4.

Solution
Introduction
Solubility
 Solubility is defined in quantitative terms as the concentration of solute in a saturated
solution at a certain temperature and in a qualitative way; it can be defined as the
spontaneous interaction of two or more substances to form a homogeneous molecular
dispersion
 It is the amount of a substance that passes into solution when equilibrium is
established between the solution and excess (undissolved) substance
 Solubility is an intrinsic material property that can be altered only by chemical
modification of the molecule
 Generally speaking, the solubility of a compound depends on the physical and
chemical properties of the solute and the solvent as well as on such factors as
temperature, pressure, the pH of the solution, and, to a lesser extent, the state of
subdivision of the solute
o So, in definition of solubility we always mention the pressure and
temperature "fixed"
 In contrast to this, dissolution is an extrinsic material property that can be influenced by
various chemical, physical, or crystallographic means such as complexation, particle size,
surface properties, solid-state modification, or solubilization
 The transfer of molecules or ions from a solid state into solution is known as
dissolution
 The extent to which the dissolution proceeds under a given set of experimental
conditions is referred to as the solubility of the solute in the solvent
 True solution: is a mixture of two or more components that form a homogenous
molecular dispersion. The components are referred to the solute & the solvent
 Solute: is the dissolved agent (less abundant part of the solution)
o They are dispersed as ion or as a molecule in the solvent

1
  Solvent: is the component in which the solute is dissolved (more abundant part of
the solution)
o It is the component that determines the phase of the solution
 A saturated solution: is one in which an equilibrium is established between dissolved
and undissolved solute at a definite temperature i.e. solute in a solution is in equilibrium
with the solid phase
 An unsaturated or subsaturated solution: is one containing the dissolved solute in a
concentration below that necessary for complete saturation at a definite temperature
 A supersaturated solution: contains more of the dissolved solute than it would normally
contain in a saturated state at a definite temperature where undissolved solutes are present

Intermolecular forces
 They are forces that act between stable molecules or between functional groups of
macromolecules. Intermolecular forces include momentary attractions between
molecules, diatomic free elements, and individual atoms
 Intermolecular forces are due to differences in charge density in molecules
 Generally, intermolecular forces are much weaker than intramolecular forces
 Attractive forces between atoms lead to the formation of molecules and ions. The
intermolecular forces, which are developed between like molecules, are responsible for
the physical state (solid, liquid, or gas) of the substance under given conditions, such as
temperature and pressure.
 Knowledge of these forces and their balance (equilibrium) is important for understanding
 Properties of gases, liquids, and solids, interfacial phenomena, flocculation in
suspensions, stabilization of emulsions, compaction of powder in capsules,
dispersion of powders or liquid droplets in aerosols, and the compression of
granules to form tablets
 Cohesion, attraction between like molecules, or adhesion, attraction between unlike
molecules, are manifestation of intermolecular forces
 Repulsion is a reaction between two molecules that forces them apart

2
  When molecules interact, both repulsive arid attractive forces operate. The negatively
charged electron clouds of the molecules largely govern the balance (equilibrium) of
forces between the two molecules
 As two atoms or molecules are brought closer together, the opposite charges and
binding forces in the two molecules are closer together than the similar charges
and forces, causing the molecules to attract one another
 When the molecules are brought so close that the outer charge clouds touch, they
repel each other like rigid elastic bodies
o Repulsion is due to the interpenetration of the electronic clouds of
molecules and increases exponentially with a decrease in distance between
the molecules
 Thus, attractive forces are necessary for molecules to cohere whereas repulsive forces act
to prevent the molecules from interpenetrating and annihilating each other
 At certain equilibrium distance, about (3 to 4) x 10 -8 cm (3 to 4 angstroms), the
repulsive and attractive forces are equal. At this position. the potential energy of
the two molecules is a minimum and the system is most stable

Fig.1. Repulsive and attractive energies and net energy as a function of the distance
between molecules
 The various types of attractive intermolecular forces include:-

1. Van der Walls Forces

 These forces relate to nonionic interaction between molecules, yet they involve charge-
charge interactions.

3
 The partial charge on a molecule can be permanent or can be induced by neighboring
groups, and they reflect the polarity of the molecule
 The three types of Van der Wells force include:-
 Dipole-dipole or Keesom forces - is weak interaction between two dipole
molecules
o Dipolar molecules frequently tend to align themselves with their
neighbors, so that the negative pole of one molecule points toward the
positive pole of the next

Fig.2. Dipole-Dipole interaction

 Dipole-induced dipole or Debye interactions- is an interaction between a
permanent dipole and neutral molecule
o Permanent dipoles are capable of inducing an electric dipole in nonpolar
molecules (which are easily polarizable)
o Polarizability is the ease with which the electron distribution in the atom
or molecule can be distorted

Fig.3. Dipole-induced Dipole interaction

 Induced dipole-induced dipole or London attractions (Dispersion force) – is
an interaction between two neutral or nonpolar molecules
o Nonpolar molecules can induce polarity in one another

4
 Fig.4. Induced dipole-induced dipole interaction
 In all three types of van der Waals forces, the potential energy of attraction varies
inversely with the distance of separation r, raised to the sixth power, r6

2. Ion dipole or ion induced dipole interaction

 In addition to the dipolar interactions known as van der Waals forces, other attractions
occur between polar or nonpolar molecules and ions
 An ion may interact with a polar molecule (ion-dipole) or an ion may induce polarity in
nonpolar molecule (ion induced dipole)
 Ion dipole interactions account in part for the solubility of ionic crystalline
substances in water: the cation, for example, attracts the relatively negative
oxygen atom of water and the anion attracts the hydrogen atoms of the dipolar
water molecules.

