Acta Scientific Pharmaceutical Sciences (ISSN: 2581-5423)

Volume 6 Issue 4 April 2022

Review Article

A Comprehensive Review on Pharmaceutical Liquid Dosage Form

Himanshu1*, Sameeksha1 and Mukesh Kumar2

Received: March 18, 2022
1
Bachelor of Pharmacy, NGI College of Pharmacy, NGI Campus, Near Sardar
Published: March 29, 2022
Vallabh Bhai Patel Agriculture University, Modipuram, Meerut, Uttar Pradesh,
© All rights are reserved by Himanshu., et al.
India
2
Department of Pharmaceutics, Kharvel Subharti College of Pharmacy, Swami
Vivekanand Subharti University, Subhartipuram, Delhi-Haridwar Bypass Road,
Meerut, Uttar Pradesh, India
*Corresponding Author: Himanshu, Bachelor of Pharmacy, NGI College of
Pharmacy, NGI Campus, Near Sardar Vallabh Bhai Patel Agriculture University,
Modipuram, Meerut, Uttar Pradesh, India.

DOI: 10.31080/ASPS.2022.06.0867

Abstract
Pharmaceutical liquid dosage forms are the liquid solutions that can be ingested, applied topically, or administered intravenously.
These dosage forms are made up of a mixture of active medicines and excipients that produce a quick beginning of action after inges-
tion and provide the best therapeutic response in a given population. Pharmaceutical liquid dose forms are helpful and efficient for
pediatric, elderly, and comatose patients who have difficulty swallowing solid dosage forms such as pills, capsules, and other medica-
tions. As a result, pharmaceutical liquid dosage forms are extremely important in the treatment and management of a wide range
of disorders around the global. This article covers a wide range of topics related to pharmaceutical liquid dosage forms, including
classification, benefits and drawbacks, excipients utilised in pharmaceutical liquid dosage forms, solubility enhancement techniques,
and some of the instruments used to improve mixing.

Keywords: Solubility; Bioavailability; Excipients; Lipophilicity

Introduction dissolve). In pharmaceutical liquid preparations, parenteral routes

Pharmaceutical liquid dosage forms are those preparations are available in sterile forms, whereas oral liquids are non-sterile
that contains a combination of active drugs and excipients (emul- and can be administered via oral or parenteral routes (Injectable,
sifying, dispersing, solubilizing, stabilising, suspending, wetting, inhalation, otic, tropical, nasal and ophthalmic). With the help of a
thickening agent, preservative, sweetening agent, flavoring agent, chart, the classification of liquid dosage forms is presented below.
and colouring agent) that are dissolved or suspended in appropri-
Monophasic liquid dosage forms are the liquid solutions that
ate solvents and used as a drug or medication [1]. It is the sim-
comprise two or more components in a single phase. True solu-
plest type of pharmaceutical preparations for high absorption of
tions, which are homogeneous mixtures created by dissolving sol-
medicinal drugs and rapid onset in which two components are
ute in long-term solvents, are also known as true solutions [2].
enhanced to complete a liquid dosage form solute (a component
that dissolves) and solvents (the medium in which the solute will

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

13

Linctus
Linctus is a viscous, monophasic liquid solution with a high
syrup concentration that is used to treat cough and sore throat.
It’s made by dissolving citric acid in chloroform, adding pepper-
mint water, amaranth solution, and syrup (as a carrier) to reach
the desired volume [6]. However, the majority of linctus comprises
chemicals that have expectorant, sedative, and antibacterial prop-
erties [7].

