Solutions

Introduction:
Definition:
A solution is a homogenous one-phase system
consisting of two or more components.
It is a type of dispersion in which the solid particles dispersed
phase consists of particles smaller than 1 nm. The particles are
uniformly distributed and can’t be detected by electron microscope.
The phase in which the dispersion occurs is called the solvent.
The solute is the component dispersed in the solvent. Usually, the
amount of solvent is greater than the amount of solute. But this is not
a general rule. For example, 66.7% sucrose syrup contains more
solute (sucrose) than solvent (water).
Pharmaceutical solutions usually consist of liquid solvent and
solid (or liquid in some cases) solute.

Advantages:
1. Liquids are easier to swallow, therefore more acceptable to
pediatric and geriatric patients.
2. We know that a drug must be in solution before absorption. So if
a drug is administered as solution then it is immediately
available absorption and gives faster response compare to solid
dosage form.
3. The solution is homogenous meaning it is evenly distributed. So
there is no chance of dose variation which may be possible with
suspensions or emulsions.
4. The drugs irritating to the gastric mucosa are given as solutions
to minimize irritation.

Disadvantages:
1. Liquids are inconvenient for transport. If the container breaks,
all of the preparation is lost irreversibly.
2. Degradation by hydrolysis is more prevalent in solution form
compare to the solid dosage forms.
3. Microbial growth is also more prevalent in solutions compare to
the solid dosage forms (except sucrose syrup).
4. Accurate dosage depends on the one who is administering the
medicine. If 5 mL can’t be taken accurately, then dosage will be
inaccurate. This problem is not faced with tablets or capsules.
5. Taste of bitter drug becomes more pronounced in solution form.
Of course, this can be corrected using suitable flavors and
sweeteners.

Types of liquid preparations:

 Different types of pharmaceutical solutions are available for
both oral and topical use. They are described below.

1. Liquids for cutaneous applications

2. Eye preparations
3. Ear preparations
4. Irrigations
5. Oromucosal preparations
6. Nasal preparations
7. Oral liquids
8. Parenteral products
9. Rectal products
10. Intermediate products

Liquids cutaneous applications:

Lotions:
Lotions are formulated as alcohol based solutions or one
containing humectants. Lotions are intended to be applied on
unbroken skin without friction.
If it is alcohol based, alcohol evaporates giving a cooling, dry
effect. If containing humectant it retains moisture.

Liniments:
Liniments are solutions applied by massage (with friction) on
unbroken skin.
It is mainly used to reduce inflammation and may contain
counterirritants such as methyl salicylate.

Paints:
Paints are applied on broken skin using a brush. The solvent
(alcohol, acetone, ether etc.) evaporates leaving a soft film of active
ingredients.

Collodions:
Collodions are similar to paints, but they produce a tough,
flexible film intended to seal the broken skin. The film may also hold
drugs (e.g. hydroconazole – analgesic) to the skin.
The film is formed by pyroxylin in alcohol+ether or
acetone+ether solvent blend.

Eye preparations:
These are water-based solutions containing drugs e.g.
antibiotics (e.g. chloramphenicol), anti-inflammatory drugs etc.
These are used on the eye ball or the conjuctival sac for local
effect. These solutions must be isotonic in nature.
Ear preparations:
These are simple solutions for local use applied to the external
auditory canal for as drops, sprays or washes.
They may contain drugs like antibiotics, antiseptics, wax
softeners etc.

Irrigations:
This are prepared as sterile large volume solutions sued to
cleanse body cavities and wounds. The whole of the solution is used
up in an operation. The solution is isotonic with the fluid of the target
site.

Oromucosal preparations:
Mouthwashes and gargles:
These are aqueous solutions which are gargled and then spat
out. They are aqueous based.
These are used to prevent and treat different problems of the
mouth and throat and may contain drugs e.g. antiseptics, analgesics
etc.

Gingival and sublingual preparations:

These are given as sprays or drops for application to specific
part of oral mucosa for systemic or local effect.

Nasal preparations:
These are small volume aqueous (before oils were used)
solutions prepared for administration into the nasal cavity.
These solutions must have a pH of 6.8 (due to low buffering
capacity of nasal mucosa) and must be isotonic. Drugs usually
administered this way include antibiotics, anti-inflammatory and
decongestants.

Oral liquids:
Elixir:
Elixirs have following criteria
1. An hydro-alcoholic solution
2. Must contain ethanol (15-50%)
3. Sweet in taste and flavored

Elixirs are classified as medicated and non-medicated. Non-

medicated elixirs are used as solvents pharmaceutically. Medicated
elixirs contain anti-tussive, anti-inflammatory drugs.

Linctuses:
These are solutions formulated in solvent containing high
amount of sucrose. These are used to remove cough.
Mixtures:
Mixtures are solutions which are prepared in the compounding
area of retail pharmacy having a shelf life of few weeks.
It is used in multiple doses.

