The document discusses liquid oral dosage forms such as syrups and elixirs. It covers formulation and manufacturing considerations for liquid orals including solubility enhancement techniques, preservation, viscosity control, sweetening agents, flavors, and stability testing. Specific types of oral liquids are described like solutions, suspensions, emulsions. The key steps in formulation of syrups and elixirs involve solubility of drugs, addition of preservatives, viscosity agents, sweeteners and flavors. Manufacturing involves selection of raw materials, equipment used for mixing, filling and packaging.

1. UNIT II
LIQUID ORALS
• Formulation and manufacturing consideration of
syrups and elixirs
suspensions and emulsions
• Filling and packaging
• Evaluation of liquid orals official in
pharmacopoeia

2. Definition: Liquid dosage form defined as the active
ingredients are dissolved or suspended in aqueous or non
aqueous solvent (or) incorporating the drug into one of the
two phases of an oil and water system.
Advantages
• Immediately available for absorption
• Easy administration
• Easy to color, flavor, sweeten
• Easy to change the dose
Disadvantages
• Bulky than tablets or capsule, so difficult to carry.
• Less stable & Less accuracy in dose.
• Better Incompatibility than solid dosage form.
• Accident breakage of container

4. ORAL LIQUID SOLUTIONS
Defn: It is a homogenous formulation contains one phase in
which the Drug and excipients used are dissolved in the given
solvent to form clear solutions
• Formulation of solutions have many technical problems to
the industrial pharmacist
• Some drugs are very unstable in solution form
• Special techniques are adopted for poorly soluble drugs
• Final formulation should be pharmaceutically elegant
with regard to tast, appearance and viscosity
• So, it is important to consider the factors influencing the
formulations and manufacture of Pharmaceutical oral
solutions.

5. FORMULATION AND MANUFACTURING CONSIDERATION
OF LIQUID ORAL SOLUTIONS (Syrups and Elixirs)
Formulation consideration:
1. Solubility
•pH
•Cosolvency
•Dielectric constant
•Solubilization
•Complexation
•Hydrotrophy
•Chemical modification of
the drug
2. Preservation, Viscosity
control, Sweetening Agents,
Flavors, Appearance
3. Stability
Manufacturing consideration:
1. Raw material
2. Equipment
3. Compounding procedure
4. Packaging

6. FORMULATION CONSIDERATIONS
1. Solubility:
• Substance (whether it is drug or excipient) should dissolve
in given system
• It depends on the nature and intensity of forces present in
solute and the solvent and their interation
• For that the equibilirium solubility is to be determined. The
excess amount of finely powdered drug is placed in vial
along with solvent and agitated with constant temperature
(usually 30°C or room temp).
• The amount of drug dissolved in solvent is determined
periodically by assay of filtered solution
• The study to be conducted at various temperature
condition for designing the formulation.
• Solubility can be increased by considering the following
factors,

7. • pH
• Drugs are usually a weak acids or weak bases
• Solubility of their drug is affected by pH of their
environment
• The Solution of acidic drugs is equal to the solubility of
undissociated acid in moles per liter.
DH (Solid) + Solvent → DH(Solution) + D- + H+
• The pH of a solution is a measure of the molar
concentration of hydrogen ions in the solution and as such
is a measure of the acidity or basicity of the solution
• The pH of the solution or the buffer selection should
satisfies the stability and physiological compatibility.
• For many drugs, pH adjustment doesnot provide the
effective formulation and will affect the stability of the
formulation (Sugars and Flavors)
• This is overcome by using cosolvency, solubilization,
complex phenomena or chemical modification of the drug

8. • Co Solvency:
• Weak electrolytes and non polar molecules have poor
water solubility
• It is increased by addition of water miscible solvent in
which the drug has good solubility. This process is known as
Cosolvency
• The solvents used in combination to increase the solubility
of the solute is known as Cosolvents
• Co solvent system mechanism: It reduce the interfacial
tension bet. aq solvents and the hydrophobic solute
• Another theory is that the cosolvents surrounds and adsorb
the solute and hence it reduce the interfacial tension of
hydrophobic surface and water
• Eg of cosolvents: Ethanol, Sorbitol, Glycerin, Propylene
glycol, PVP, Ethyl lactate, 1,3 butylene glycol.