Elixirs
An elixir is a sweet fragrant liquid mixture that is administered
orally for medical purposes. It contains a variety of active substanc-
Figure 1: Classification of liquid dosage form.
es, including ethyl alcohol, propylene glycol, water, glycerin, and
flavoring agents, all of which are necessary for elixir manufacture.
Solutions Medicated elixirs and non-medicated elixirs are the two types of
Solid materials are dissolved in an appropriate solvent, which elixirs available [8]. Non-medicated elixirs are used as vehicles or
are homogeneous mixture containing one or more chemical com- solvents for medicated elixirs, which include potent medications as
pounds. Solutions are one of the oldest dosage forms and are made antihistaminic, antibiotics, hypnotics, and sedatives, and should be
by dissolving a solid, liquid, or gas into a solvent in which the solute kept in a light-resistant, firmly closed container away from sunlight
molecules are dissolved into a solvent such as water, alcohol or car- [9].
bonated beverages [3].
Gargles
Syrup Gargles are aqueous concentrated solutions that are used to
Syrup is a sugar-in-water saturated aqueous solution with or treat throat infections by coming into touch with the mucus mem-
without medicinal, ingredients. Syrups have a high percentage brane in the buccal cavity. Gargles are delivered in a concentrated
of sucrose (66.7% w/w I.P. and 85% w/v USP). Prepare sucrose form, but when used, they are diluted with warm water. Gargles are
66.7% w/w syrup in filtered water, stirring constantly while heat- kept in an airtight jar with a plastic screw cover [10].
ing. It’s crucial not to let the temperature climb above 1600°C while
heating [4]. After cooling, it’s kept in a cool, dry area in a tightly Mouthwash
sealed container to keep moisture and foreign particles out. Vita- Mouthwashes are aqueous solutions with a pleasant taste and
mins, sedatives, saline medicines, and antibiotics all use syrups in odour that are used to keep the buccal cavity clean and deodorised.
their compositions [5]. Alcohol, glycerin, antimicrobial, colouring, and flavoring agents are
all found in mouthwashes. Food particles caught deep inside the
Simple Syrup I.P. Simple Syrup U.S.P.
throat and mucous in the mouth can be eliminated with the help
66.7% w/w solution of mouthwashes with strong flavors and alcohol, which function
85% w/v solution of sucrose in
of sucrose in
purified water. by producing cough. Mouthwashes come in a variety of flavors,
purified water.
including antibacterial and anti-plaque mouthwashes, anti-cavity
It is prepared by hot
It is prepared by cold process. mouth rinses, and more. The antiseptic mouthwashes eliminate
process.
the bacterial plaque that causes bad breath, caries, and gingivitis,
It can be checked
during the process It cannot be checked during the while the fluoride-containing mouthwashes protect against tooth
by using process. decay [11]. It’s primarily used for dental hygiene. In general, some
saccharometer. firms suggest that when mouthwash is used, you should not drink
Invert sugar. water right away. However, mouthwashes are ineffective in remov-
Sucrose heat → Sucrose ing plaque and bad breath, thus brushing and flossing are required
Invert sugar [12].
More stable Less stable

Table 1: Difference between simple syrup I.P and simple syrup

U.S.P.
Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

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Lotions maceutical outflow through tears, unpredictability of dosages,

Lotions are liquid preparations for application to the skin’s sur- and lacrimal fluid. The inherent physiology of the eye continues to
face. Lotions are applied to the skin’s surface with cotton wool for make ocular drug distribution difficult [19]. The efficient removal
purposes of protection, such as cooling and relaxing. Antiseptic, mechanism at the site of action (rapid tear turnover, blinking) and
antibacterial, antifungal, moisturising, and protective substances low corneal permeability combine to diminish the efficacy of oph-
are prescribed by dermatologists to treat or prevent skin problems thalmic formulations and restrict drug bioavailability to less than
[13]. 5%.

Liniment Biphasic liquid dosage forms

Liniment is a liquid dose form of medication that is applied to Biphasic liquid dosage forms are ones that have two phases in
the affected area with friction or rubbing action. Liniments are a them. This comprises the medicine that has been dissolved as well
blend of substances with qualities such as analgesic, relaxing or as the solvent (vehicle). There are two types of biphasic liquid dos-
stimulating. These should only be used on the outside of the body age forms.
and should not be used on broken skin. • Suspension
• Emulsion
Nasal drops
Nasal drops are liquid or greasy solutions that are sprayed into Suspension
the nostrils with a dropper. Antiseptics, local analgesics, and va- Suspensions are biphasic liquid dosage forms of medication in
soconstrictors are all present in these solutions. The droplets are which the internal phase is uniformly distributed with finely di-
usually watery rather than greasy [14]. Nasal drops are isotonic be- vided solid particles in a liquid dispersion medium over a period
cause they have a neutral pH and a viscosity that is similar to nasal of 0.5 to 5 minutes. In pharmaceutical solutions, solid particles act
secretions, thanks to the usage of methyl alcohol [15]. as a disperse phase, while liquid vehicles act as a continuous phase.
The external phase, also known as the suspending medium, [20].
Ear drop
Pharmaceutical suspension formulations are done for the follow-
Ear drops are solutions made from water, glycerin, or propylene
ing reasons.
glycol that are infused into the ear using a dropper. They are used
• To improve the drug stability of the suspensions.
to clean the ear canal, soften wax, and treat minor infections. When
viewed under a microscope under suitable conditions of visibility, • To reduce the bitterness.
ear drops are clear solutions that do not include any particles [16]. • The medication is insoluble in the delivery medium in this
Ear drops are also available as suspensions, which generate sedi- formulation.
ment that disperses widely when the container is shaken and stays • To achieve long term medication release (sustained release).
disseminated for a long time [17].
Classification of suspension: Suspensions are categorised us-
Throat paints ing the following framework:
Throat paints are the viscous liquid dosage form of medica- • Determined by administration route
ments which are used for the purpose of mouth and throat infec-
• Oral
tions. Glycerin is typically used as a base in significant amounts to
ensure that the medicine stays in contact with the mucous mem- • Parenteral
brane for a long time and has a pleasant flavour [18]. • Topical
• Based on the nature of solid particles electro kinetics
Eye drops
• Flocculated suspension
Eye drops are ocular dosage forms of medications with draw-
backs such as limited availability, frequent administration, phar-

