Chapter-5

Liquid Pharmaceutical
Preparations

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 Liquid Pharmaceutical Preparations
 Liquid oral preparations are composed of many types of
formulations, both aqueous and nonaqueous, including
 Solutions,
 Suspensions, and
 Emulsions.
 Oral solutions are homogeneous mixtures of one or more
solutes dissolved in a suitable solvent or mixture of mutually
miscible solvents.
 In pharmaceutical terms, solutions are defined as “liquid
preparations that contain one or more soluble chemical
substances, usually dissolved in water.
 Solutions are classified on the basis of physical properties,
method of preparation, use, and type of ingredients

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A disperse system is defined as a heterogenous, two-
phase system in which the internal (dispersed, dis-
continuous) phase is distributed or dispersed within
the continuous (external) phase or vehicle.

Molecular dispersions are homogeneous in character

and form true solutions.

Colloidal dispersions are intermediate in size

between true solutions and coarse dispersions.

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 Cont
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Production of Solution
Definition: Solution is a liquid preparation that
contains one or more chemical substances dissolved in
a suitable solvent or mixture of mutually miscible
solvents.
 Classifications
 a) Types – any combination of the three state of matter
(S, L, & G)
 Nine type are possible but solid in liquid (S/L) and
 liquid in liquid (L/L) are major pharmaceutical interest
 b) Use

Oral
Op
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… c) Composition
 Syrup – aqueous solution containing sugar
 Elixir – sweetened hydro alcoholic solutions
 Spirits – solution of aromatic materials when the solvent is

alcoholic
Aromatic water – solutions of aromatic materials when the
solvent is
aqueous
Tinctures – solutions prepared by extracting active
constituents from crude drugs

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 APPLICATIONS
 Patient compliance
Easily adjusted as fractional doses by dilution
to meet the needs of the patients
Some deliquescent and hygroscopic
powders are
more easily dispensed as liquids
Some drugs that are not tolerated in a
concentrated form may be less irritating if
dissolved in soothing liquid.
Higher rate of absorption

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 Cont…
 LIMITATIONS
Are less stable
Special techniques are required to solubilize poorly soluble
drugs
Masking the taste of inherently very bitter
drugs is
sometimes difficult.
Extremely potent drugs with a low therapeutic index
cannot be given in an oral liquid dosage form
Cannot be administered to the unconscious patient.

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 Cont
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 Formulation consideration
The formulation of solutions presents many technical
problems to
the industrial pharmacist or chemist.
Some drugs are inherently unstable. this property is
magnified when the drug in solution
Special techniques are required to solublize poorly soluble
drugs
The final preparation must satisfy the requirements of
pharmaceutical elegance with regard to taste, appearance and
viscosity.
To solve these and many other formulation problems
encountered with pharmaceutical liquids, on interesting
dichotomy of investigative skills is required.
Successful formulation requires a blend of scientific
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 Cont…
1)Solubility
Whether or not a substance dissolves in a given
system and the extent to which is dissolves depend
largely on the nature and intensity of the forces
present in the solute, the solvent and resultant solute
solvent interaction.
When a solute dissolves, the substance’s
intermolecular force of attraction exists between the
solute and solvent molecule.
This entails breaking of the solute-solute forces and the
solvent- solvent forces to achieve the solute-solvent
attraction.
Temperature is an important factor in determining the
solubility of a drug and in preparing its solution.
Solubility studies are generally conducted at fixed
temperatures, preferably at temperature some what
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 Cont
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 Solubility determination
Solubility of a drug in a given solvent may be
determined by preparing a saturated solution of it at
a specified temperature and determining by chemical
analysis, the amount of the drug dissolved in a given
weight of solution.
The amount of solvent required to dissolve the
amount of
solute can be determined by simple calculation.
The solubility is expressed as grams of solute
dissolved in ml of solvent.

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 Cont
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 2- pH
A large number of modern drugs are either weak
acids or bases, and their solubility depends on the
PH of the solvent.
Therefore the solubility of drugs can be predicted
as a function
of PH with a considerable degree of accuracy.
In selecting the PH for adequate solubility several
other factors should be considered.
The PH that satisfies the solubility requirement
must not conflict with drug stability and
physiologic compatibility.
In addition, if PH is critical to maintaining drug
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buffered.
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 Cont…
 Improving solubility
For poorly water soluble drugs solubility is improved
by using different methods
 Use of solubilizing agents
E.g Polyoxyethyle
. ne Sorbitan
Fatty acid esters
Sucrose
monoesters
Lanolin

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 Cont
…Use of co-solvents


Co-solvency:- increasing solubility of poorly water

soluble drug by the addition of a water miscible
solvent in which the drug has good solubility.The
solvent used in combination is known as co-solvent.
E.g. Ethanol, Sorbitol, Glycerin, Propylene glycol
Complexation: use of complexing agent.
Chemical modification of the drug to water soluble
derivatives