Fig.5. Ion-dipole interaction

5
 Fig.6. Ion-induced dipole and dipole induced dipole interactions

3. Ion-Ion interactions
 Another important interaction that involves charge is the ion— ion interaction. An
ionic electrovalent bond between two counter ions is the strongest bonding interaction
and can persist over the longest distance.
 However, weaker ion—ion interactions, in particular salt formations, exist and
influence pharmaceutical systems
 It is well established that ions form because of valency changes in an atom. At
neutrality, the number of protons and the number of electrons in the atom are equal.
Imbalance in the ratio of protons to neutrons gives rise to a change in charge state, and
the valency will dictate whether the species is cationic or anionic.
 A cation on one compound will interact with an anion on another compound
giving rise to an intermolecular association
 Ion—ion interactions can also be repulsive when two ions of like charge are
brought closely together
 Ion—ion interactions may be intermolecular (e.g., a hydrochloride salt of a drug) or
intramolecular (e.g., a salt- bridge interaction between counter ions in proteins)

4. Hydrogen Bond

6
 The hydrogen bond is a special dipole-dipole interaction between the hydrogen atom in
a polar N-H, O-H, or F-H bond and an electronegative O, N, or F atom

 It is the interaction between a molecule containing a hydrogen atom and a

strongly electronegative atom such as fluorine, oxygen or nitrogen
 Because of the small size of the hydrogen atom and its large electrostatic field, it can
move in close to an electronegative atom and form an electrostatic type of union known
as a hydrogen bond or hydrogen bridge
 It exists in ice and in liquid water and it accounts for many of the unusual properties of
water including its high dielectric constant, abnormally low vapor pressure, and high
boiling point.

Fig.7. On the right (Salicylic acid showing both intra and intermolecular hydrogen
bond) and on the left (Water showing intermolecular hydrogen bond)

Table.1. Energies associated with molecular interactions

Bond type Dissociation energy (kcal)

Ionic Bonds ˃100

Covalent 50-150

Hydrogen bonds 2-8

Van der Walls forces 1-10

7
The Phase Rule
 The three primary phases (solid, liquid, and gaseous) of matter are often defined
individually under different conditions but in most systems we usually encounter phases
in coexistence
 For example. a glass of ice water on a hot summer day comprises three
coexisting phases: ice (solid), water (liquid), and vapor (gaseous)
 A suspension consists of solid particles suspended in a liquid vehicle and
evaporation may occur in the headspace of the container
 Phase rule is a relationship for determining the least number of intensive variables
(independent variables that do not depend on the volume or size of the phase, e.g.
temperature, pressure, density and concentration) that can be changed without changing
the equilibrium state of the system or alternately, the least number required in define the
state of the system.
 This critical number is called F, the number of degrees of freedom of the system,
and the rule is expressed as follows:
F = C - P + 2,
Where C: - The number of the components
P: - The number of phases present
2:- 2 intensive parameters (Temperature and Pressure mostly)
 Phase is defined as a homogeneous, physically distinct portion of a system that is
separated from other portions of the system by bounding surfaces.
 A system containing water and its vapor is a two-phase system.
 An equilibrium mixture of ice, liquid water, and water vapor is a three-phase
system
o Phases may either be pure compounds or mixtures such as solid or
aqueous solutions--but they must "behave" as a coherent substance with
fixed chemical and physical properties
 The number of components is the smallest number of constituents by which the
composition of each phase in the system at equilibrium can be expressed in the form of a
chemical formula or equation i.e. is the minimum number of independent chemical
components needed to form the system or, in other words, to define all the phases
8
  Independent means:

o If you have equilibrium balance between reactants and products, the

number of components will be reduced by one
o If you have equal amounts (concentrations) of products formed, the
number of components will also be reduced by one

 If two possible components always occur in the same proportions

in multiple phases in a system, these can be combined into a single
component
 The number of components in the equilibrium mixture of ice, liquid water, and
water vapor is one because the composition of all three phases is described by the
chemical formula H20
 In the three-phase system CaCO3 ⇆ CaO + CO2, the composition of each phase
can be expressed by a combination of any two of the chemical species present.
For example, if we choose to use CaCO 3 and CO2, we can write CaO as (CaCO 3 -
CO2) – so the number of components is two
 The number of degrees of freedom is the least number of intensive or independent
variables such as temperature, pressure, concentration, that must be fixed or known to
describe the system completely. It may be Uni, Bi, Tri or Non-variant.
 Univariant means we must define only one variable (either Temperature or Pressure) to
define the system
 Bivariant means we must define two variables to define the system
 Both T and P may vary without losing the system
 Non-variant or invariant means if we attempt to vary any variable, we will lose our
system. That means the system is fixed or unique
 Herein lies the utility of the phase rule. Although a large number of intensive
properties are associated with any system, it is not necessary to report all of these
to define the system.
 For example, let us consider a given mass of a gas, say, water vapor, confined to a
particular volume. Using the phase rule only two independent variables are