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

15

• Deflocculated suspension are insoluble in ordinary solvents.

• The dose forms make the suspensions more resistant to hy-
Oral suspensions
drolysis and suspensions.
For oral administration, an oral suspension consists of undis-
• Controlled release formulation is possible in parenteral sus-
solved particles and active substances suspended in sweetening,
pensions.
flavoring, or viscous vehicles with therapeutic agents. Oral sus-
pensions are commonly used to treat oral fungal infections. “Oral • There’s a chance of a hepatic first-pass effect.
suspensions allow for dose flexibility and are cost-effective when Disadvantages of parenteral suspensions
a patient requires dose titration, however many pharmaceutical • Manufacturing difficulty: Crystallization, particle size reduc-
medications are not available as oral suspensions [22]. Insoluble tion, wetting, and sterilising operations are facilitated, which
components are suspended in a dispersion media with suspend- are necessary to maintain aseptic manufacturing conditions.
ing agents to create oral suspensions. Suspending agents are used
• Formulation difficulty: Suspending agents, viscosity inducing
to help disperse powders evenly throughout the preparation and
agents, wetting agents, stabilisers, and preservatives for this
avoid particle flocculation [23].
form of parenteral suspension are challenging to choose.

Advantages of oral suspensions • In this dosage type, physical stability is extremely difficult to
maintain.
• It must be pleasant as well as stable.
• At the time of administration, the dose is not uniform
• There should be no gritty particles in it.
• Particles that are dispersed should not settle easily. Factors affecting medication release from parenteral suspen-
sions [27]
Parenteral suspensions
• Injectable suspension formulations are approved by paren-
Parenteral suspensions are sterile preparations that are intend-
teral suspensions; the medicine is soluble in biological fluids
ed to be administered directly into the systemic circulation of peo-
at the injection site.
ple [24]. Parenteral suspensions are insoluble medication particles
• Because of injectability and syringeability, these suspensions
dispersed in a heterogeneous system that must be resuspended in
are frequently diluted due to their viscosity limitations.
an aqueous or vegetable oil vehicle before being administered to
patients. • Pka of the medicine and the rate at which solids from its dose
forms dissolve [28].
Ideal characteristics of parenteral suspension [25]
Tropical suspensions
• Parenteral suspensions should be small and uniform.
Tropical suspensions are liquid treatments that contain solid
• Particle re-suspension becomes very simple.
particles suspended in a liquid carrier for skin application.
• The viscosity of the suspension determines its injectability.
• Sterility of the product during usage and storage. Tropical drug delivery
• After shaking, dispersed particles do not settle quickly. A tropical drug delivery system is a localised delivery system
• During the shelf life of the cake, it does not form. that allows therapeutic chemicals to be delivered locally via the
skin to treat cutaneous problems. Skin infections are commonly
• The elegance of the product should be preserved throughout
treated using tropical suspensions. Tropical suspensions are de-
its shelf life.
signed to provide effective and efficient medication action as well
• These are non-irritating and isotonic. as an influence on the site of action.

