Chapter 8: Liquid Dosage Forms

Liquid dosage forms: Advantages and disadvantages of liquid dosage forms. Excipients used in
formulation of liquid dosage forms. Solubility enhancement techniques

8.1 Introduction
Liquid dosage forms are preparations in which one or more active pharmaceutical ingredient(s) (APIs)
are dissolved, suspended, or emulsified in a suitable liquid vehicle. Liquid dosage forms are for use
internally or externally; for oral, parenteral, or topical use.
8.2 Definition
As defined by IP/USP, "Liquid dosage forms are pharmaceutical preparations in which drugs are
dissolved, suspended, or emulsified in a suitable vehicle for internal or external use."
Examples: Syrups, Elixirs, Linctuses, Gargles, Mouthwashes, Solutions, Suspensions, Emulsions, Ear
drops, Eye drops, Injections, etc.
8.3 Benefits of Liquid Dosage Forms
o A liquid dosage form offers flexibility of dose and is acceptable by children and the elderly.
o Liquid dosage forms have increased absorption and faster actions.
o Liquid dosage forms can be convenient for patients who cannot take solid dosage forms.
o Liquid dosage forms allow bitter and nauseous drugs to be delivered in a palatable fashion
(flavouring and sweetening).
o Liquid dosage forms can be used topically, orally, parenterally, and mucosally.
o Liquid dosage forms can deliver large doses with relative ease.

8.4 Disadvantages of Liquid Dosage Forms

o Bulky (difficulty in transport and storage).
o Stability concerns (risk of microbial contamination, oxidation, hydrolysis).
o Inaccurate dosing compared to unit-dose solids.
o Unpleasant taste, and need for flavouring/sweetening agents.
o Expensive packaging (bottle/syringe/dropper).
o Special storage conditions (temperature/preservatives).
o Some drugs have a lower solubility in water.

Table 15: Comparison of characteristics of various liquid dosage forms

Characteristic Solutions Suspensions Emulsions

Definition Monophasic system in Biphasic system composed Biphasic system in which

which solute is dispersed of finely divided insoluble one liquid is dispersed
molecularly in a suitable solid suspended in a liquid throughout another liquid in
solvent medium form of minute droplets
Thermodynamic Thermodynamically stable Unstable, undergo caking Unstable, undergo creaming
Stability on storage on storage on storage
Homogeneity Homogenous system, No Heterogenous system, Heterogenous system, Dose
dose variation Dose variation variation

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 Appearance Clear dispersions Cloudy Greasy/Smooth

Pharmacokinetics Rapid onset of action Slowest onset of action Slower onset of action

Viscosity Low viscosity High viscosity Highest viscosity

8.5. Excipients for Liquid Dosage Formulation

Excipients are inactive ingredients in liquid formulations that are used as carriers, stability agents, or
additives of the drug product. They provide the palatability, stability, appearance, and acceptance to the
final dosage form. The selection of excipients is based on drug compatibility, safety, stability, and
patient acceptability.
A. Sweetening Agents
Sweeteners help mask bitterness or an unpleasant taste in oral liquids. Sweeteners are divided into:
o Nutritive (caloric): Provide sweetness and calories.
o Non-nutritive (non-caloric): Used for diabetic or calorie-restricted patients.

Sweeteners used are:

Sucrose: The most commonly used sweetener is stable when used between pH 4-8 and above 65% can
inhibit microbial growth by reducing water activity. Depending on how the bottle is capped, it can cause
"cap-locking" through crystallization around the threads of the bottle.
Liquid glucose: A thick, syrupy material of sweetening agents is obtained by partial hydrolysis of starch
(incomplete hydrolysis). Liquid glucose can be both sweet and viscous.
Sorbitol, mannitol, honey: Natural sweeteners which collectively provide a mild laxative effect,
especially sorbitol.
Saccharin: A non-nutritive sweetener that is approximately 500× sweeter than sucrose. It would be
useful for diabetics despite the possible after taste.
Aspartame: Approximately 200× sweeter than sucrose, no aftertaste, adequate solubility.
Sucralose: Approximately 600× sweeter than sucrose, stable upon heat treatment, stable throughout a
pH range, and therefore appropriate for baked products and commercial cinnamon roll products.
Sodium cyclamate: It is approximately 30× sweeter than sucrose but is banned for sale in certain
countries due to safety issues.
B. Viscosity-Controlling Agents
Viscosity enhancers improve:
o Palatability (mouthfeel, taste masking).
o Pourability and suspension properties.
o Stability, by limiting sedimentation.

Examples:
Natural polymers: Acacia, tragacanth.
Synthetic polymers: Polyvinylpyrrolidone (PVP), Methylcellulose, sodium carboxymethylcellulose
(Na-CMC), xanthan gum.

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C. Buffers
Buffers assist in maintaining a stable pH during storage, thus preventing drug degradation, while
maintaining solubility.
Common systems: Phosphate systems, citrate systems, acetate systems, and glutamate systems.
A buffer should be able to:
o Maintain a sufficient capacity without affecting the stability of the drug.
o Have a minimal contribution to ionic strength.
o Special care must be taken, since buffers may at times act as catalysts in the degradation of
drugs (i.e., general acid-base catalysis).