9
 required to define the system. F = 1 — 1 + 2 = 2. Because we need to know two
of the variables to define the gaseous system completely, we say that the system
has two degrees of freedom.
o Therefore, even though this volume is known, it would be impossible for
one to duplicate this system exactly (except by pure chance) unless the
temperature, pressure, or another variable is known that may be varied
independent of the volume of the gas

One component system

 The curve OA in the pressure— temperature diagram in Figure 8 is known as the vapor
pressure curve. Along the vapor pressure curve, vapor and liquid coexist in equilibrium
 Curve OC is the sublimation curve, and here vapor and solid exist together in
equilibrium.
 Curve OB is the melting point curve, at which liquid and solid are in equilibrium. The
negative slope of OB shows that the freezing point of water decreases with increasing
external pressure

Fig.8. Phase diagram for water

 The result of changes in pressure (at fixed temperature) or changes in temperature (at
fixed pressure) becomes evident by referring to the phase diagram.
 If the temperature is held constant at t 1, where water is in the gaseous state above
the critical temperature, no matter how much the pressure is raised, the system
remains as a gas

10
  At a temperature t2 below the critical temperature, Water vapor is converted into
liquid water by an increase of pressure because the compression brings the
molecules within the range at the attractive intermolecular forces.
 At a temperature below the triple point, say t3, an increase of pressure on water in
the vapor state converts the vapor first to ice and then at higher pressure into
liquid water. This sequence, vapor - ice - liquid, is due to the fact that ice occupies
a larger volume than liquid water below the triple point.
 At the triple point, all three phases are in equilibrium, that is, the only equilibrium is at
4.58 mm Hg pressure and at this temperature of 0.0098°C (or with respect to the phase
rule, F = 0)
 If we attempt to vary the particular conditions of temperature or pressure

necessary to maintain this system, we will lose a phase. Thus, if we wish to

prepare the three-phase system of ice-water-vapor, we have no choice as to the

temperature or pressure at which we will work; the combination is fixed and

unique. This is known as the critical point

Table.2. The phase rule for one component system

System Nature of Degree of Comments

phase freedom
(F)
Gas, Liquid or solid 1 2
Gas-Liquid, Liquid- 2 1
Solid or Gas-Solid
Gas-liquid-solid 3 0
System is bivariant and it
lies anywhere within the
area marked vapor, liquid
or solids
System is univariant and it
lies anywhere along the
line between two phase
regions, AO, CO or BO in
the figure 8
System is invariant and

11
 only lies at the point of
intersection of the lines
bounding the three phases
(point O in the figure 8)

 As the number of components increases, so do the required degrees of freedom needed to

define the system.
 Therefore, as the system becomes more complex, it becomes necessary to fix
more variables to define the system
 The greater the number of phases in equilibrium, however, the fewer are the
degrees of freedom

Condensed systems
 A maximum of three degrees of freedom is possible in a two-component system, for
example, temperature, pressure and concentration. To represent the effect of all these
variables upon the phase equilibria of such a system, it would be necessary to use a three-
dimensional model rather than the planar figure used in the case of water.
 In a two-component system only two variables (temperature and concentration) remain,
and we are able to portray the interaction of these variables by the use of planar figures
on rectangular- coordinate graph paper
 We frequently choose to disregard the vapor phase and work under normal
conditions of 1atm pressure. In this mariner, we reduce the number of degrees of
freedom by one
 Systems in which the vapor phase is ignored and only solid and/or liquid phases
are considered are termed condensed system
 It is important to realize that in aerosol and gaseous systems, vapor cannot be
ignored. Condensed systems are most appropriate for solid and liquid dosage
forms

Solubility expressions
 The United State Pharmacopeia (USP) describes the solubility of a drug as part of the
solvent required for one part of the solute.

12
 It lists the solubility of drugs as the number of ml of solvent in which 1 g of solute will
dissolve. E.g. 1g of boric acid dissolves in 18mL of water, and in 4mL of glycerin
Table.3. Descriptive solubility
Solubility definition Part of the solvent required for one part of
the solute
Very soluble (VS) ˂1
Freely soluble (FS) From 1 to 10
Soluble From 10 to 30
Sparingly soluble (SPS) From 30 to 100
Slightly soluble (SS) From 100 to 1000
Very slightly soluble (VSS) From 1000 to 10,000
Partially insoluble (PS ) ˃ 10,000

 Solubility of a drug can also be described quantitatively in terms of molarity, molality

and percentage
 Molarity = number of mole (gram per molecular weight) of a solute in 1 liter
of the solution
 Molality (m) – is number of moles of solute in 1000g of solvent
o Molal solutions are prepared by adding the proper weight of solvent to a
carefully weighed quantity of a solute
o The volume of the solvent can be calculated from specific gravity and the
solvent can be measured from a burette
 Percentage expressions
o Percent Weigh in weight (w/w) is the number of grams of the solute in
100 gram of the solution
% w/v = Weight of the solute × 100%
Gram of the solution
o Percent Weigh in Volume (w/v) is the number of grams of the solute
in 100ml of the solution
o Percent Volume in Volume (V/V) is the milliliter of the solute in 100
ml of the solution