Parenteral suspensions have a number of advantages [26] Emulsion

• The parenteral suspensions are utilised therapeutically and A biphasic liquid dosage form of a drug is an emulsion, which is

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

16

Flocculated lets scattered throughout the aqueous phase. Fats and oils for oral
Non-flocculated suspension administration are always manufactured as oil-in-water (O/W)
suspension
Unpleasant sediment emulsions shows in figure 2, whether as carriers for oil-soluble
Pleasant sediment appears.
appears. medications or as medicines in their own right. They’re non-greasy
A clear supernatant is and easy to wipe away from the skin’s surface [30]. They are ap-
Cloudy supernatant is obtained.
obtained. plied physically to provide a cooling effect and internally to mask
Particles form loose
aggregates and form a Particles exist as separate entities.
network like structure.
Attractive forces exist Repulsive forces exist between the
between the particles. particles.
Sedimentation rate is
Sedimentation rate is slow.
high.
Particles settle independently and
Particles settle as flocs.
separately.
Sediment is easy to
Sediment is difficult to redisperse.
redisperse.
The sediment is loosely
packed, thus they The sediment is closely packed, thus
Figure 2: Oil in water types of emulsion.
doesn’t forms a hard they forms a hard cake.
cake.
In the potential energy the oil’s unpleasant taste.
In the potential curves, it represents
curves, it represents the
the primary minimum.
secondary minimum. Water-in-oil emulsions (W/O)
Bioavailability is low. Bioavailability is high. W/O emulsions (water-in-oil emulsions) are medicinal emul-
The floccules stick to The floccules do not stick to the sions in which water is scattered as globules in oil continuous
the sides of the bottle. sides of the bottle. phase shows in figure 3. Water-in-oil emulsions have an occlu-
Table 2: Distinction between Flocculated and Non-flocculated sive action, which hydrates the stratum corneum and prevents
suspension. the evaporation of eccrine secretions. They’re oily but not water-
soluble, and they’re used to maintain moisture from evaporating
made up of two immiscible liquids, one of which is the dispersed
phase and the other the continuous phase. Emulsions are a ther-
modynamically unstable system that must be stabilised by adding
a third component called an emulsifier. Emulsifiers stabilise the
system by forming a thin film around the dispersed phase globules,
which range in size from 0.1 to 100 micrometers in diameter [29].

Types of emulsion
The two basic types of emulsions such as

• O/W (oil dispersed in water)

• W/O (water dispersed in oil).

Figure 3: Water in oil types of emulsion.

Oil-in-water emulsions (O/W)
Pharmaceutical emulsions are made up of a mixture of oil drop-

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

17

from the skin’s surface while cleansing it of oil-soluble dirt [31]. • They have to be physiologically inactive.
Example: Cold cream. • They must be physically and chemically stable.

Selection, qualities and functions of excipients • They should be less affected by machinery and processes.

Excipients are substances in a formulation that are not active • They have to be non-toxic.
compounds. They can be natural or synthetic substances added • They must be acceptable in terms of organoleptic qualities.
with the drug for long-term stability, formulations including the • There is no effect on medication bioavailability.
drug, or therapeutic augmentation of the drug in the final dos-
• Excipients must not include pathogenic bacteria.
age form. Excipients are non-active or inactive chemicals that are
• They must meet the requirements of the regulating agency.
added to pharmaceutical compositions during the manufacture of
dosage forms. They have no therapeutic effect but are required to • They must be cost-effective.
alter the drug’s and dosage form’s function. Because they are inert
Excipients utilised in liquid dosage form formulation
in nature, they have no pharmacological impact.
Excipients are categorised according to the function they per-
It mostly aids in the manufacturing process by preventing non- form; however, different excipients respond differently at different
stick qualities and maintaining in vitro stability, such as aiding concentrations, and one excipient might be employed for numer-
flow-ability or aggregating over time. As a result, excipients are ous purposes depending on the dosage form’s requirements. Oral
an essential component of pharmaceutical dosage forms, and they liquid formulations are made by mixing various chemicals to ac-
are included in higher proportion in most formulations than the complish activities such as wetting and solubilization, stability, and
medication. Although excipients are considered inert substances, the addition of appropriate colour, taste, and viscosity. Compatible,
several of them have been discovered to have a direct impact on non-reactive, and stable formulations are required. The following
dissolution rate and medication absorption. Some excipients were excipients are commonly used in liquid formulations:
discovered to have some efficacy in terms of promoting penetra- • Vehicles
tion into tumor cells. Specific investigations validated concerns
• Solubilizers
about the prevalence of some negative effects connected with
the presence of certain types of excipients, such as sugar and lac- • Preservatives
tose; paraben and menthol are linked to hyperglycemia, stomach • Stabilizers
cramps, hypersensitivity reactions, and laryngeal spasms in new- • Organoleptic agents.
borns, respectively.
Vehicles
Selection of excipients
Solvents
It depends on upon its physicochemical properties, charac-
In liquid pharmaceutical formulations, vehicles are important
teristics of active drug and route of drug administration. Regula-
components that serve as a base for dissolving or dispersing drugs
tory acceptance, material consistency, source, cost and availability,
and other excipients. They work by breaking bonds and reducing
stability and compatibility issues, pharmacokinetic parameters,
effective charge on ions, increasing solute-solvent attraction forces,
permeation characteristics, segmental absorption, behavior, drug
which eventually outnumber solute-solute and solvent-solvent at-
delivery platform, intellectual property issues, and so on are all fac-
traction forces. Water, hydro-alcoholic liquid systems, polyhydric
tors to consider. Knowledge of API, excipients, their interactions,
alcohols, acetic acid, ethyl acetate, and buffers are examples of such
and process parameters is essential for a successful pharmaceuti-
substances. Thin liquids, thick syrupy liquids, mucilage, and hydro-
cal formulation.
colloid bases are all possibilities [32]. Vegetable oils, mineral oils,
Ideal qualities of excipients organic oily bases or emulsified bases are examples of oily vehicles.