Drought:
Drought is a mixture which is used in a single dose (may be 2-3
times if possible). It is prepared in the amount of usually 50 mL.

Parenteral solutions:
These are sterile solutions to be injected or infused into the
body.

Rectal products:
Solutions are also available for rectal administration for
diagnostic, cleansing or therapeutic reasons purposes.
These are called enemas. For example, before administering
suppositories enemas are commonly applied for cleansing purposes.

Intermediate products:
Aromatic water:
Aromatic water is the solution of volatile substances in water.
Aromatic water itself may have therapeutic activity but usually it is
used for manufacture of other preparations. For example anise water
is used as flavoring agent.

Spirit:
Spirits are similar to aromatic water but the solvent is alcohol.
It is also used as flavoring agent.

Infusion, Extract and Tincture:

Infusion is a solution obtained by extracting the drug from the
natural source using 25% alcohol.
Extract is prepared by concentrating the infusion by
evaporation.
Tinctures are alcoholic extract of drugs but more diluted
compare to extracts.

Syrups:
Syrups are concentrated solutions of sucrose (or other sugars)
to which medicinal agents may or may not be added.
Syrups can contain upto 85% sugar (sucrose). Due to this high
conc. of sugar, it is hypertonic and therefore resists bacterial growth.
The disadvantage of syrup is that, after storage for some times,
an upper diluted layer is obtained where microbial growth is possible.
The upper dilute layer is formed due to spontaneous evaporation of
water. Due to sealed container the water is re-liquefied and remains
on the top.
Crystal growth is also possible in syrups.
For this reasons, polyhydric alcohols (sorbitol, glycerol) are
used instead of sucrose sometimes.

Formulation of solutions:
Proper formulation of solutions require following components
other than the active drug.

1. Solvent:
Water is the solvent most widely used in pharmaceutical
sector. But sometimes water can’t be used. In such cases, a blend
of solvent may be used. If the solution should be non-aqueous then
fixed oils or alcohols may be used.

2. Buffering agents:
Buffering agents are substances which upon addition to a
product will resist the change of pH of the product upon addition of
a small amount of acid or alkali
Since most drugs are themselves weak acids or bases they
act as buffers. But their buffering capacity is very limited and
therefore buffering agents should be added to maintain stability
and solubility.
Pharmaceutically acceptable buffers includes carbonates,
citrates, gluconates, phosphates etc. But mostly monobasic or
dibasic sodium phosphate is used.

3. Density modifiers:
Density modifiers are used to control the density of solutions.
They are not always required. But in same cases density must be
modified.
For example, spinal anesthetics must be of same density as
that of cerebrospinal fluid (isobaric). If density is higher the term
“hyperbaric” and if density is lower then “hypobaric” are used.
Dextrose is the density modifier most widely used.

4. Isotonicity modifiers:
Parenteral solutions, ophthalmic solutions and solution to be
applied on the mucosa must be isotonic. Otherwise they cause
irritation and may cause cell injury.
Dextrose and NaCl are most widely used for this purpose.
0.9% w/v NaCl solution
0.9N???
5. Viscosity modifiers:
Viscosity modifiers are used for two reasons
a. To ensure smooth release of medicine from container
b. To ensure that the solution for topical target remains in
place for a significant amount of time.
For these purpose, povidone, hydroxycellulose, carbomer etc
are used.

6. Preservatives:
Aqueous solutions are prone to microbial attack and
therefore preservatives should be added. When choosing a
preservative following parameters should be checked-
a. The packaging should not absorb the preservative
b. It is effective in the intended pH of the solution
c. Not unproductive in presence of other ingredients
(Examples in the “Excipient” chapter).

7. Sweetening agents:
Sweeteners are required to mask the bitter taste of the drug.
most wide used sweetener is sucrose because of following criteria
a. Cheap and available
b. Stable over a wide range of pH (4-8)
c. Gives a soothing effect
d. Colorless and highly soluble in water
Unfortunately it is caryogenic. Polyhydric alcohols (e.g.
sorbitol, mannitol) can also be used. They are used in diabetic
patients where sucrose can’t be used. There are also six artificial
sweeteners that can be used
a. Sodium and calcium salts of saccharin
b. Aspartame
c. Acesulfame potassium
d. Thaumatin
e. Sodium cyclamate
f. Neohespiridine

8. Flavors:
Flavors are used along with sweeteners to mask bitter taste of
drugs. Various factors contribute to a choice of flavor.
9. Antioxidants and reducing agents:
Auto oxidation is more likely process for solutions compare to
solid dosage form. Thus antioxidants (e.g. BHA, BHT) or reducing
agents are used (sodium metabisulphite) to control oxidation.

10. Colors:
Colors are used to improve the appearance of the product.
These are also chosen based on variety of factors depending on the
 target demographic.

It should be noted, that when density, isotonicity or viscosity

modifiers are used, calculations must be made by considering the final
product without the respective additive.