9. • Dielectric Constant:
• Dielectric constant of the solvent used for dissolving the solute is
important for considering the solubility, Stability and organoleptic
characterics of the formulation
• Every solute shows maximum solubility at some specific dielectric
constant of the given solvent system
• Solubilization:
• It is defined as the spontaneous passage of poorly water soluble
solute molecules into an aqueous solution of surfactant, in which
it is thermodynamically stable.
• The property of Surfactant to form colloidal aggregates known as
micelles and the concentration of surfactant at which the micelles
are formed is known as Critical micellar concentration
• The drug gets entrapped into the miscelles and thus it reduces
interfacial tension bet hydrophobic surface and water and the
solubility gets increased
• HLB value of surfactants is higher than, they are best solubilizing
agent Eg: Tween (Polysorbates), Lanolin esters and ethers, Sucrose
monoesters

10. • Complexation:
• Organic compounds in solution are generally tend to
associate with each other
• Complexation of solute with complexing agent will increase
the solubility.
• The selection of complexing agent is important and it is
done by considering the safety, stability and therapeutic
efficacy of the drug product
• Also the interaction of complexing agent with other
excipients also considered Eg: Tween 80 will form complex
with parabens and inactive its preservative property

11. • Hydrotrophy:
• It means the increasing the solubility of drug in water by
addition of large amount of some additives.
• This phenomenon is closely related to complexing agent
• Eg: Large conc of sodium benzoate(Preservative) will
increase the solubility of caffeine
• Chemical modification of the drug
• Many poorly soluble drugs can be chemically modified to
water soluble derivatives.
• EG: Disodium phosphate salt of betamethasone is more
soluble than Betamethasone
• But it has limitation. It is considered as new drug and it is
evaluated for its pharmacological activity, toxicity and
pharmaceutical evaluation

12. 2. Preservation
• Preservatives are added to the oral liquid formulation to prevent
the microbial contamination
• Microbial growth in formulation will lead to health hazard to the
user and also affect the product stability
• Single preservative cannot achieve the broad spectrum of killing
microorganism and so it is used in formulation as combinations
• Four groups of Preservatives:
• Acidic Eg: Phenol, Cl- Cresol, Benzoic acid and its esters, Alkyl
esters of parahydroxy benzoic acid
• Neutral Eg: Chlorobutanol, Benzyl alcohol
• Mercurial Eg: Thiomersal, Phenyl mercuric nitrate and acetate
• Quartenary ammonium compounds Eg: Benzalkonium chloride,
Cetylpyridinium chloride
• Syrups containing 85% sugar, propylene glycol, glycerin may resist
bacterial growth as it exert high osmotic pressure on
microorganisms.
• Common organism seen in oral liquids are Salmonella, E.coli,
Pseudomonas, Enterobacter species, Clostridium and candida
albicans

13. 3. Sweetening agents:
• These are the major portion of the oral liquids to provide
the pleasant taste to the formulation
• Sucrose is the main and major excipient
• It is frequently used in combination with sorbitol, glycern
and other polyols which reduce crystallization of sucrose
• Crystallizaton of sucrose will create the Caplocking problem
• Other than Sucrose, liquid glucose is used as sweetening
agent but it is difficult to handle since its viscosity is very
high and gummy nature
• To impart additonal sweet to the formulation of bitter
drugs, Saccharine, Aspartame, Neotame, Sucralose are
added as artificial sweeter. These are many times more
sweeter than sucrose.