• Excipients perform well in their intended applications.

Co-solvents

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

18

Co-solvents are organic solvents that are water miscible and maceutical formulations; they are air adsorbed at solid particle
utilised in liquid medicine formulations to boost the solubility of surfaces and keep them away from vehicles, allowing the vehicle
weakly water soluble compounds or to improve the chemical sta- to penetrate the pores and capillaries of the particles. Mineral oils
bility of a drug. A co-solvent boosts a drug’s solubility. The dielec- are widely used as wetting agents in non-aqueous based formula-
tric constant of an ideal co-solvent should be between 25 and 80. tions because hydrophobic medication particles are difficult to wet
A water/ethanol blend is the most generally utilised solution that even after adsorbed air has been removed. In such instances, it is
will handle this range. When administered for oral or parental use, vital to minimise the surface. The particles and the liquid vehicles
it should not cause toxicity or irritancy. Sorbitol, glycerol, propyl- are in a state of tension. Branched hydrophobic chains with core
ene glycol, and syrup are some of the other co-solvents. hydrophilic groups or short hydrophobic chains with hydrophilic
end groups make up surface active compounds that operate as wet-
Solubilizers ting agents. One of the most often utilised surface-active chemicals
Solubilizers are a type of fungicide that to improve the drug’s as a wetting agent is sodium lauryl sulphate [33]. When dissolved
solubility, make the following pH adjustments: By incorporating a in water, it lowers the water’s contact angle and aids in the spread
buffer into the formula. To control potential pH variations, buffers of water across the particles’ surfaces, removing the air layer at the
act by binding hydrogen formulations. In acids, buffers bind hydro- surface and replacing it with the liquid phase.
gen ions, while in bases, they donate hydrogen ions. The acid-base
form’s suitability for use in oral liquids, the stability of the medicine Preservatives
and excipients in the buffer, and the buffer’s compatibility with the A major issue with aqueous-based liquid dosage forms is mi-
container should all be considered when choosing a suitable buf- crobial contamination. In such instances, the use of preservatives
fer. The possible reactivity between excipients and medication is becomes unavoidable to inhibit the growth of microorganisms dur-
determined by the stabilising impact of buffers. ing production and storage. In fact, developing a preservative-free
formulation is desirable to avoid the negative effects of these ex-
Carbonate, citrate, tartarate, and phosphate salts, for example,
cipients. Most of the preservatives are bacteriostatic rather than
may precipitate with calcium ions to generate sparingly soluble
bactericidal and come in both acid and non-acid forms [34]. The
salts. Temperature, ionic, strength, dilution, and the number and
following conditions must be met by preservatives: Efficacious
kind of co-valents present are all factors that can change the pH
against a wide range of bacteria.
of a solution. The pH of acetate buffers, for example, is known to
rise with temperature, but the pH of boric acid buffers is known to For the duration of the product’s life, it must be physically,
fall with temperature. It’s crucial to understand that the medicine chemically, and microbiologically stable.
in solution might act as a buffer. If the drug is a weak electrolyte
like salicylic acid or ephedrine, adding a base or acid will produce a Types of Preservatives
situation where the drug can operate as a buffer. • Acidic: Phenol, benzoic acid, sorbic acid

Example: phosphate buffers, acetate buffers, citric acid phos- • Neutral preservatives: Chlorobutanol, benzyl alcohol
phate buffers etc. • Quarternary ammonium compounds : Benzalkonium chloride.