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 Cont…
 Factors affecting solubility
 1. Particle size
An increase in surface area to the solvent will
increase rate of solution.
Reducing particle size => increase SA => increase
dissolution.
 2. Agitation
Increase the rate of solubility by increasing solvent
flow over solute surface.
 3.Temperature
By increasing the frequency which solvent
molecules collide with the surface of dissolving
mixture.
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 Cont…
Molecular structure
General rule “LIKE DISSOLVES LIKE”
PH
Many organic substances which are used medicinally are
either weak acid or weak bases; and their aqueous solubility
depend upon the PH of solvent.
 Manufacturing consideration
1. Raw Materials
Raw materials used in manufacturing liquids should
conform to specification.
These specifications should assure identity, purity, uniformity and
freedom from excessive microbial contamination.
Incoming raw materials should be improved and thoroughly
tested before they are released for manufacturing.
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 Cont…
Additional processing may be a desirable property such
as particle size or freedom from MOs.
Typical MOs affecting drug microbiological stability are
Pseudomonas, Escherichia coli, Salmonella , and
Staphylococcus.
With regard to microbial contamination of raw materials
it is
usually much easier to begin with low counts in the raw
materials.
Chemical instability reactions appear with or without
microbiological contribution through reactions such as hydrolysis,
oxidation, isomerization, and epimerization.
Interactions between ingredients and ingredients with
container closure materials are established as the principal
causes of these reactions, for instance,
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 The hydrolysis of cefotaxime sodium,
 The oxidation of vitamin C,
 The isomerization of epinephrine, and
 The epimerization of tetracycline.
Aside from active ingredients, water is usually the
most
important constituent in a liquid product.
Water used should meet USP requirements for purified
water.
Water may be obtained by distillation, ion exchange
method, reverse osmosis, UV sterilization, and Membrane
filtration.

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 Cont…
 COMPONENTS A N D ADDITIVES
Sweetening Agents
o They are used to mask bitter or unacceptable
tastes of constituents.
o Sweetening agents constitute a major portion of the
solid
content in most liquid oral dosage forms.
o The most commonly used sweeteners include
sucrose, sorbitol, mannitol, liquid
glucose, honey molasses, sacchrin, and
aspartame.
o Official Simple Syrup is an 85% w/v solution of sucrose
in water.
o It is frequently used in conjunction with sorbitol,
1 glycerin, and other polyols, which reduce its
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Cont…
Flavoring Agents
Coloring Agents
Preservatives–
Liquid oral preparations are the most likely of all nonsterile
pharmaceutical products to be contaminated by micro-
organisms.
Antioxidants--Many drugs in solution are subject to
oxidative degradation.
 Sulfites are the most common antioxidants in
aqueous solutions.
 Certain compounds (e.g., ascorbic and citric acids) have
been found to act as synergists, increasing the effectiveness of
antioxidants, particularly those that block oxidative reactions.
Frequently, chelating agents such as EDTA are used in
formulations containing trace amounts of heavy metals that
would otherwise catalyze oxidative reactions.
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 Viscosity-Controlling Agents
It is sometimes desirable to increase the viscosity of a
liquid to provide or to improve palatability or
pourability.
This can be achieved by viscosity-controlling agents such as
PVP or CMC.These compounds give aqueous solutions
that are stable over a wide pH range.
2.Equipments
Equipments used in the manufacture of oral solutions
consists
 Mixing tanks equipped with a means of agitation
 Measuring devices for large and small amount of solids and liquids
 Filtration system for the final polishing, sterilization of the solution.
 System for bulk material handling, discharging

2 All equipments must be thoroughly cleaned and sanitized
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before use
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 3. Compounding procedure
Dilute solution of rapidly dissolving materials are prepared
by charging the solute to the solvent and agitating until
the solution is homogeneous.
When more concentrated solutions are being made or
when the solute is slowly dissolving, it is advantageous
to employ heat.

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 Flow chart for processing of medicated syrup

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Manufacturing Considerations:-
Manufacture of Liquid in Pharmaceuticals “Flow Chart “

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 – MAX 125 /min
– MAX 325/min

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 •Capping and sealing is done in the same
machine.

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 Filling and Packaging
Methods used for filling a pharmaceutical liquid varies
depending on the character tics of liquid (e.g.: viscosity),
types of package into which the liquid is placed and the
required production output.
Three basic filling methods commonly used in liquid filling
are
 Gravimetric filling
 Volumetric filling
 Constant level filling

Gravimetric filling: filling containers to a given weight is generally

limited to large containers or to highly viscous product.
Volumetric filling can be accomplished by the pumping of a liquid at
a constant pressure through an orifice of constant size for
predetermined period of time.
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Constant level filling uses the container as the means for controlling
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which the container is filled.
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 The principle of vacuum filling is
illustrated in Figure below,

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 Solutions: pharmaceutical excipients

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 Formula Per ml Per batch (5000 L)
Drug 2.00mg. 10.0kg.
Sodium Benzoate USP 1.00mg. 5.0kg.
Menthol, USP 0.10mg. 0.5kg.
Alcohol, USP 0.05ml. (40.8mg.) 250.0liters (204.0 kg.)

Flavor 0.005ml. (4.5 mg.) 25.0 liters (22.5 kg.)

Dye FD &C Yellow No:6 0.10mg 0.5kg.

Glycerin 0.05ml. (62.45 mg.) 250.0 liters (312.250kg)

Sorbitol solution, USP 0.10 ml. ( 128.5mg) 500.0 liters (642.5kg.)
Standard granulated 550.00mg. 2750.0kg.
sugar

Purified water ,USP q.s to 1.0ml. 5000 liters

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