14. 4. Viscosity Control
• Viscosity of the formulation is increased to improve the
platability and pourability of the liquids
• This is achieved by increasing sugar concentration, or by
incorporating viscosity enhancers like PVP, Methylcellulose,
HPMC, HPC, Sod.CMC
5. Flavouring agent:
• These agents are added in the formulation to mask the
taste sensations effectively
• Menthol, Chloroform and various salts are flavor adjuncts
• It produces their own flavour and odour and give mild
anaesthetic effect to the taste buds. By this the bitter and
unpleasant taste and odour are not observed by taste buds

16. 6. Appearance:
• Overall appearance of the liquid products depends
primarily on their color and clarity
• The color and dye used in formulation should be approved
by FD&C
• Clarity is achieved by Clarification and Filtration of the
formulated liquid product. Eg: Centrifugation, Decantation,
Filtration etc
7. Stability
• Chemical Stability:
• It is low risk in homogeneous system than heterogeneous
system.
• Techniques for prediction the chemical stability are well
defined

17. • Physical Stability:
• It means the formulation should retains the viscosity,
color, clarity, taste and odor throughout its shelf life
• Color are measured by spectrophotometrically
• Clarity is determined by allowing focussed beam of light
through the solution - Undissolved particles scatter the
light
• Taste and odor tested by unbiased taste sensitive
individual
• Flavors and color of the formulation are often changes
with time due to adsorption to containers or closures,
evaporation, concentration of product or chemical
breakdown of the drug

18. • MANUFACTURING CONSIDERATIONS
Raw materals:
• The raw materials used in the formulations should comply
all the specification like identity, purity, uniformity and free
from microorganism
• Water is the main vehicle and it should be a purified water
and meet the USP spec. It is obtained by distillation or ion
exchange treatment or UV sterilization of water or by
filtration
Equipment
• Mixing tanks with agitator
• Measuring device
• Filtration system
• Sterilization aid
• Discharging bins

19. • All equipments are cleaned and sanitized before use
• Tanks are made of Polished Stainless steel made of steam
jacketed or cooling jacket with see through charging ports
and illumination
• After formulation, the liquids are clarified through filtration
and transported to filling area through piping
Compounding procedure:
• The rate at which the oral solution is achieved is influenced
by compounding procedure
• Oral solutions are prepared by charging rapidly dissolving
materials to the solvent and agitated until the solution is
homogeneous.
• When more concentrated solute is added to the solvent,
heat is used to aid dissolving

20. Packaging
• Filling of oral solution is influenced by viscosity, surface tension,
foam production and compatability of materials with packaging
material
• Filling methods - Gravimetric, Volumetric and Constant level
• Gravimetric Filling: Containers are filled with liquid to a given
weight. Limited to Large container or high viscous products.
Cannot be used in high speed and automatic equipments
• Volumetric Filling: It is done by positive displacement piston
action. Each filling station is equipped with measuring piston and
cylinder
• Constant level: It uses the container as the means for controlling
the fill of each unit. Any dimensional variations in the containers
result in variation in the fill
Tecchniques of Filling:
• Vacuum filling
• Gravity Vacuum filling
• Pressure Vacuum filling.

21. SYRUPS
Defn: “Syrups are concentrated aqueous preparations of a sugar or
sugar substitute with or without flavoring agents and medicinal
substances.”
Types of Syrups
Simple syrup
Medicated syrups
Non-medicated syrups
Simple Syrups
A simple syrup contains only sucrose and purified water
Concentration of Syrup:
According to B.P:
67.7% W/W
According to USP:
85% W/V

22. Non Medicated Syrups
• “Syrups containing flavoring agents but not medicinal
substances are called non-medicated or flavored syrups”
• Use:
• These syrups are to serve as pleasant tasting vehicle for
medicinal substances to be added in the preparation of a
standard formula for a medicated syrup.
• Example:
Cocoa syrup
Suspension of cocoa powder in aqueous vehicle sweetened
and thickened with sucrose
Orange syrup
Sucrose-based syrup uses sweet orange peel tincture
Raspberry syrup
Sucrose-based syrup with raspberry juice about 48% by
volume.