Co-solvency is achieved by mixing a water miscible solvent with Stabilizers

a medication that has a high solubility. Co-solvent is a type of sol-
In liquid dosage forms, oxidation, photolysis and dehydration
vent. When a Complexing agent is added to a solution, it forms a
are frequent changes. Because of their low activation energies, oxi-
complexation with the drug.
dation and photodecomposition of drugs are relatively prevalent

Wetting agent mechanisms of drug disintegration and are difficult to manage. The
oxidation reaction is triggered by trace levels of contaminants that
Wetting agents and surfactants are commonly utilised in phar-

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

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are typically present in the medicine or excipient. When drugs are tion of stable foams. Simethicone, organic phosphates, alcohols,
continuously exposed to an open environment in their reduced paraffin oils, and other similar substances are examples.
form, they demonstrate greater vulnerability. Because ionised ver-
sions of these medications are extremely susceptible to oxidation Suspending agents
at specific pH. Agents for Suspension and Viscosity Enhancement: One of the
most important aspects of preparing a pharmacological suspen-
Physical stability sion is choosing the right suspending agent. Suspending agents
Throughout its shelf life, a stable formulation maintains its vis- cause particle settling by imparting viscosity. The intended rheo-
cosity, colour, clarity, taste, and odour. Colour can be determined logical property supendability in the system, chemical compatibil-
via Spectrophotometry. Measurement of turbidity or light scat- ity with other excipients, pH stability, hydration time, repeatability,
tering equipment can be used to estimate clarity. Viscometers are and cost are all considerations to consider when choosing the right
used to measure viscosity. A pharmaceutical investigator or a panel suspending and viscosity boosting agent. Example: Clays, natural
of unbiased, taste-sensitive individuals can determine taste and gums, and synthetic gums.
odour. pH, temperature, ionic strength, solvent effects, light, and
oxygen all have an impact on the formulation’s chemical stability. For improved benefits, these excipients are frequently used in
combination in numerous formulations. Humectants are hygro-
Buffering agents, antioxidants, and proper packaging can all scopic chemicals that help to prevent aqueous vehicles from evapo-
help to prevent instabilities (eg: use of amber bottle for light sensi- rating from dosage forms. These excipients are utilised in aqueous
tive products). suspensions and emulsions for external application at a concentra-
tion of 5%. They’re also used to keep the product from drying out
Antioxidants operate as chain terminators, reacting with free after it’s been applied to the skin, as well as to keep the product
radicals in solution to halt the proliferation of free radicals. To from drying out after it’s been opened. It also aids in preventing
achieve a synergistic impact, chelating agents and antioxidants are cap-locking caused by condensation on the container-neck clo-
frequently combined. Because several of these chemicals operate at sures during the initial opening. Example: Propylene glycol, glyc-
different stages of the oxidative process, this is the case. Products erol, and polyethylene glycol.
having a disagreeable odour, taste appearance, ppt, discoloration,
or even a minor loss of activity result from oxidation of formulation Prevent caking with flocculating chemicals. The zeta potential
components. Unsaturated oils/fats, chemicals containing aldehyde of dispersed particles is reduced when an electrolyte is added. Ex-
or phenolic groups, colours, flavours, sweeteners, plastics, and rub- ample, starch with sodium alginate.
bers, the latter of which is utilised in product containers, are all
susceptible to oxidation. Chelating agents are chemicals that form complexes with metal
ions in order to activate their catalytic activity in the oxidation of
Acetone sodium bisulfite, acetylcysteine, ascorbic acid, and pharmaceuticals. These agents can build complexes with the drug
thiourea are among examples. that involve more than one bond; a complex compound is one that
has one or more rings in its structure. Protect the medication from
Emulsifying chemicals that prevent dispersed globules from co- catalysts that speed up the oxidation process. Example: Disodium
alescing. It reduces interfacial tension by forming barriers at the EDTA, dihydroxy ethyl glycine, citric acid, and tartaric acid [5].
interface. Example: sodium lauryl sulphate, cetrimide, and macro- Properties of the organoleptic system.
gol [35].
Flavoring agents are introduced to the solvent or vehicle com-
Antifoaming agents ponent of the formulation where they are most soluble or miscible
Foam development during manufacturing procedures or when in liquid medicinal formulations.
re-forming liquid dosage forms can be undesirable and disruptive.
Antifoaming chemicals work by reducing the surface tension and Water soluble flavours are added to the aqueous component
cohesive binding of the liquid phase, which prevents the produc- of a formulation, while flavours that are weakly water soluble are