Choice of solvents:
Choice of proper solvent depends on multiple factors. E.g. for
oily solutions, fixed oils or alcohols are used.
Normally the most widely used solvent is water.

Pharmaceutical water:
Water is most widely used because-
1. It is non-toxic
2. Cheap and available
3. A physiologic component therefore highly compatible with body
fluids
4. Has a high dielectric constant and thus can dissolve a wide
range of ionizable materials

Its disadvantages are-

1. It is non-selective for dissolving substances. Thus it can carry
inorganic and organic impurities.
2. Supports microbial growth

To formulate solutions for oral use, potable water (tap water) is

purified by processes like distillation, deionization or reverse osmosis.
But water for injection and ophthalmic products must be sterile.
So the purified water is made pyrogen-free and then sterilized
immediately.
For some specific drugs e.g. chloropheniramine, WFI must be O2
free. Similarly for aminophylline WFI must be free of CO2.

POTABLE WATER, DISTILLED WATER, WFI, SWFI,

Unfortunately not all drugs are sufficiently soluble in water. For

this reason, following methods are used to increase the aqueous
solubility.

Cosolvency and dielectric constant:

The solubility of a weak electrolyte or non-polar compound can
be improved by using cosolvent.
When more than one solvent is used in combination to increase
the solubility of a drug, they are called cosolvents.
It has been shown that the solubility of a drug is maximum at a
particular dielectric constant. So suitable blends of solvents may help
dissolve many drugs. Ideally ethanol is most used as cosolvent. The
dielectric constant of water is 80 and of ethanol is 25. So their blends
have dielectric constants between 25 and 80.
Other cosolvents e.g. sorbitol, glycerol, propylene glycol are
also used.

pH:
A large number of drugs are either weak acid or bases. Their
solubility is therefore dependant upon the pH of the product.
This pH at which maximum solubility occurs can be calculated
using the Henderson-Hasselbach equation. But when this pH we must
remember that
1. This pH will not affect other ingredients
2. Must not be irritating to the target site of administration
3. Stability is not hampered.

Sometimes use of cosolvent require pH control. Then, dielectric

constant of solvent is decreased and unionized drug solubility is
increased. So pH may be increased. In many cases, the pH of optimal
solubility doesn’t match pH of optimal stability. Then a balance must
be made to obtain maximum solubility coupled with stability.

Solubilization using surfactants:

Insoluble or poorly soluble drugs may be solubilized in water by
adding surfactants above CMC.- Critical Micelle Conc.
The amount of surfactant added must be controlled properly.
Excess may lead to high cost and toxicity where insufficient amount
may not give the solubilization effect. To ensure that, optimum
quantity of surfactant is used following procedure is followed-

Several vials are taken and in a known conc. of surfactant is

taken in each one. Varying amount of solute (drug) is added to the
vials in ascending order. The maximum conc. of solute (MAC) that
forms a clear solution is determined. Plotting a graph of MAC against
surfactant conc. critical micelle conc. (CMC) is determined.
Complexation:
A less soluble drug may be solubilized by complexing it with a
soluble compound. The conditions are
a. The complex must be water-soluble
b. The complex formation is reversible
Example is, iodine is complexed with PVP to improve its
aqueous solubility.

Chemical modification:
Chemical modification is done as a last resort. Usually salt
formation is done to increase the water solubility.

Particle size control:

Decrease in particle size increases the solubility. But this is not
a very effective method.

Non-aqueous solutions:
Oily solutions can’t be formed in water. Such solutions are
prepared for administration to the muscle. IM injection of oily solution
will form globule in the muscle and since the muscular fluid is
aqueous, the drug is slowly released from the globules. This is depot
therapy.
When a non-aqueous solvent is chosen, following criteria are
considered-
1. Toxicity
2. Irritancy
3. Flammability
4. Stability
5. Cost
6. Compatibility with other ingredients

Non aqueous solvents include

1. Fixed oils → Almond oil (phenol injections), Arachis oil
(dimercaprol injection)
 2. Alcohols → Ethanol, isopropyl alcohol
3. Polyhydric alcohols → Propylene glycol (most other glycols are
toxic), glycerol, macrogols
4. Dimethylsulphoxide
5. Ethyl ether
6. Liquid paraffin (mineral oil)

Manufacture of solutions:
For both small and large scale operation, the apparatus
required are mixing vessel, means of agitation and filtration system.
The solute is mixed with solvent in a mixing vessel and stirred
until homogeneity is achieved. Coloring agents are dissolved in small
amount separately and added to the original solution at the last step.
The solution is filtered to remove any insoluble materials.
Glass is the material of choice for packaging of finished product.

Stability of solvents:
The preparation must be chemically and physically stable during
its self life.
Physical stability indicators are clarity, color, odor, taste and
viscosity. These may be determined by personal sensation.
Chemical stability is the stability against different degrading
reactions. This is determined by chemical assay.