23. Medicated Syrups
• Syrups containing therapeutic agent are called medicated
Syrups.
• Eg: Paracetamol syrup - Analgesic and Antipyretic
Sodium Valproate syrup - Anticonvulsant
Components of Syrups:
• Sugar
• Antimicrobial preservatics
• Flavorants
• Colorants
• Special solvents, Thickeners, Solubilizers, Stabilizers etc

24. • Sugar and its derivatives:
• Sugar Eg: Sucrose & Dextrose
• Non Sugar Eg: Sorbitol, Glycerin, Propylene glycol
Functions of sucrose or its derivatives:
i. Viscosity
ii. Sweetness
iii. Flavoring agent
iv. Masking bitter taste.
Most syrups contain a high proportion of sucrose, usually
60% to 80% for desirable sweetness, viscosity and stability.
Sugar is replaced with its derivatives at certain circumstances
like Diabetic

25. • Antimicrobial Preservatives:
• To protect a syrup against microbial growth
• Its concentration varies with proportion of water
• Eg:
• Benzoic acid, Sod. benzoate, Methyl paraben, Propyl
paraben, Alcohol
• Flavoring agents:
• To aid the syrup pleasant taste
• Eg: Natural occuring flavor - Orange oil, Synthetic flavor -
Vanillin
• Colorants:
• To enhance the appearance of syrup Eg: FDC accepted
colors are used
• It should be water soluble and stable in all pH range.

26. • Preparation of Syrups
• With aid of heat
• Agitation without heat
• Addition of Sugar to medicted liquid
• Percolation
• With the aid of heat
• It is made when the components are not damaged or
volatilized by heat
• Sugar is dissolved in water with the aid of heat. With the
hot syrup, the heat stable materials are dissolved in it.
• After dissolving, cool it to obtain for room temperature
• Agitation without the aid of heat:
• Sucrose or other ingredients are dissolved in water with the
help of high speed agitator and without heat
• It is more time consuming but provides maximum stability

27. • Addition of sucrose to medicated liquid
• Used often for tinctures when contain alcohol soluble
substance
• Prepared with alcohol or hydroalcoholic vehicles
• Water Or Alcohol insoluble substance get separated and
filtered
• The filtrates are medicated liquid which is added to Sugar
syrup
• Solution by Extraction:
• Vegetable or animal origin are often extracted with suitable
solvent.
• Eg: Ipecac Syrup - By percolation method
• Powdered Ipecac → Add Glycerin Syrup → Extracted →
Alkaloids, Emetine, Cephaeline and Psycotrine are
extracted from Ipecac Use: As Emetic

28. • Packaging of Syrup:
• Syrup, as a pharmaceutical product requires safe, secure
and tamper-proof handling while packaging.
• Packaging of syrups needs to ensure complete protection
from contamination and microbial growth.
• It should ensure that it provides extended shelf life.
• The general process:
• Filling
• Capping
• Sealing
• Coding & labeling
• Wrapping

29. • Process involved in the syrup packaging
• Empty Bottles are rinsed though Air-jet cleaning
• After complete cleaning, bottles are tested & transferred
ahead for filling
• Filling machines with their automatic piston fills the bottles
with accurate volume of syrup
• Capping is done on bottle through capping machines
• Plastic or aluminum are bound over the neck of the bottle
for secure sealing
• Important details regarding packaging date & expiry date
are printed on bottles

30. • Labelling
• Every pharmaceutical preparation requires a label to be
produced before the product can be dispensed or sold to
patient.
• The accuracy of the label is of very importance as it conveys
essential information to the patient on the use of
preparation
• Storage
• Store in room temperature and in dark place
• Advantage of syrup:
• Beneficial for childrens and old age patients
• Unpleasant taste masking
• Palatable
• Easiest route of administration

31. • Disadvantages of Syrup
• Delayed onset of action because absorption takes time.
• Not suitable in emergency and for unconscious patients.
• Not convenient for a patient with a certain disorders such
as diarrhea, ulceration, and nausea.
• Can’t avoid first pass metabolism

