Definition of Solution

A solution is homogenous one-phase system consisting of

two or more components.
Dosage forms prepared by dissolving the active
ingredient(s) in an aqueous or non aqueous solvent.
or
A solution is a homogenous one-phase system consisting
of two or more components. The solvent, or mixture of
solvents, is the phase in which the dispersion occurs, and
the solute is the component which is dispersed as
molecules or ions in the solvent.
Solution, Solute, Solvent & Syrup
 A simple solution is basically two substances that are
evenly mixed together.
One of them is called the solute and the other is the solvent.

 A solute is the substance to be dissolved (sugar).

 The solvent is the one doing the dissolving (water).

 Syrup : A thick sticky liquid consisting of a concentrated

solution of sugar and water with or without the addition of a
flavoring agent or medicinal substance.
 Advantages of Solution
 Easier to swallow therefore easier for children, old aged,
unconscious people.
 More quickly effective than tablets and capsules.
 Homogenous therefore give uniform dose than suspension or
emulsion which need shaking.
 Decrease irritant action of some drugs (aspirin, Kl, KBr) and
minimize adverse effects in the GIT.
 Easy to measure accurately.
 Willing to administration by any route.
 No lag time [Delay] due to dissolution i.e. rapid onset of
action
Disadvantages of Solution
 Bulky therefore difficult to transport and store
 Unpleasant taste or odors are difficult to mask
 Needs an accurate spoon to measure the dose
 Dose variation may occur due to patients inability of
measurement
 Less stable than solid dosage forms
 Highly susceptible to microbial contamination
Disadvantages of Solution

 Major signs of instability:

– color change.
– precipitation.
– microbial growth.
– chemical gas formation.
ClassificationofLiquiddosageforms:

A. On the basis of route of administration:

 Orally: Syrups, elixirs, drops
 In mouth and throat : Mouth washes, gargles, throat sprays.
 In body cavities: Ear drops, nasal sprays.
 On body Surfaces: lotions.
 IV/IM Injection
 ClassificationofLiquiddosageforms:

B. On the basis of particle size:

 Micromolecular solution.
 Miceller solution
 Macromolecular solution

C. On the basis of solvent used:

 Aqueous solution
 Non-aqueous solution
D. On the basis of saturation:
 Subsaturated solution
 Saturated solution
 Supersaturated solution
 Solutions can be formulated
 Aqueous solutions

 Non-aqueous solutions
Formulation of a Liquid Dosage Form
 In formulation of a liquid dosage
form, the following factors have to be
considered ~

A. Vehicle –
1. water
2. an aromatic water
3. active ingredients/medicaments
Formulation of a Liquid Dosage Form
B. Adjuvants (excipients/formulation additives) -
1. chemical stabilizer (antioxidants)
2. buffer/buffering agent
3. viscosity modifier
4. isotonicity modifier
5. coloring agent
6. sweetening agent
7. flavoring agent
8. preservatives (antimicrobial agent)
9. density modifier
Formulation of a Liquid Dosage Form
B. Vehicle:
water: water is the solvent most widely used as vehicle for pharmaceutical
products because of the various properties-
 It is non-toxic
 Nonirritant
 Widely available
 Tasteless
 Easy to store
 Physiologically compatible to the body
 A wide range of materials dissolve in water
 Its purity is constant
 Lack of pharmacological activity
 High dielectric constant
Types of Pharmaceutical Water-
a. Potable Water
For many preparations potable water can be
used. This is the water freshly drawn from main
system & which is suitable for drinking.
b. Pharmacopoeial Purified Water BP:
This type of water has been freshly boiled &
cooled immediately before use to destroy any
vegetative microorganisms that might be
present. Purified water is normally prepared by
the distillation or deionization of potable water
or by the process of reverse osmosis.
Types of Pharmaceutical Water-
c. Water for Injection:
Water for injection must be used for the
formulation of parenteral solutions & is
obtained by sterilizing pyrogen-free distilled
water immediately after collection.
Water for injection BP is used in the
formulation of – phenobarbitone sodium or
aminophylline, apomorphine, ergotamine.
METHODS TO INCREASE/IMPROVE AQUEOUS SOLUBILITY

 Cosolvency / use of a co-solvent

 pH control
 Solubilization
 Complexation
 Chemical modification
 Particle size control
Co-solvency / use of co-solvents
 Weak electrolytes and nonpolar molecules frequently
have poor water solubility.

 Their solubility usually can be increased by the addition

of a water-miscible solvent in which the drug has a good
solubility.

 This process is known as cosolvency and the solvents

used in combination to increase the solubility of the
solute are known as cosolvents.
pH control
 A large number of drugs are either weak acids or
weak bases, and therefore their solubilities in water
can be influenced by the pH of the system.