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

20

applied to the alcoholic or non-aqueous solvent component. Care ute and the surface of the solvent to improve wetting and salvation
must be taken to keep flavorants in solution in a hydro-alcoholic or contact. Surfactants such as Polyglycolyzed glycerides, Tweens,
other multi-solvent system. This is performed by keeping the fla- Spans, Polyoxyethylene stearates, and synthetic block copolymers
vorants solvent at a safe level. such as Poly (propylene oxide)-poly (ethylene oxide)-poly (pro-
pylene oxide)-poly (ethylene oxide)-poly (ethylene oxide)-poly
Sweetening agents (ethylene oxide)-poly (ethylene oxide)-poly (ethylene oxide)-poly
Sucrose increases the viscosity of liquids while also providing a (ethylene oxide)-poly (ethylene. The use of amphiphilic surfactants
nice mouth feel. Sweetening chemicals such as sorbitol, mannitol, improves drug solubility by lowering surface tension between the
saccharin, and aspartame, as well as sugars such as sucrose and drug and the solvent, improving wetting qualities, and micellar
fructose, are included in the term sugar free solution. A number solubilization [36].
of artificial sweetening compounds, in addition to sucrose, have
been utilized in food and medications over the years. The FDA has pH adjustments
questioned the safety of several of these ingredients, such as aspar- Increasing the water solubility of ionizable substances is as
tane, saccharin, and cyclamate, and has placed restrictions on their simple as adjusting the pH of the microenvironment to change the
use and sale. In reality, the FDA outlawed the use of cyclamates in ionisation behaviour. Ionization of a chemical is reliant on the pH
the United States in 1969. Sucralose is widely used because of its of the media and the pKa of the medication, according to the pH-
exceptional sweetness, non-cryogenic properties, low calorie con- partition theory and the Handerson- Hasselbach equation. In situ
tent, and gaining regulatory acceptance, however it is quite costly. salt production can also be caused by a change in the ionic environ-
ment. For unionised chemicals, however, this salt production is im-
De-coloration agent possible [37]. In the gastrointestinal tract, the produced salts may
It’s important to distinguish between agents that are naturally react with the relevant acid or base forms.
colored and those that are used as colorants. According to the D&C
Act 1940, colours used in liquid dosage forms must be FDA certi- Salt formation
fied. Sulphur (yellow), riboflavin (yellow), cupric sulphate (blue), For decades, salt production of poorly soluble medication can-
ferrous sulphate (bluish green), cyanocobalamin (red), and red didates (weak acids and bases) has been used to improve solubil-
mercuric iodide (vivid red) are examples of substances that have ity. It works effectively in both parenteral and other liquid formula-
inherent colour and are not considered medicinal colorants in the tions as well as solid dose forms. Between 1995 and 2006, the FDA
traditional sense. Although the majority of pharmaceutical colo- approved over 300 novel chemical entities for marketing, 120 of
rants are synthetic today, a few are derived from natural mineral which were salt forms. Furthermore, hydrochloric acid was used
and plant sources. Red ferric oxide, for example, is blended in small to produce 54 of the 101 approved salts of basic medicines, indi-
amounts with zinc oxide powder to give calamine its distinctive cating that hydrochloride was the most common salt type [38]. An
pink colour, which is meant to complement the skin tone when acidic or basic drug’s water solubility as a function of pH deter-
applied. Because particular age groups seem to favour certain fla- mines whether the chemical will form appropriate salts [39]. The
vours, the age of the intended patient should also be considered pH-solubility interrelationships also determine what counter ions
when choosing a flavoring agent. Children like sweet candy-like are required to create salts, how quickly the salts dissociate into
preparations with fruity flavours, whereas adults prefer a less their free acid or basic forms, how salts dissolve under varied GI
sweet preparation with a sour flavour rather than a fruit flavour. pH conditions, and if common ion influences salt solubility and dis-
solution rate.
Solubility enhancement techniques
Surfactants Co-solvents

The traditional strategy to solubilizing a poorly soluble chemi- A co-solvent system is a concoction of miscible solvents that is
cal is to lower the interfacial tension between the surface of the sol- commonly employed to dissolve lipophilic medicines. Polyethylene