13
  Other means of expressing solubility include mole fraction and normality
o Normality is the gram equivalent weight of the solute in 1 liter of the
solution
o Mole fraction is the ratio of mole of one constituent of a solution to
the total mole of all the constituent (solute and the solvent)

Solute-Solvent interactions
 In pre-or early formulation, selection of the most suitable solvent is based on the
principle of “like dissolves like”. That is, a solute dissolves best in a solvent with similar
chemical properties
 Polar solutes dissolve in polar solvents. E.g. salts & sugar dissolve in water
 Non polar solutes dissolve in non polar solvents. E.g. naphthalene dissolves
in benzene
 If the solvent is A & the solute is B, and the forces of attraction are represented by A-A,
B-B and A-B, one of the following conditions will occur
 If A-A >> A-B, the affinity of the solvent molecules for its own molecule is
marked greatly than its affinity for solute molecule, the solvent molecules will be
attracted to each other & form aggregates from which the solute will be excluded.
Example: Benzene & water, where benzene molecules are unable to penetrate the
closely bound water aggregates
 If B-B >> A-A, the solvent will not be able to break the binding forces between
solute molecules. Example: NaCl in benzene, where the NaCl crystal is held by
strong electrovalent forces which cannot be broken by benzene
 If A-B >> A-A or B-B, or the three forces are equal, the solute will disperse &
form a solution. Example: NaCl in water
 Solubility depends on chemical, electrical & structural effects that lead to mutual
interactions between the solute and the solvent
 This means not only likeness should be considered but other factors like dielectric
constant, polarity, association, solvation, internal pressure, acid-base reactions
should also be considered

14
Classification of solvents
1) Polar solvents
 The solubility of the drug is due in large measure to the polarity of the solvent, that is, to
its dipole moment
 Polar solvents like water, glycol, alcohols, dissolve ionic solutes and other polar
substances
 Also due to their high dielectric constant, polar solvents reduce the force of
attraction between oppositely charged ions in crystals
o Example: water possessing a high dielectric constant (> = 80) can dissolve
NaCl while chloroform & benzene cannot (Ionic compounds are
practically insoluble in these 2 solvents)
 However consideration of dipole moment alone is not sufficient to explain the solubility
of polar substances in water
 The ability of the solute to form hydrogen bond is a far more significant factor
than its polarity
o Water dissolves phenols, alcohols, aldehydes, ketones, amines, and other
oxygen and nitrogen containing compounds that can form hydrogen bonds
with water
 In addition to the above factors, the solubility of a substance also depends on
structural features such as the ratio of the polar to the nonpolar groups of the
molecule
 As the length of a nonpolar chain of an aliphatic alcohol increases, the
solubility of the compound in water decreases
o Straight-chain monohydroxy alcohols, aldehydes, ketones and acids with
more than four or five carbons cannot enter into the hydrogen-bonded
structure of water and hence are only slightly soluble
o When additional polar groups are present in the molecule, as found in
propylene glycol, glycerin, and tartaric acid, water solubility increases
greatly

15
  Branching of the carbon chain reduces the nonpolar effect and leads to increased
water solubility
o Tertiary butyl alcohol is miscible in all proportions with water, whereas n-
butyl alcohol dissolves to the extent of about 8g/100mL of water at 200C
2) Non-polar solvents
 The solvent action of nonpolar liquids, such as the hydrocarbons, differs from that of
polar substances.
 Nonpolar solvents are unable to reduce the attraction between the ions of strong
and weak electrolytes because of the solvents low dielectric constants
 They can’t also break covalent bonds and ionize weak electrolytes, because they
belong to the group known as aprotic solvents (a solvent that cannot serve as a
hydrogen bond donor) and they cannot form hydrogen bridges with
nonelectrolytes
o Hence, ionic and polar solutes are not soluble or are only slightly soluble
in nonpolar solvents
 Nonpolar compounds, however, can dissolve nonpolar solutes with similar internal
pressures through induced dipole interactions
 The solute molecules are kept in solution by the weak Van der Waals—London
type of forces
o Oils, alkaloids, fats dissolve in nonpolar solvents like carbon
tetrachloride, benzene, and mineral oil
3) Semi-polar solvents
 Semipolar solvents, such as ketones and alcohols, can induce a certain degree of polarity
in nonpolar solvent molecules
 They can act as intermediate solvent to bring about miscibility of polar and
nonpolar liquids
o For example, acetone increases the solubility of ether in water, alcohol on
water-castor oil mixtures, Propylene glycol in water and peppermint oil
and of water and benzyl benzoate