 The solubility of a weak base can be increased by

lowering the pH of its solution, whereas the solubility
of a weak acid is improved by an increase in pH.
 Solubilization
 The solubility of a drug that is normally insoluble or
poorly soluble in water can often be improved by the
addition of a surface-active agent.
• These molecules form different types of micelles, ranging
from simple spherical structures to more complex
liposomes, niosomes and liquid crystals.
• This phenomenon of micellar solubilization has been
widely used for the formulation of solutions of poorly
soluble drugs.
• In aqueous systems, non-polar molecules will dissolve in
the interior of the micelle.
 Complexation

 Complexation is the combination of individual atom groups,

ions or molecules to create one large ion or molecule. It may
be possible to interact a poorly soluble drug with a soluble
material to form a soluble intermolecular complex.
 As most complexes are macromolecular, however, they tend to
be inactive, being unable to cross lipid membranes.
 It is therefore essential that complex formation is easily
reversible, so that the free drug is released during or before
contact with biological fluids.
 Example : the complexation of iodine with a 10-15% solution of
polyvinylpyrrolidone (PVP) to improve the aqueous solubility of
the active agent.
Chemical modification
 Chemical modification of a drug may be necessary in
order to produce a water-soluble derivative.

 Examples include the synthesis of the sodium

phosphate salts of hydrocortisone, prednisolone
and betamethasone.
Particle size control
 The size and shape of very small particles, if less than 1
μm diameter, can affect their solubilities.

 As particle size decreases solubility will increase, and

molecular dispersions of drugs in solid/solid solutions
can exhibit improved bioavailability owing to the
increase in solubility of the dispersed drug.

 In practice, however, this phenomenon has little

application in the formulation of solutions, but is of
particular relevance in suspension formulation.
Non-aqueous solutions

Reasons to use non-aqueous solutions :

 To ensure complete solution of the ingredients
at all storage temperatures, if the drug is
unstable in aqueous systems.
 Other advantages - for example, the intramuscular
injection of solutions of drugs in oils is often used for
depot therapy. The oily solution remains as a separate
entity within the muscle tissue, releasing the drug
slowly into the surrounding tissue by dividing.
Non-aqueous solutions
 Fixed oils of vegetable origin
 Alcohols
 Polyhydric alcohols
 Dimethylsulphoxide
 Liquid paraffin
 Miscellaneous solvents
Fixed oils of vegetable origin
 A natural animal or vegetable oil that is not volatile : a mixture
of esters of fatty acids, usually triglycerides also called.
 These are non-volatile oils that consist mainly of fatty acid
esters of glycerol, for example, which consists of glycerides
mainly of oleic acid, is used as a solvent for oily phenol
injections.
 Olive oil, maize oil, cottonseed oil, soya oil and castor oil are
all suitable for parenteral use.
Alcohols
 Ethyl alcohol is the most widely used solvent
in this class, such products as salicylic acid
lotion.

 An alcohol possessing similar properties is

isopropyl alcohol.
Polyhydric alcohols
 Alcohols containing two hydroxyl groups per molecule
are known as glycols, but because of their toxicity
they are rarely used internally. One important
exception to this is propylene glycol : HO-CH2-CH(OH)-
CH3
 Injection, and some formulations of Diazepam
Injection, Co-trimoxazole Intravenous Infusion and as
the diluent for both Chloramphenicol Ear Drops and
some brands of hydrocortisone ear drops, and in
many preparations for oral use.
 Polyhydric alcohols
 The lower molecular weight polyethylene glycols (PEG) or
macrogols have the general formula: H-(O-CH2-CH2)n-OH
which is often used in conjunction with water or glycerol as
a cosolvent.
 It is used, for example, in the formulation of Digoxin
Injection, Phenobarbital Injection, and some formulations of
Diazepam Injection, Co-trimoxazole Intravenous Infusion
and as the diluent for both Chloramphenicol Ear Drops.
 Glycerol, an alcohol possessing three hydroxyl groups per
molecule, is also widely used, particularly as a cosolvent
with water for oral use.
Dimethylsulphoxide
 This is a highly polar compound and is thought to aid the
penetration of drugs through the skin.
 Although used mainly as a solvent for veterinary drugs,

