Liquid Dosage Form

Liquid Dosage Form

Liquid dosage form is one of the oldest dosage form used in the treatment of
patients and affords rapid and high absorption of medicinal products. Therefore, the
compounding of liquid dosage form retains a particularly useful for individuals who
have difficulty in swallowing solid dosage forms (for example pediatric, geriatric,
intensive care and psychiatric patients) and in case where precise, individualized
dosages are required. Liquid dosage forms prepared by dissolving the active ingredients
in an aqueous or non-aqueous solvent, including solutions, suspensions and emulsions
etc. Liquid dosage forms needs various excipients including vehicle, stabilizer and
viscosity builders, preservatives, sweeteners, color and flavor. In addition, solubilizes
are required in case of clear liquids; suspending agents are needed for suspensions and
emulsifying agents for emulsions.

Advantages of liquid dosage form

 The active agent is homogeneously dispensed throughout the product
 The active agent is in solution, and does not need to undergo dissolution:
therefore, the therapeutic response is generally faster than solid dosage form like
tablet or capsule
 The dose of the active agent is easily and conveniently adjusted by measuring a
different volume
 Solution may be swallowed by patients, who have difficulty taking tablets or
capsules, as might be the case with pediatric or geriatric patients
 Drugs such as potassium chloride that may cause ulceration to the mucosa in a
tablet formulation avoid this side effect when present in solution
 Bitter and unpleasant drugs can be given in sweetened, colored and flavored
vehicles
 Hygroscopic and deliquescent medicaments which are not suitably dispensed in
solid dosage form can easily be given in liquid dosage form.
 The products like adsorbents and antacids are more effective in liquid dosage
form.
 The liquid dosage form is expected for certain types of products like cough
medicaments

Disadvantages
 The active ingredients, when present in solution, are usually more susceptible to
chemical degradation, particularly hydrolysis, than when they are in a solid
dosage form.
 The shelf-life of a liquid dosage form is often much shorter than that of the
corresponding solid preparation.

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 Solution often provides suitable media for the growth of microorganism and may
therefore require the incorporation of a preservative
 Liquids are bulky and therefore inconvenient to transport and store
 Liquid dosage forms may require special storage facilities such as antibiotic
suspension
 The taste of a drug, which is usually unpleasant, is always more prominent when
in solution than in a solid form
 The delivery of the dose depends upon the patient measuring the proper volume.
This can be significant issue for vision-impaired patients, patients with arthritis,
or patients unable to read the numbers on an oral dosing syringe or medicine cup
 Solution is often susceptible to microorganism, and therefore preservative are
frequently incorporated into the formulation. Some patients may be allergic to
certain preservatives
 Two incompatible drugs cannot be dispensed together as it is possible in case of
solid dosage forms

Excipients: Selection, properties and functions

Excipients are defined as components of a formulation other than the active
ingredients. They can be natural or synthetic substance combined with the drug for the
purpose of long term stability, making up formulation that contain drug or to confer a
therapeutic enhancement on the drug in the final dosage form.
Excipients are non-active or inactive ingredients added into the pharmaceutical
compositions during the development of the dosage forms and don’t have any
therapeutic value but are needed to affect the functioning of the drug and dosage form.
They inert in nature they generally have no pharmacological effect.
It mainly helps in manufacturing process to avoid non-stick properties and to maintain
in vitro stability such as by facilitating flow-ability or aggregation over the shelf life.
Therefore, excipients is indispensable component of pharmaceutical dosage form and in
most of the formulations, they are present in greater proportion in comparison to the
drug. Although excipients are inert substance but this has been found wrong as some of
the excipient have shown direct influence in dissolution rate and drug absorption. Some
excipients had been found to encounter some activity regarding the facilitating of
penetration inside the tumor cell. Some studies confirmed the doubts on presence of
some side effects associated with presence of certain types of excipients, for example,
the presence of sucrose, lactose; parabens and menthol are associated with diabetes
mellitus, stomach cramps, hypersensitivity reaction, spasms of the larynx in infants,
respectively.

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(a) Selection of Excipient

It depends on upon its physico-chemical properties, characteristics of active drug and
route of drug administration.
It depends upon regulatory acceptance, consistency of the material, source, cost and
availability, stability and compatibility issues, pharmacokinetic parameters, permeation
characteristics, segmental absorption, behavior, drug delivery platform, intellectual
property issues etc.
The key a successful pharmaceutical formulation is to have knowledge of API,
excipients, their interaction and process parameters.