Solubility of gases in liquids

16
  Pharmaceutical solutions of gases include HCl, ammonia water & effervescent
preparations containing CO2 maintained in solution under pressure
 Aerosol products, which contain propellant either CO 2 or nitrogen, some of which
is dissolved under pressure, belong to this class
 The solubility of a gas in a liquid is the concentration of dissolved gas when it is in
equilibrium with some of the pure gas above the solution
 The amount of the gas that dissolves in a liquid depends or is determined by the nature of
the two components (presence of salts & chemical reactions that sometimes the gas
undergoes with the solvent) and by pressure and temperature
Effect of Pressure
 The pressure of a gas above the solution is an important consideration in gaseous
solutions because it changes the solubility of the dissolved gas in equilibrium with it
 Pressure changes have little or no effect on solubility of liquids and solids
 Provided that no reaction occurs between the gas and liquid, then the effect of pressure on
the solubility of gases is indicated by Henry's law which states that
 In a very dilute solution at constant temperature, the concentration of dissolved
gas is proportional to the partial pressure of the gas above the solution at
equilibrium
 The partial pressure of the gas is obtained by subtracting the vapor pressure of the
solvent from the total pressure above the solution
C2 = σ p
Where C2 is the conc. of the dissolved gas in grams per liter of the solvent
p is the partial pressure in millimeter of the undissolved gas
σ is the solubility coefficient and is the inverse of Henry’s law constant, k
k= p2 = p2
X2 c or m
Where p2 is the pressure of gas (solute) in torrs or atmospheres
c or m is molarity, molality or g/liter of gas in solution
X2 is the mole fraction of the gas in solution
 This theory states that solubility of a gas increases directly with the pressure of the gas
and the reverse is true

17
  In effervescent solutions, when the stopper of the container is removed a gas
escapes with violence when the pressure above the solution is released. This is
due to a decrease in solubility due to a decrease in pressure
 Henry's law is most applicable at high temperatures and low pressures, when solubility is
low
 It also provides a satisfactory description of the behavior of most systems at
normal temperatures and reasonable pressures, unless solubility is very high or
reaction occurs

Effect of Temperature
 Temperature also has a marked influence on the solubility of a gas in a liquid
 As the temperature increases, the solubility of most gases decreases, owing to the
greater tendency of the gas to expand
 The pharmacist should be cautious in opening containers of gaseous solutions in warm
climates or conditions of elevated temperature
 A container filled with a gaseous solution or a liquid with high vapor pressure,
such as ethyl nitrite, should be immersed in ice or cold water, before opening the
container, to reduce the temperature and pressure of the gas
 This effect of temperature provides a means of removing dissolved gases. For example,
water for injections free from either carbon dioxide or air may be prepared by boiling
water with minimal exposure to air and preventing the access of air during cooling

Salting out
 Gases are often liberated form solutions in which they are dissolved by the introduction
of an electrolyte such as sodium chloride and sometimes by a nonelectrolyte such as
sucrose. This phenomenon is known as salting out
 This is caused by the marked attraction exerted between electrolyte and water
which reduces the density of the aqueous environment adjacent to the gas
molecules
 Salting out can also occur in solutions of liquids in liquids and solids in liquids

18
Effect of chemical reaction
 A chemical reaction between the solute and the solvent increases their bonding and hence
enhances the solubility of the solute
 Gases such as NH3, HCl and CO2 become more soluble in a solvent by reacting
with the solvent ( react with water by hydrogen bonding)
 Their solubility also increase as their partial pressure is increased but not in the way that
can be predicted by Henry’s law

Solubility calculations
 The solubility of a gas in a liquid can be expressed either by the inverse Henry’s law
constant, σ, or the Bunsen absorption coefficient, α
 The Bunsen coefficient is defined as the volume of gas in liters (reduced to standard
conditions of 00C and 760mm Hg pressure) that dissolves in 1 liter of a solvent under a
partial pressure of 1 atm of the gas at a definite temperature
Vgas (STP) = α p
Vsoln
Where Vgas is the volume of the gas at standard temperature and pressure (STP)
dissolved in a volume Vsoln of solution at a partial pressure p
 Example:- If 0.0160g of oxygen dissolves in 1 liter of water at a temperature of 25 0C and
at an oxygen pressure of 300 mm Hg, calculate (a) σ and (b) α
(a) C2 = σ p ⇒ σ = C2 (g/liter)/p (mm Hg)
σ = 0.0160g/L = 5.33 × 10-5g/L.mm Hg
300mm Hg
(b) To compute the Bunsen coefficient, one must first reduce the volume of the gas to
STP. According to the ideal gas equation
Vgas (STP) = nRT
p
Where n is the number of moles = given mass/molecular weight
R- Universal gas constant (0.08205atm.L/ 0K.mol)
T- Absolute temperature in Kelvin
p- Pressure