D. Antioxidants
Oxidation is a significant degradation pathway for liquid formulations--especially with regards to
vitamins, alkaloids, and oils.
Oxidation is defined as the loss of electrons or the gain of oxygen, and is often catalyzed by trace metals.
Common antioxidants:
o Sulphites: sodium metabisulphite (acidic), sodium bisulphite (neutral), sodium sulphite
(alkaline).
o Ascorbic acid & citric acid: often used moieties that act as synergists.
o Chelating agents (e.g., EDTA): chelator of trace metals which can reduce metal-catalyzed
oxidation.
o Phenolic antioxidants (e.g., BHT and BHA): hydrogen atom donors. Ideal, effectivity in oil-
based formulations.

E. Flavoring Agents
Flavors enhance patient acceptability because they mask unpleasant tastes. Flavoring agents provide
sensations of taste + smell.
Selection criteria:
 Must be compatible with the sweetener and colourant.
 Should be stable during storage.
 Must take into consideration intended use (internal vs external)

Table 16: Taste–flavour matching:

Taste Sensation Suitable Flavours
Salty Butterscotch, maple, peach, vanilla, wintergreen
Bitter Wild cherry, chocolate, mint, anise, walnut
Sweet Fruit flavours, vanilla
Sour Citrus flavours, raspberry, liquorice

F. Preservatives
Preservatives can maintain purity and prevent microbial contamination during manufacture, storage,
and use.
Desirable preservative characteristics:

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 o Effectiveness against a wide range of microbes.
o Stable microbiologically, chemically, and physically.
o Non-toxic, non-sensitizing, and organoleptically acceptable.

Mechanisms of action:
 Affect cell membrane permeability.
 Denature enzymes and proteins.
 Oxidize cell components.
 Hydrolyze important biomolecules.

Examples:

 Acidic preservatives: Phenol, chlorocresol, parabens, benzoic acid, boric acid, sorbic acid.
 Neutral preservatives: chlorobutanol, benzyl alcohol, phenylethyl alcohol.
 Mercurial agents: thiomersal, phenylmercuric salts, nitromersol.
 Quaternary ammonium compounds: benzalkonium chloride, cetylpyridinium chloride.

8.6. Solubility
Definition
The amount of solute that can be molecularly dispersed in a given amount of solvent under a set of
conditions of temperature, pressure, and pH.
Method of Determination
 Add excess solute to solvent at a controlled temperature.
 Stir at a constant rate until equilibrium is attained.
 Verify undissolved solute is present (to demonstrate saturation).
 Isolate an aliquot of the saturated solution (generally by filtration).
 Measure drug concentrations using spectrophotometry, HPLC or titration.

Table 18: Expression of Solubility (IP/USP Descriptive Terms)

Descriptive Term Parts of Solvent Required for 1 Part of Solute
Very soluble <1
Freely soluble 1 – 10
Soluble 10 – 30
Sparingly soluble 30 – 100
Slightly soluble 100 – 1000
Very slightly soluble 1000 – 10,000
Practically insoluble > 10,000

8.7. Solubility Enhancement Techniques

Therapeutic efficacy and bioavailability is affected by lack of solubility. Enhancement strategies are
viewed as either physical or chemical modification.

1. Physical Modification
a. Particle Size Reduction

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Micronization: Reduction of particle size to below 1–10 µm which increases surface area allowing for
increased dissolution/rate.
Nanonization: Changing a drug into nanocrystals (nanoscale crystals, typically 200–600 nm) to allow
for better dissolution and absorption.
b. Modification of Crystal Habit
Polymorphs: A single drug may exist as multiple crystalline forms having different solubilities. An
example is: Chloramphenicol palmitate polymorph A (the more soluble and best absorbed form) vs.
polymorph B.
Pseudopolymorphs (solvates/hydrates): Solvent molecule(s) are incorporated in the crystal lattice.
Hydrates are often less soluble than anhydrous.
c. Drug Dispersion in Carriers
Eutectic mixtures: Two solids liquefy in mix at room temp due to melting point depression (e.g.,
camphor + menthol).
Solid dispersions: Drug in hydrophilic polymer (PEG, PVP) → improves wettability and solubility.
Solid solutions: Drug is dispersed in a crystalline carrier → greatest degree of solubility enhancement.
d. Solubilization by surfactants
Surfactants reduce surface tension when in a solution and when at the critical micelle concentration
(CMC), they aggregate together and form micelles.
Microemulsions: Thermodynamically stable, transparent (oil-water-surfactant) dispersions.
Self-Emulsifying Drug Delivery Systems (SEDDS) produce fine oil-in-water emulsions in GIT to
improve solubility and/or absorption.

2. Chemical Modifications
Salt Formation
A common, straightforward technique for ionizable drugs.
Example: Atropine → atropine sulphate; Diclofenac → diclofenac sodium.
Complexation
Inclusion or non-inclusion complexes are formed with a variety of carriers, such as cyclodextrins,
caffeine, or tannins. This modification can enhance solubility.
Co-crystallization
Co-crystals are formed with a co-former (in defined stoichiometric ratio) → solubility, stability,
bioavailability.
Co-solvency
A co-solvent is added that is miscible in water, but in which the drug is soluble.
Example: Diazepam injection was formulated with propylene glycol.
Hydrotropy

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A large amount of hydrotropic agents (e.g. sodium benzoate, sodium salicylate) are able to enhance
solubility.
While the exact mechanism is still under investigation- they may complex or form micelle-like
aggregates.

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