(b)Ideal properties of Excipients

 Excipients have efficient functionality for intended use
 They must be physiologically inert
 They must have good physical and chemical stability
 They should be less sensitive to equipment and process
 They must be non-toxic
 They must be acceptable with regards to organoleptic characteristics
 No influence on drug bioavailability
 Excipients needs to be free form pathogenic microorganisms
 They must be in conformance with the regulatory agency requirement
 They must be economical

(c) Function of Excipients

Excipients used in the liquid dosage forms may have a variety of function to perform
 They may be added to maintain the integrity of the dosage form
 The provide protection, support or stability to the formulation
 They help to make-up enough formulation size in case of potent drug for
assisting in accurate dose and handling
 They help to improve patient acceptance
 They continue for improving patient acceptance
 They contribute for improving bioavailability of drug
 They work to enhance and maintain overall safety and effectiveness of the
formulation during its storage and use

Excipients used in formulation of liquid dosage forms

They are classified based upon the function they perform; however, several excipients
behave differently at different concentration and one excipient can be used for multiple
purposes depending upon the need of the dosage form. Oral liquid formulation is
prepared by combining different ingredients to perform functions like wetting and
solubilsation, stabilization and to impart suitable color, taste and viscosity. The
formulation should be compatible, non-reactive and stable. The common excipients
generally required for any liquid formulation are:

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(1) Vehicles
(2) Solubilizers
(3) Preservatives
(4) Stabilizers
(5) Organoleptic agents

(1)Vehicles
Solvents: In liquid pharmaceutical formulations, vehicles are major components used
as a base in which drugs and other excipients are dissolved or dispersed. They function
by breaking of bond and reducing effective charge on ions thus increasing solute-solvent
forces of attraction which are eventually greater than solute-solute and solvent-solvent
forces of attraction. Eg: water, hydro-alcoholic liquid systems, polyhydric alcohols,
acetic acid, ethyl acetate and buffers. These may be thin liquids, thick syrupy liquids,
mucilage or hydrocolloid bases. The oily vehicles include vegetable oils, mineral oils,
organic oily bases or emulsified bases etc.
Co-solvent: are defined as water- miscible organic solvents that are used in liquid drug
formulations to increase the solubility of poorly water soluble substances or to enhance
the chemical stability of a drug. Co-solvent increases the solubility of a drug. An ideal
co-solvent should possess values of dielectric constant between 25 and 80. The most
widely used system that will cover this range is a water/ethanol blend. It should not
cause toxicity or irritancy when administrated for oral or parental use. Other co-solvents
are sorbitol, glycerol, propylene glycol and syrup.
Water
They contain large number of dissolved and suspended particles as impurities like
inorganic salts sodium, potassium, calcium, magnesium and iron as chlorides, sulfates
and bicarbonates, organic impurities are either soluble or insoluble state. Micro-
organism is other impurities present in water.
Drinking water contains less than 0.1 % of total solid. For the preparation in
pharmaceutical formulation IP refers water as clear, odorless, colorless and neutral with
slight deviation in pH due to dissolved solids and gases. Purified water IP is commonly
used as vehicle or as a component of vehicle for aqueous liquid formulations but not for
those intended for parenteral administration.
Ethanol, frequently referred as alcohol is the most commonly used solvent in liquid
pharmaceutical formulation next to water. It is generally used as hydro-alcoholic
mixture to dissolve water and soluble drugs and excipients. Diluted ethanol is prepared
by mixing equal volumes of ethanol IP and purified water IP is a most useful solvent in
various pharmaceutical processes and formulations to dissolve poorly soluble
substances
Glycerol is called glycerin is a clear, colorless liquid with thick, syrupy consistency, oily
to the touch, odorless, very sweet and slightly warm to taste. They are prepared by the
decomposition of vegetable or animal fats or fixed oils and containing not less than 95%
of absolute glycerin. It is soluble in all proportions, in water or alcohol; also soluble in a
mixture of 3 parts of alcohol and 1 part of ether, but insoluble in ether, chloroform,
carbon di-sulphide, benzene, benzol, and fixed or volatile oils.