19
 Vgas (STP) = (0.0160/32) mol × 0.08205 × 273.150K
1atm
Vgas (STP) = 0.0112L at STP
And α will be
α = Vgas/ (Vsoln×p)
α= 0.0112L = 0.0284
1L× 300mm Hg/760mm Hg
(c) How many grams of oxygen can be dissolved in 250 ml of aqueous solution when the
total pressure of the mixture is 760 mm Hg? The partial pressure of oxygen in the
solution is 0.263 atm and the temperature is 250C.
C2 = σ p = 5.33 × 10-5 g/L.mm Hg × (0.263 × 760mm Hg)
C2 = 0.0107g/liter or 0.0027g/250ml
 Example: - The partial pressure of oxygen the blood is 75 mm Hg and the percent of
saturation oxygen in the red blood cells has been determined to be 92.8%. What is the
concentration of oxygen dissolved in the red blood cells, exclusive of the binding of
oxygen by iron in the hemoglobin? (The value of solubility coefficient at 37 0C for
oxygen is 4.1× 10-5cm3 02/cm3 RBC content/mm Hg)
C2 = σ p = 4.1× 10-5cm3 02/cm3 RBC content/mm Hg × (75mm Hg)
C2 = 3.075 × 10-3 cm3 02/cm3 RBC content
 However, oxygen in RBC is at only 92.8% of saturation, therefore,
C2 = 0.928 × (3.075 × 10-3) = 2.85× 10-3 cm3 02/cm3 RBC content
 Example: - What is the solubility of oxygen in water at 1atm pressure at a temperature of
250C if the value of the Henry law constant is 4.34 × 10 4atm/mole fraction? (Express the
result in both molality and molarity)
 Useful equation for converting mole fraction (X2) into molality (m) and molarity (c) are
 m = 1000X2 and c= 1000 d.X2
M1 (1-X2) M1 (1-X2) + M2X2
Where M1- Molecular weight of the solvent
M2- Molecular weight of the solute and d is the density of the solution

20
  In a solution sufficiently dilute for Henry’s law to apply, d is essentially 1 and M 2X2 may
be ignored in the equation for c (thus c = m)
k = p2/X2
X2= p2/k = 1atm/4.34 × 104atm/mole fraction
X2= 2.30 × 10-5
m= 1000(2.30 × 10-5) = 0.00128mole/kg of H20 = c
18.015 (1-(2.30 × 10-5))
 (b) Calculate the Henry’s law constant, k, for methane at 1atm and 25 0C, expressed in
torr/(mole/kg H20) if the value of k is 4.13× 104atm/mole fraction?
k = p2/X2
X2= p2/k = 1atm/4.13 × 104atm/mole fraction
X2= 2.42 × 10-5
m= 1000(2.42 × 10-5) = 1.344× 10-3 mole/kg of H20 = c
18.015 (1-(2.42 × 10-5))
Therefore k in torr/(mole/kg of H2O) is
k= 1atm×760torr/atm = 5.65× 105 torr/(mole/kg of H2O)
1.344× 10-3 mole/kg of H20
Solubility of liquids in liquids
 The mixtures of two liquids are common in pharmaceutical formulations. Some example
include:-
 Hydroalcoholic solutions:- Alcohol-Water mixture
 Aromatic waters:- Volatile oils with Water
 Spirits and Elixirs:- Volatile oils with Alcohol
 Colloidons:- Ether with Alcohol

Ideal and Real solutions

 Raoult’s law:- States that the partial pressure of a component in a liquid mixture at a
definite temperatures is equal to the vapor pressure in the pure state multiplied by the
mole fraction of the component in the solution

21
 pi = XiPOi

Where pi-Partial pressure of the constituent

POi-Vapor pressure of the pure constituent

Xi-Mole fraction of the component in the solution

 If additional volatile components are present in the solution, each will produce a partial
pressure above the solution and the total pressure is the sum of the partial pressure of all
the constituent
 If two components A and B are present
PA = XA POA and PB = XB POB
P T = P A + P B = X A P OA + X B P OB
 Ideal Solution:-Is a solution in which there is no change in the properties of the
components other than dilution, when they are mixed to form the solution.
 They are solution formed by mixing substance with similar properties E.g.
Benzene and Toluene
o No heat is evolved or absorbed during the mixing process
o The final volume of the solution represents an additive property of the
individual constituents
 No shrinkage or expansion occurs when substances are mixed
o The constitutive properties like vapor pressure, refractive index, surface
tension and the viscosity of the solution, are the weighted averages of the
properties of the pure individual constituents
 The mixture is said to be ideal when the component of the solution obey Raoult’s law
over the whole range of composition
 All solutions which deviate from ideal behavior are referred to as real solutions
 Deviation from Raoult’s law
 Positive deviation
o Occurs if attractive force between the solute and the solvent is less than
solute-solute or solvent-solvent interactions

22
  This leads to decrease solubility and it results from the association
of the molecules of one of the constituents to form double
molecules (dimers) or polymers of higher order
 These attractive forces, which may occur in gases, liquids, or
solids between similar molecules are called internal pressures or
cohesion forces
o E.g. A mixture of alcohol and benzene, water + diethyl ether, benzene +
water
 Negative deviation
o Occurs if attractive force between the solute and the solvent is greater
than solute-solute or solvent-solvent interactions
 This leads to increased solubility of the solute and it is frequently
associated with hydrogen bonding between polar compounds
 The interaction of the solute and the solvent is called solvation
o E.g. chloroform + acetone, pyridine + acetic acid, water + nitric acid
 Most systems are non-ideal and deviate either positively or negatively from Raoult's law
 Such deviations are small when a solution is dilute because the effects of a small
amount of solute on interactions between solvent molecules are minimal
 Conversely, large deviations may be observed when the concentration of a
solution is high