32. • ELIXIRS
• Defn: “Elixirs are clear, sweetened, flavored, hydro-
alcoholic solutions intended for oral use and are usually
flavored to enhance their palatability.”
• Need of Elixir:
• Some drug are insoluble in water so in this case we can’t
use syrups & suspension.
• So we have to make a dosage form which could dissolve
non polar compounds
• Aid in masking the unpleasant taste of the active
ingredients
• Components of Elixirs:
• Water and Alcohol
• Sweetening agents
• Propylene glycol
• Preservatives
• flavorants

33. • Water and Alcohol:
• Each elixir requires a specific blend of alcohol and water to
maintain all of the components in solution.
• Naturally, proportion of requirement of alcohol is greater
for those elixirs having components with poor water
solubility than those elixirs having components with good
water solubility.
• Sweetening Agents
• sucrose or with sucrose syrup,
• Sorbitol, glycerine
• Artificial sweetner
• Elixirs having a high alcoholic content usually contain
artificial sweetner such as saccharine,which is required in
very small amount rather than sucrose
• Propylene glycol
• A colorless viscous liquid used as a solvent in the
preparation of certain medications. It also inhibits the
growth of fungi and microorganisms

34. • Preservatives:
• Methyl Paraben and Propyl Paraben
• Sodium and Potassium benzoates
• Elixirs containing more than 10 to 12 % of alcohol are
usually act as self preserving and donot require additional
antimicrobial agent
• Flavoring agent
• It aids palatable taste to the formulation
• Mask the bitter taste
• Eg: Natural flavor and Synthetic flavors

35. • Preparation of Elixirs
• Elixirs are usually prepared by simple solution with
agitation.
• Alcohol-soluble and water-soluble components are
generally dissolved separately in alcohol and in purified
water, respectively.
• Then the aqueous solution is added to the alcoholic
solution to maintain the highest possible alcoholic strength
at all times so that minimal separation of the alcohol-
soluble components occurs.
• When the two solutions are completely mixed, the mixture
is made to volume with the specified solvent or vehicle.
• Finally filtration is done to obtain clear liquid
• Types of Elixir:
• Non medicated
• Medicated

36. • Non medicated Elixir:
• These are simple elixirs that donot contain medicated
agents
• It is used for addition of a drug into it or dilution to an
existing medicated elixir.
• It only contains Water, alcohol, sweetening agent and
coloring agent
• Eg: Aromatic Elixir, Compound benzaldehyde elixir,
Isoalcoholic elixir
• Medicated Elixir
• Medicated elixirs are a solution of the active ingredient
dissolved in water and an alcohol often along with other
excipients such as preservatives
• Mostly single therapeutic agent is present
• Eg: Antihistaminic Elixir - Diphenhydramine HCl, Analgesic
Elixir - Acetaminophen, Cardiotonic Elixir - Digoxin

37. • Storage:
• Keep below 30°C (at room temperature).
• Container should be tightly closed.
• Keep in light resistant ambered color container;
• Protect from direct sunlight and keep away from ignition
• Advantages of Elixir:
• Self preservative
• Stable
• Easily prepared and administered
• Disadvantage of Elixir
• Less effective than syrup in masking the taste
• Contains alcohol can be harmful to children and adults
• Since it is volatile, air tight screw top container is required

38. • SUSPENSIONS
• Defn:
• These are two phase system contains continuous phase and
dispersed phase. The continuous phase is generally a liquid
and the dispersed phase is made up of particles but
dispersed throughout the continuous phase intended for
physiological absorption.
• Almost all suspension systems separate on standing
• Main consideration in formulation is
• to prevent the separation or
• to decrease the rate of settling and
• to permit easy resuspendability