(2) Solubilizers: To increase the solubility of the drug

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pH adjustment : By addition of buffer to the formulation .buffers act by binding

hydrogen formulations to control potential changes in the pH. Buffers act by binding
hydrogen ions in acids and donating hydrogen ions in bases. The selection of as suitable
buffer should be based on suitability of acid-base form for use in oral liquids, stability of
the drug and excipients in the buffer, and compatibility between the buffer and
container.
The stabilizing effect of buffers determines the potential reaction between excipients
and drug. For example, buffers containing carbonate, citrate, tartarate and phosphate
salts may precipitate with calcium ions by forming sparingly soluble salts.
The other factors that may affect the solution pH include temperature, ionic, strength,
dilution and the amount and the type of co-valents presents.
For example the pH of acetate buffers is known to increase with temperature, whereas
the pH of boric acid buffers decreases with temperature. It is important to know that the
drug in solution may itself act as a buffer. If the drug is a weak electrolyte such as
salicyclic acid or ephedrine, the addition of base or acids, respectively will create system
in which the drug can act as a buffer
Eg: phosphate buffers, acetate buffers, citric acid phosphate buffers etc.
Co-solvency:By addition of water miscible solvent in which drug has good solubility. The
solvent known as co-solvent.
Complexation: Drug-complexing agent complexation formed when complexing agent
is added to solution. It increase solubility of drug on the basis of Le Chatelier’s principle
or “ The equilibriumlaw”.
Eg disodium EDTA, dihydroxy ethyl glycine, citric acid.
Micronization: The processes involve size reduction of drug particle 1 to 10microns
either by spray drying or fluid energy mill.
Hydrotrophy : Drug dissolve in the cluster of hydrotropic agent. Also there is drug-
hydrotrophy agent complexation formation to increase drug solubility
Wetting agents and surfactants: In pharmaceutical formulations wetting agents are
routinely used, they air adsorbed at solid particles surfaces keep them away from vehicles
which ultimately promotes penetration of the vehicle into pores and capillaries of the
particles. For non-aqueous based formulations mineral oils are commonly we use wetting
agents because hydrophobic drug particles are difficult to wet even after the removal of
adsorbed air. In such cases it is necessary it is necessary to reduce the surface tension
between the particles and the liquid vehicles. Surface active agents that work as wetting
agents, comprises of branched hydrophobic chains with central hydrophilic groups or short
hydrophobic chains with hydrophilic end groups.
For example Sodium lauryl sulphate is one of the most commonly used surface-active agents
as a wetting agents. When dissolved in water, it lowers the contact angle of water and
support in spreading of water on the particles surface to remove the air layer at the surface
and replace it with the liquid phase.
(3)Preservatives
Microbial contamination is major problem encountered by aqueous based liquid dosage
forms. Use of preservatives becomes unavoidable in such cases to prevent the growth of
micro-organisms during production and over storage time. In fact, it is desirable to develop a
preservative-free formulation to avoid unwanted effects of these excipients. The majorities of

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preservatives are of both acid and non-acid types and are bacteriostatic rather than
bactericidal.
Preservatives must have following criteria:
Effective against broad spectrum ofmicroorganisms.
Physically, chemically and microbiologically stable for lifetime of the
product.
Non toxic, non sensitizing, soluble, compatible and with acceptable taste and
odour.
Types of Preservatives
Acidic : phenol, benzoic acid, sorbicacid
Neutral preservatives : chlorobutanol, benzylalcohol
Quarternary ammonium compounds : Benzalkoniumchloride
(4)Stabilizers
Oxidation, photolysis, solvolysis and dehydration are common transformations taking
place in liquid dosage forms. Amongst them for oxidation and photodecomposition of
drug are very common pathways of drug decomposition and are very difficult to control
due to low activation energies. Trace amounts of impurities, which are invariably
present in the drug or excipient intitates the oxidation reaction. Drugs exists in reduced
form show increased susceptibility when it is consistently exposed an open
environment. The pH of the solution may contribute in the oxidation of drugs because
ionized forms of these drugs at particular pH are very prone oxidation
Physical stability: A stable formulation retains its viscosity, color, calarity, taste and
odour throughout its shelf life
Color can be measured spectrophotometrically. Clarity can be determined by
measurement of its turbidity or light scattering equipment. Viscosity can be measured
by use of viscometers. Taste and odour can be determined either by pharmaceutical
investigator or by a panel of unbiased, taste sensitive individuals.
Chemical stability of the formulation is affected by pH, temperature, Ionic Strength,
Solvent effects, Light, Oxygen
Instability can be prevented by use of: Buffering agents, Antioxidants, Proper packaging
(eg: use of amber bottle for light sensitive products)
Antioxidants act as chain terminators where it reacts with free radicals in solution to
stop the free-radical propagation cycle. A combination of chelating agents with anti-
oxidants is often used to exert synergistic effect. This is because many of these agents act
at differing steps in the oxidative process. Oxidation of formulation component leads to
products with an unpleasant odor taste appearance, ppt, discoloration or even a slight
loss of activity. Some substances prone to oxidation include unsaturated oils/fats,
compounds with aldehyde or phenolic groups, colors, flavors, sweeteners, plastics and
rubbers, the latter being used in containers for products.
Eg: acetone sodium bisulfite, acetylcysteine, ascorbic acid, thiourea

