thick viscid, adhesive liquids,
produced by dispersing gum (acacia or tragacanth) in
water.
Mucilages are used as suspending agents for insoluble
substances in liquids; their colloidal character and
viscosity prevent immediate sedimentation.
Synthetic agents e.g. carboxymethylcellulose (CMC) or
polyvinyl alcohol are nonglycogenetic and may be used
for diabetic patients.
Jellies
 A class of gels in which the structural coherent matrix
contain high portion of liquid, water.
 Preparations having a jelly-like consistency. They are
prepared also from gums.
 Are used as lubricants for surgical gloves and
catheters
 Lidocaine HCl Jelly USP is used as a topical
anaesthetic.
Advantages
 If the drug is not completely soluble or unstable in
aqueous medium it may be necessary to use an
alternative non-aqueous solvent.
 Oily solutions of drugs are often used for depot therapy
e.g. in muscles (Depo Provera and haloperidol
decanoate.)

 Note: depot therapy is in Long-acting forms of

subcutaneous/intramuscular injections
This section is devoted to four groups of non-
aqueous solutions:
1. alcoholic or hydroalcoholic solutions, e.g. elixirs and
spirits,

2. ethereal solutions, e.g. the collodions

3. glycerin solutions, e.g. the glycerites,

4. oleaginous soIutions e.g. the liniments, medicated oils,

oleo- vitamins, sprays, and toothache drops.
ELIXIRS
 Are clear, pleasantly flavored, sweetened
hydroalcoholic liquids intended for oral use.
 They are used as flavors and vehicles e.g.
Dexamethasone Elixir USP and Phenobarbital Elixir
USP.
 The main ingredients in elixirs are ethanol and water but
glycerin, sorbitol, propylene glycol, flavoring agents,
preservatives, and syrups are often used in the
preparation of the final product.
 EIixirs contain ethyl alcohol, however, the alcoholic
content will vary greatly, from elixir containing only a
small quantity to those that contain a considerable
portion as a necessary aid to solubility
SPIRITS
 Alcoholic or hydroalcoholic solutions of volatile
substances. The active ingredient may be gas, liquid or
solid.
 Spirits may be used internally for their medicinal value,
by inhalation but is mostly used as flavouring agents.
 Spirits should be stored in tight, light-resistant
containers and in a cool place,
 Spirits are preparation of high alcoholic strength and
when diluted with aqueous solutions or liquids of low
alcoholic content turbidity may occur.
COLLODIONS
 Are liquid preparations containing pyroxylin (a
nitrocellulose) in a mixture of ethyl ether and ethanol.
 They are applied to the skin by means of a soft brush or
other suitable applicator and, when the ether and
ethanol have evaporated, leave a film of pyroxylin on the
surface.
GLYCERINS
 Glycerins or glycerites are solutions or mixtures of
medicinal substances in not less than 50% by weight of
glycerin.
 Most of the glycerins are extremely viscous.
 Glycerin is a valuable pharmaceutical solvent forming
permanent and concentrated solutions not otherwise
obtainable.
 Glycerins are hygroscopic and should be: stored in
tightly closed containers.
LINIMENTS
 Are alcoholic or oil-based solutions or emulsion
containing therapeutic agents intended for external
application
 They are applied with rubbing to the affected area,
embrocations
 Alcoholic liniments are used generally for their
rubefaciant and counterirritant effects. Such liniments
penetrate the skin more readily than do those with an oil
base.
 Oily liniments, have milder action but are more useful
when massage is required.
Rubefacient
a substance for external application that
produces redness of the skin e.g. by causing
dilation of the capillaries and an increase in
blood circulation.
Counterirritant
a medicine applied locally to produce superficial
inflammation in order to reduce deeper
inflammation
OLEO VITAMINS
 Oleo vitamins are fish liver oils diluted with edible
vegetable oil or solutions of the indicated vitamins
(usually vitamins A and D).
 The indicated vitamins are unstable in the presence of
rancid oils and, therefore, those preparations, should
be stored in small, tight containers, preferably under
vacuum or under an atmosphere of an inert gas,
protected from light.
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