Complete and partial miscibility

 Liquid-liquid system can be divided into two categories according to the solubility of the
substance in one another
 Complete solubility
 Partial miscibility
 Miscibility refers to the mutual solubilities of the components in liquid-liquid system
Complete Miscibility
 For two liquid mixtures to be called complete miscible, they should mix in all
proportions

23
  It occurs when the adhesive forces between different molecules is greater than the
cohesive forces between like molecules
 Example:-
 Polar and semi-polar solvents:- Water-alcohol, Glycerin-alcohol, Alcohol-acetone
 Nonpolar solvents:-Benzene-carbon tetrachloride
Partial Miscibility
 Two liquids may form a miscible mixtures or immiscible mixtures. Between these two
extremes lies a whole range of systems that exhibit partial miscibility or immiscibility
 When two liquids which are partially miscible are mixed, two liquid layers are formed,
each containing some of the other liquid in the dissolved state
 It occurs when the cohesive forces of the constituents of a mixture are quite
different
 A two-component condensed system having one liquid phase, F = 3. Because the
pressure is fixed, F is reduced to 2, and it is necessary to fix both temperature and
concentration to define the system.
 When two liquid phases are present, F = 2: again, pressure is fixed. We need only
define temperature to completely define the system because F is reduced to l
 E.g. Water-Ether and Water-Phenol mixtures

Fig.9. Temperature-composition diagram of phenol-water mixture

24
 The curve gbhci shows the limits of temperature and concentration within which two
liquid phases exist in equilibrium. The region outside this curve contains systems having
one liquid phase.
 By applying the phase rule, for the area outside the curve gbhci, the number of
components equals 2, the number of phases equals one, then the number of degrees of
freedom F will be 2
 This means that we have two degrees of freedom. This means that we can vary the
temperature and composition independently in this region
 For any point contained within the curve, the number of phases in two and the number of
degrees of freedom is 1
 This means that if we change the temperature independently, the composition will
automatically change and vice versa.
 Starting at the point a, equivalent to a system containing 100% water (i.e.. pure water) at
500C, adding known increments of phenol to a fixed weight of water, the whole being
maintained at 500C, will result in the formation of a single liquid phase until the point b
is reached, at which point a minute amount of a second phase appears.
 The concentration of phenol and water at which this occurs is 11% by weight of
phenol in water.
 The phenol-rich phase denoted by the point c on the phase diagram shows it to contain
63% by weight of phenol in water

 The amount of water decreases where as the amount of phenol increase as we

proceed from right to left in the phase diagram
 The maximum temperature at which the two-phase region exists is termed the critical
solution or upper consolute temperature. In the case of the phenol-water system, this is
680C (point h).
 All combinations of phenol and water above this temperature are completely
miscible and yield one-phase liquid systems
 The line bc drawn across the region containing two phases is termed a tie line. An
important feature of phase diagrams is that all systems prepared on a tie line, at
equilibrium, will separate into phases of constant composition. These phases are termed
conjugate phases and they can be used to determine the weight of the two phases

25
  For example, if we prepare a system containing 24% by weight of phenol and
76% by weight of water (point d), at equilibrium we have two liquid phases, A
(11% phenol in water) and B (63% phenol in water) present in the tube.
Weight of phase A = Length dc
Weight of phase B Length bd
 For example, because point b = 11%, point c = 63%, and point d = 24%, the ratio
dc/bd = (63 — 24)/(24 — 11) = 39/13 = 3/1
 This means, for every 10 g of a liquid system in equilibrium represented by point
d, one finds 7.5 g of phase A and 2.5 g of phase B.
 Working on a tie line in a phase diagram enables us to calculate the composition of each
phase
 Example:- let us suppose that we mixed 24 g of phenol with 76 g of water,
warmed the mixture to 500C, and allowed it to reach equilibrium at this
temperature. On separation of the two phases, we would find 75 g of phase A
(containing 11% by weight of phenol) and 25 g of phase B (containing 63% by
weight of phenol).
o Phase A therefore contains a total of (11 x 75)/100 = 8.25 g of phenol,
whereas phase B contains a total of (63 x 25)/100) = 15.75 g of phenol.
This gives a sum total of 24 g of phenol in the whole system
 Example: - A mixture of phenol and water at 20 0C has a total composition of
50% phenol. The tie line at this temperature cuts the binodal at points equivalent
to 8.4% and 72.2%w/w phenol. What is the weight of the aqueous layer and of
the phenol layer in 500g of the mixture and how many grams of phenol are
present in each of the two layers?
 Let Z be the weight in grams of the aqueous layer and 500-Z will be the weight
in grams of the phenol layer and the sum of the percentage of phenol in the two
layers must equal the overall composition of 50% (50% x500=250g)
o Z(8.4%) + (500 – Z)72.2% = 250
 Z = 174g and weight of the phenol layer = 500-Z = 326g
o Weight of phenol in the aqueous layer = 174g x 8.4% = 15g
o Weight of phenol in the phenol layer = 326 x 72.2.% = 235g

26
 There are liquid mixtures that show no upper consolute temperature but instead have a
lower consolute temperature below which the components are miscible in all proportions
i.e. their solubility increases as the temperature is lowered
 Example:- Triethylamine-water system