Liquid paraffin
 The oily nature of this material makes it unpleasant to use
externally, although it is often used as a solvent for the topical
application of drugs in emulsion formulations.
Miscellaneous solvents
 Isopropyl myristate and isopropyl palmitate are used
as solvents for external use, particularly in cosmetics,
where their low viscosity and lack of greasiness make
them pleasant to use.
 Glycofurol is a useful solvent for parenteral products,
particularly the intramuscular injection of antibiotics.
 As with aqueous systems, it may be possible to
improve the solubility of a drug in a particular vehicle
by the addition of a cosolvent. The formulation of
Digoxin Injection, too, is best achieved by the
inclusion of both ethyl alcohol and propylene glycol.
ADDITIVES_______________
Additives are agents which are used other than active ingredients.
 Preservative: Phenol, Boric acid, Benzoic acid & their salts.
 Antioxidant : e.g. Sodium Sulphate, Ascorbic acid.
 Sweetening agent: e.g. Sucrose, Glucose, Saccharine, Sorbitol etc
 Flavoring agent: e.g. Vanilla, Orange etc
 Coloring agent: red color, green, yellow etc
 Solvent: Water.
 Co solvent: e.g. Poly propylene glycol, Liq. glucose, Sorbitol[70%]
 Viscosity increasing agent: e.g. Povidone, Methyl cellulose.
 Surface active agents: e.g. Tween-80
 Buffering agent: Phosphate buffer
 Tonicity imparting agent: dextrose, Nacl.
PRESERVATIVES
Solution may become contaminated for a number reasons.

 Raw materials used in the manufacture of solutions

are excellent growth media for bacterial substances
such as gums, dispersing agents, sugars and flavors.
 Equipment, environment and personnel contribute to
product contamination.
 Consumer usage pattern may result in the introduction of
microorganism.
A preservative inhibits the microbial growth
PRESERVATIVE :
Agents which are used to prevent the presence/
growth of microorganism.
An ideal preservative should meet some
characteristics:
 It must be effective against a broad spectrum of
microorganism.
 It must be physically, chemically and
microbiologically stable for the lifetime of the
product.
 It must be non-toxic, non-sensitizing, adequately
soluble.
Classification of Preservative :

 Acidic: e.g. Phenol, boric acid & its salts, benzoic acid & its
salts, methyl- paraben, propyl- paraben, butyl-paraben
 Neutral: - chlorobutanol, benzyl alcohol

 Mercurials: - phenyl mercuric acetate, phenyl mercuric

nitrate.
 Ammonium compound: e.g. Benzal konium chloride.
Sweetening agents :
Sweetening agents are agents, which are used to,
sweetened the preparation & make it palatable.
 Sucrose: (Not for diabetes patient)
 Liquid glucose: (For diabetes patient)
 Saccharine
 Aspartame
 Sorbitol: (For diabetes patient)
 Glycerin: (For diabetes patient)
VISCOSITY INCREASING AGENT:

To increase the viscosity of a liquid either to serve as

contiguous to improve pour ability.
Example:
 Poly vinyl pyrrolidone (Povidone)
 Methyl cellulose (Methocel)
 Sodium carboxy methyl cellulose
 Acacia, Tragacanth, Sodium-Alginate.
TONICITY IMPARTING AGENT:
Solution [For injection, for application to mucous membrane
and large volume solutions for ophthalmic use] must be made
isosmotic with tissue fluid to avoid pain & irritation
 The most widely used isotonicity modifiers are dextrose and
sodium chloride.

 Isotonicity adjustments can be made after the addition of all

other ingredients, because each ingredient will contribute to
the overall osmotic pressure of a solution.
Flavoring Agent:

Adding flavor to the pharmaceutical formulation & make it

palatable. It has aesthetic value.
There are four basic taste sensations:
 Salty,
 Bitter,
 Sweet,
 Sour
A combination of flavoring agent is usually required to mask
these taste sensation.
Example of flavoring agent:
 Sweet flavor: Fruit, Berry, and Vanilla.
 Sour flavor: Citrus flavor, Raspberry
 Salty flavor: Wintergreen, Mint
 Bitter flavor: Wild cherry, Chocolate.
COLORING AGENT:
Purpose of using coloring agent
 Produces aesthetic value
 Helps in Differentiation
 Helps in Identification
Coloring agents are classified into three types.
 Food, Drug and Cosmetic color
 Drug and Cosmetic color
 External Cosmetic color
BUFFERS:
Changes in pH of a preparation may occur during storage because
of degradation of the product, interactions with container
components, or dissolution of gases and vapors.
To avoid these problems, buffers are added to stabilize pH levels.
The choice of suitable buffer depends on the pH and
buffering capacity required.
It must be compatible with other excipients and have a
low toxicity.
Most pharmaceutically acceptable buffering systems are
based on carbonates, citrates, gluconates, lactates,
phosphates or tartrates.
Solution :
Syrups are concentrated solutions of sugar such
as sucrose in water or other aqueous liquid.

 Simple syrup: when water is used alone for making syrup.