39. Formulation and Manufacturing considerations:
• Theoretical Considerations:
• Wetting:
• It is defined as that the ability of liquid to contact the
surface of the solid according to its affinity towards it
• There exist a angle of contact between the liquid and the
solid. This contact angle θ results from an equililbrium
formed between three interfacial tensions (Liqud-Vapor,
Liquid-Solid, Solid- Vapor)
• Hydrophobic substances repel water and difficult to
disperse and float on the surface of the liquid due to
interfacial tension
• Wetting agent (Usually surfactant) which reduce the solid-
liquid interfacial tension. It will hold both hydrophobic
substance and water
• Other materials such as Hydrophilic Polymers (Na.CMC),
Water insoluble hydrophilic materials (Bentonite,
Aluminium Magnesium Silicate) aided in dispersion also for
viscosity building

40. • Wettabiity is measured by wet point and flow point
method
• Wet point is the amount of vehicle needed to wet all the
powder
• Flow point is the amount of vehicle needed to produce
pourability
• Low wet point and low flow point indicates the good
dispersion
• Particle interactions and Behaviour
• Presence of large amount of electrolytes will result in
salting out effects due to aggregation of particles
• Increasing the conc. of ions will decrease the thickness of
diffuse double layer and hence aggregation is done
• Aggregation is further termed as Flocculation, Coagulation

41. • Flocculation - It is a fibrous, fluffy open network of
aggregated particles. The structure is quite rigid and hence
these aggregates settles quickly to form high sediment
height but easily redispersible because the particles
contains individual aggregates are apart from one another
to prevent from caking

42. • Coagulation - It is a tight packing produced by surface film
bonding. These aggregates settle down slowly to low
sediment heights. But formed sediment heights is
composed of closed aggregates are not easily redispersed.

43. • The tendency of particles to aggregate depends on the
forces of attraction and repulsion between them
• The attractive forces is due to Vander waals forces.
(Combination of ionic, dipole and induced dipole
interaction)
• Caking is defined as the formation of non redispersible
sediment within a suspension system. It is due to crystal
bridging and coagule formation
• Crystal bridging - particle surface crystal growth occurs on
two or more particles which results in steady formation of
crystal linked particles.
• Ostwald ripening - Small changes in temperature causes
crystal bridging lead to rapid caking during storage of
suspension.

44. • Sedimentation Rates
• According to Stokes equation, the velocity of particle in
suspension is
• Factors influencing the sedimentation rates are particles
charges, aggregation, Zeta potential and aqueous system
used
• Crystal habit:
• It is defined as the outward appearance of an
agglomeration of crystals.
• It is used to study the suspension redispersibility,
sedimentation rate, physical stability and appearance and
also affect the dissolution properties
• Individual particles crystal characteristics are differ from
agglomerate crystal particles

45. • Crystal structure factors:
• Effect of Crystal properties are more produced when the
suspension is made from precipitation techniques than
dispersion technique
• The rate of cooling, degree of agitation and size & number
of nuclei will affect the degree of supersaturation lead to
change in crystal habit.
• Change in crystal characteristics leads to drug
decomposition, salting out, change in pH, change in particle
size distribution and also change in temperature
• Polymorphism is the term used to specify the different
crystal structure formed by same chemical compound
which exhibit different solubilities, melting points and x ray
diffraction patterns

46. Formation of Suspension:
• Precipitation methods:
• Organic solvent precipitation
• Water insoluble drugs can be precipitated by dissolving
them in water miscible organic solvents and then the
organic phase is added to the water Eg: Ethanol, Methanol,
Propylene glycol and Polyethylene glycol
• Different polymeric forms are obtained when the organic
phase is changed Eg: Prednisolone in methanol gives
sesquihydrate form, where in acetone it gives anhydrous
crystal form. Former is easily suspended in water
• Precipitation effected by changing the pH of medium
• It is applicable to drugs in which solubility is dependent on
pH value. Eg: Estradiol suspensions can be prepared by
changing the pH of its aqueous solution. It is readily soluble
in alkali pH.
• Double decomposition is a simple reaction in which the
positive and negative ions in two compounds switch
between them to form new compounds

47. • Dispersion Methods
• Solid phase is dispersed in Continuous phase by wetting of
solid by liquid readily
• This is achieved by use of Surfactants, Suspending agents
such as synthetic polymers, polyelectrolytes, natural gums,
clay etc and particle size reduction