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Emulsifying agents which prevent coalescence of the dispersed globules. Forms barriers
at interface, and reduce interfacial tension
Eg sodium lauryl sulphat, cetrimide, macrogols
Antifoaming agents: the formation of foams during manufacturing processes or
when re constituting the liquid dosage forms can be undesirable and disruptive. Anti-
foaming agents are effective at discouraging the formation of stable foams of stable
foams by lowering surface tension and cohesive binding of the liquid phase.
Eg: Simethicone, organic phosphates, alcohols, paraffin oils etc
Suspending and Viscosity Enhancing Agents: The selection of an appropriate
suspending agent is one of the most crucial factors in formulating a pharmaceutical
suspension. Suspending agents impart viscosity and thus regard particle settling. Other
factors considered in the selection of the appropriate suspending and viscosity enhancing
agent include desired reheological property supendability in the system, chemical
compatibility with other excipients, pH stability, hydration time, reproducibility, and the
cost.
Eg: clays, natural gums, synthetic gums
In many formulations these excipients are employed in combination for enhanced effects
Humectants: are hygroscopic substances that help to retard evaporation of aqueous
vehicles from dosage forms. These excipients are used at 5% strength in aqueous
suspension and emulsion for external application. They are also used to prevent drying
of the product after application to the skin as well as prevent drying of product from the
container upon opening. It also helps to prevent cap-locking caused by condensation
onto neck of container-closure at first opening
Eg propylene glycol, glycerol, polyethylene glycol
Flocculating agents: prevent caking. Addition of an electrolyte reduces the
magnitude of zeta potential of dispensed particles
Eg: Starch, sodium alginate
Chelating agents: are substances that form complexes with metal ion in activating
their catalytic activity in oxidation of medicaments. These agents are capable of forming
complexes with the drug involving more than one bond it’s a complex compound
contains one or more ring in its structure. Protect drug from catalysts that accelerate the
oxidative reaction.
Eg Disoium EDTA, dihydroxy ethyl glycine, citric acid and tartaric acid
(5)Organoleptic properties
Flavouring agents: are agent in liquid pharmaceutical products is added to the
solvent or vehicle component of the formulation in which it is most soluble or miscible.

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That is water soluble flavors are added to the aqueous component of a formulation and
poorly water soluble flavors are added to the alcoholic or other non-aqueous solvent
component of the formulation. In a hydro-alcoholic or other multi-solvent system, care
must be exercised to maintain the flavorants in solution. This is accomplished by
maintaining a sufficient level of the flavorants solvent.
Sweetening agents: Sucrose enhances viscosity of liquids and also gives a pleasant
texture in the mouth. The term sugar free solution include sweetening agents such as
sorbitol, mannitol, saccharin and aspartame as alternative to sugar such as sucrose,
fructose. In addition to sucrose, a number of artificial sweetening agents have been used
in food and pharmaceuticals over the years. Some of these including asparatame,
saccharin, and cyclamate have faced challenges over the safety by the FDA and
restriction to their use and sale in fact in 1969, FDA banned cyclamates from use in US.
Sucralose is most popular due to its excellent sweetness, non-cariogenic, low calorie
wide and growing regulatory acceptability but is relatively expensive
Coloring agent: A distinction should be made between agents that have inherent color
and those that are employed as colorants. Colors used in liquid dosage form must be
certified by FDA as per D&C Act 1940. Certain agents- sulphur (yellow), riboflavin
(yellow), cupric sulfate (blue), ferrous sulfate (bluish green) cyanocobalamin (red) and
red mercuric iodide (vivid red) have inherent color and not thought of as
pharmaceutical colorants in the usual sense of the term. Although most pharmaceutical
colorants in use today are synthetic, a few are obtained from natural mineral and plant
sources. For example, red ferric oxide is mixed in small proportions with zinc oxide
powder to give calamine its characteristic pink color, which is intended to match the
skin tone upon application. The age of the intended patient should also be considered in
the selection of the flavorings agent, because certain age groups seem to prefer certain
flavors. Children prefer sweet candy-like preparations with fruity flavors, but adults
seem to prefer less sweet preparation with a tart rather than a fruit flavor.
Important question
Give advantages and disadvantages of liquid dosage form
Enlist different excipient used in liquid dosage form. What is selection criteria and
function of excipients in liquid dosage form
Explain vehicles and solubilizers used in liquid dosage form
Why pH modifier and buffering agents are used in liquid dosage form
Explain different excipients in liquid dosage form

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