 Medicated syrup: when the aqueous preparation
contains some added medicinal substance.
 Flavored syrup: which contains aromatic or
pleasantly flavored substances and is intended to be
used as a vehicle or flavor for prescriptions.
How does sugar act as a preservative?
It acts as a preservative because it’s in syrup form. This thick and
viscous form of sugar blocks out all the oxygen[in a jar or whatever
you use] so bacteria or any other commonly found microorganisms
cannot survive.
Why syrups are self preservative ?
Syrups contain up to 85% sucrose in water. Since the solution is so
saturated it has a high osmotic pressure and thus no free water
available for microbial growth.
Preparation of Simple Solution:

(a)Solution with heat

(b)Agitation without Heat

(c)Addition of a Medicating Liquid to syrup

(d)Percolation
Solution by Heat
 This is the usual method of making syrups in the absence of
volatile agents or those injured by heat
 The sucrose is added to the purified water or aqueous solution
and heated until dissolved.
Precautions…
 Excessive heating in the preparation of syrups must be avoided to
prevent inversion of sucrose with increased tendency to
fermentation.
Syrup
Machine used to make Syrup
Machine used to make Syrup
Agitation without Heat

 This process is used in those cases where heat would

cause loss of valuable volatile constituents.

 The syrup is prepared by adding sucrose to the

aqueous solution in a bottle of about twice the size
required for the syrup. This permits active agitation
and rapid solution.

 It is important to close the bottle, as it prevents

contamination and loss during the process.
Addition of a Medicating Liquid to syrup

 This method is used to in those cases in which fluid extracts,

tinctures, or other liquids are added to syrup to medicate it.

Percolation

 In this method, pure water or aqueous solution is

allowed to pass slowly through the bed of crystal
sucrose, thus it dissolves and forms a syrup.
Cotton is placed in the neck of the percolator.
 If necessary, a portion of the liquid is re-passed
through the percolator to dissolve all of the
sucrose.
 This method is used for the preparation of Syrup USP .
Percolation
Syrups
 Syrups are concentrated solutions of sucrose or other
sugars to which medicaments or flavourings are
often added.

 For example, Codeine Phosphate Syrup is used as a

cough suppressant and Orange Syrup contains dried
bitter orange peel as a flavouring agent.

 Syrups are also used in the manufacture of other

preparations such as mixtures or elixirs.
Syrups (continued)
 As syrups can contain up to 85% of sugars, they are
capable of resisting bacterial growth by virtue of
their osmotic effect.
 Syrups can contain lower concentrations of sugars
but will often include sufficient of a polyhydric
alcohol such as sorbitol, glycerol or propylene glycol
in order to maintain a high osmotic gradient.
 In addition, by acting as cosolvents they will help to
prevent crystallization and to maintain solubility of all
ingredients.
Syrups (continued)
 It is possible, however, in a closed container, for
surface dilution of a syrup to take place.
 This occurs as a result of solvent evaporation that
condenses on the upper internal surfaces of the
container and then flows back on to the surface of
the product, thereby producing a diluted layer which
provides an ideal medium for the growth of certain
microorganisms.
 For this reason syrups often contain additional
preservatives.
Syrups (continued)
 A further problem with the storage and use of syrups
involves the crystallization of the sugar within the
screw cap used to seal the containers, thereby
preventing its release.

 This can be avoided by the addition of the polyhydric

alcohols previously mentioned, or by the inclusion of
invert syrup, which is a mixture of glucose and
fructose.
Manufacture of solutions
 For both small- and large-scale manufacture of solutions the
only equipment necessary is suitable mixing vessels, a means
of agitation and a nitration system to ensure clarity of the final
solution.
 During manufacture, the solute is simply added to the solvent
in a mixing vessel and stirring is continued until dissolution is
complete.
 If the solute is more soluble at elevated temperatures it may
be advantageous to apply heat to the vessel, particularly if the
dissolution rate is normally slow.
 Care must be taken, however, should any volatile or thermo
labile materials be present.
 Size reduction of solid materials to increase their surface areas
should also speed up the process of solution.
Manufacture of solutions
 Solutes present in low concentrations, particularly
dyes, are often predissolved in a small volume of the
solvent and then added to the bulk.
 Volatile materials such as flavours and perfumes are,
where possible, added at the end of a process and
after cooling, to reduce loss by evaporation.
 Finally, it must be ensured that significant amounts of
any of the materials are not irreversibly adsorbed on
to the filtration medium used for final clarification.
Liquid Manufacturing Vessels
Liquid Filling & Sealing Machine [Manual]
Liquid Filling & Sealing Machine
Types of liquid preparations
1. Lotions and liniments
2. Paints and Collodions
3. Ear preparations
4. Eye preparations
5. Irrigations
6. Mouthwashes and gargles
7. Nasal products
8. Oral liquids – Elixirs, Linctuses, Mixtures and
draughts
9. Parenteral products
10. Rectal preparations
11. Intermediate products - Aromatic waters and spirits,
Extracts, infusions and tinctures,
REFERENCES

 The Theory and Practice of Industrial

Pharmacy – Lachman.
 Aulton’s Pharmaceutics – The
Design and Manufacture of
Medicines.

 Comprehensive Pharmacy Review by

Leon Shargel.