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

21

glycol 400 (PEG 400), ethanol, propylene glycol, and glycerin are storage. As a result, a thorough investigation of particle size and
currently the water-soluble organic solvents. For example, Pfizer’s physical stability is required [44].
Procardia (nifidipine) soft gelatin capsules contain glycerin, pep-
permint oil, PEG 400, and sodium saccharin. Long-chain triglycer- Co-precipitation
ides (peanut oil, corn oil, soybean oil, sesame oil, olive oil, pepper- Weak basic medicines, such as prochlorperazine maleate, have
mint oil, hydrogenated vegetable oil, and hydrogenated soybean strong solubility in acidic pH but not in alkaline pH, and when a
oil), medium-chain triglycerides (Miglyol 812), beeswax, d— to- standard formulation containing weak base is administered orally,
copherol (vitamin E), and oleic acid are among the water insoluble precipitation of poorly soluble free base occurs within the formula-
solvents. tion in the intestinal fluid. The medicine is no longer able to release
from the formulation, resulting in a decrease in bioavailability. This
Progesterone, a water-insoluble steroid that is soluble in peanut problem can be solved by using a co-evaporate system that com-
oil, is a commercially accessible example of this method [40]. bines a carrier with a solubilizing effect in alkaline intestinal fluid
that can operate in the microenvironment, immediately surround-
Polymeric modification
ing the drug particle, and polymers to control the dissolution rate
Polymorphs are distinct crystalline forms of a medication that in order to formulate dosage forms with maximum bioavailability
may have diverse characteristics. Physical and chemical stabil- and controlled release of weak bases [45].
ity, shelf-life, melting point, vapour pressure, intrinsic solubility,
dissolving rate, shape, density, and biological activity, as well as Solvent deposition/evaporation
bioavailability, may differ amongst polymorphs [41]. Metastable In this procedure, the medication is dissolved in a transparent
crystalline polymorphs are related with higher energy, increased solution such as methylene chloride. Stirring disperses the carrier
surface area, and thus solubility and bioavailability and efficacy, in the solution, while evaporation under temperature and pressure
when compared to stable, unstable, and metastable crystalline removes the solvent. After that, the resulting mass is dried, crushed,
polymorphs [42]. It is better to convert drugs from crystal forms and sieved. The increased dissolving rate is attributed to the small-
to metastable or amorphous forms in order to increase bioavail- er particle size of the medication deposited on the carrier and the
ability. During manufacturing and storage, however, the possibility carrier’s increased wetability of the particles. Ordered mixing is
of a conversion of the high energy amorphous or metastable poly- defined as a method of preparing ordered units in a mix in such a
morph into a low energy crystal form with limited solubility cannot way that the ordered unit is the smallest feasible sample of the mix
be ruled out. To ensure reproducible bioavailability of the product and has a composition that is nearly identical to all other ordered
across its shelf-life under a variety of real-world storage settings, units in the mix. Ordered mixing produces a near-perfect mix and
it is desirable to design the most thermodynamically stable poly- can be achieved in a variety of ways, including mechanical means,
morph of the medicine. adhesion, coating, and other techniques. The carrier particle must
dissolve quickly in order to deliver a tiny particulate suspension of
Particle size reduction
drug particles, which is a need for fast dissolution from an ordered
Micronization or nanonization is one of the most promising mixture. Dissolution rates are lowered with higher drug concentra-
techniques for improving lipophilic drug bioavailability by increas- tions, especially at loadings over monolayer coverage [46].
ing surface area and saturating solubility by reducing particle size
to sub-micron levels [43]. Particle size is a vital metric that should Steam-assisted granulation
be closely monitored during any formulation’s preformulation in- Steam can be used instead of water in wet granulation since
vestigations. Although particle size reduction is a successful ap- it allows for a faster diffusion rate into the powder and a better
proach to increase solubility, if it is not controlled and optimized, it thermal balance throughout the drying process. Water produces
might cause recrystallization and re-aggregation of the drug during a heated thin layer after condensation of steam, requiring only a
small amount of extra energy to evaporate and evaporating more

Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.
A Comprehensive Review on Pharmaceutical Liquid Dosage Form

22

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Citation: Himanshu., et al. “A Comprehensive Review on Pharmaceutical Liquid Dosage Form". Acta Scientific Pharmaceutical Sciences 6.4 (2022): 12-24.