Fig.10. Phase diagram of Trethylamine-water system

 There are liquid mixtures also that shows both a lower and an upper consolute
temperature with an intermediate temperature region in which the two liquids are only
partially miscible
 Example:- Nicotine-water system

Fig.11. Phase diagram of Nicotine-water system

27
  There are also other liquid mixtures which exhibit no critical solution temperature i.e.
they don’t have lower or upper consolute temperature and shows partial miscibility over
the entire temperature range at which the mixture exists
 E.g. Ethyl ether-Water mixture

Phase Equilibria in Three-Component Systems

 In systems containing three components but only one phase, F = 3 — 1 + 2 = 4 for a non-
condensed system. The four degrees of freedom are temperature, pressure and the
concentrations of two of the three components
 Only two concentration terms are required because the sum of these subtracted
from the total will give the concentration of the third component
 If we regard the system as condensed and hold the temperature constant, then F=2.
 Because we are dealing with a three-component system, it is more convenient to
use triangular coordinate graphs

Fig.12. The triangular diagram for three component system

 Rules Relating to Triangular Diagrams
 Each of the three corners or apexes of the triangle represent 100% by weight of
one component (A. B, or C). As a result, that same apex will represent 0% of the
other two components
 The three lines joining the corner points represent two- component mixtures of the
three possible combinations of A, B and C
 The area within the triangle represents all the possible combinations of A, B, and
C to give three-component systems.

28
 o The horizontal lines running across the triangle parallel to the line joining
the two corners denote increasing percentages of the substance
represented in the apex
 Example:- x on the diagram represents 15% of B and 55% of A
and 30% of C
 If a line is drawn through any apex to a point on the opposite side (e.g., line DC in
Fig. 12), then all systems represented by points on such a line have a constant
ratio of two components, in this case A and B
 Any line drawn parallel to one side of the triangle, for example, line HI,
represents ternary system in which the proportion (or percent by weight) of one
component is constant.
o In this instance, all systems prepared along HI will contain 20% of C and
varying concentrations of A and B

Influence of foreign substance on a binary system

 The addition of a substance to a binary liquid system produces a ternary system, that is a
system having there components.

 If the 3rd liquid is soluble only in one of the two original liquids (if the solubility in the
two liquids is markedly different), the mutual solubility of the original pair decreased

 Here, if the system has an upper critical solution temperature, it will be elevated
and if the system has a lower critical solution temperature, it will be lowered
o E.g. Addition of Naphtalene or potassium chloride in water-phenol
mixture

 On the other hand, the addition of liquid having roughly the same solubility in both
components of the original pair will result in an increase in their mutual solubility and
this way of increasing solubility is called Blending

 An upper critical solution temperature will be lowered and a lower critical

solution temperature elevated
o E.g. Addition of Succinic acid or Sodium oleate to water-phenol mixture

29
 Water and benzene are miscible only to a slight extent, and so a mixture of the two
usually produces a two-phase system. The heavier of the two phases consists of water
saturated with benzene, while the lighter phase is benzene saturated with water. On the
other hand, alcohol is completely miscible with both benzene and water.
 It is to be expected, therefore, that the addition of sufficient alcohol to a two-phase
system of benzene and water would produce a single liquid phase in which all three
components are miscible
 Raising the temperature of the phenol—water system lead to complete miscibility
of the two conjugate phases and the formation of one liquid phase.
 The addition of alcohol (B) to the benzene (C)—water (A) system achieves the
same end but by different means, namely, a solvent effect (serves as an
intermediate polar solvent) in place of a temperature effect. There is a strong
similarity between the use of heat to break cohesive forces between molecules and
the use of solvents to achieve the same result

Fig.13. A ternary system which contains one pair of immiscible liquids

 The line AC depicts binary mixtures of A and C. and the points a and c are the limits of
solubility of C in A and of A in C, respectively, at the particular temperature being used
 The curve afdei, frequently termed a binodal curve or binodal, marks the extent of
the two-phase region. The remainder of the triangle contains one liquid phase.

30
 The phase equilibria depicted in Figure 13 show that the addition of component B
(Alcohol) to a 50:50 mixture of components A (Water) and C (Benzene) will produce a
phase change from a two-liquid system to a one-liquid system at point d.
 With a 25:75 mixture of A and C, shown as point j, the addition of B leads to a phase
change at point e
 The area of the binodal decreases as the temperature is increased and miscibility is
enhanced

Fig.14. The decrease on the binodal area as the temperature increases

31
Influence of molecular connectivity, dielectric constant and molecular
surface area
 By restricting various solvent systems to solvents exhibiting similar bonding
characteristics, such as by using members of homologous chemical series or by using
solvent blends, essentially linear relationships were obtained for plots of log mole
fraction of solute versus the dielectric constant of the solvent or solvent system
 Relationships of this type (direct relationship) were demonstrated for
 A nonpolar liquid in a series of polar polyethylene glycols
 A nonpolar liquid in a series of semipolar polypropylene glycols
 A nonpolar liquids in blends of polar and semipolar solvents
 A polar liquids in blends of nonpolar and semipolar solvents
 A solid organic solute in blends of polar solvents
 Molecular connectivity is a method of bond counting from which topological indexes can
be derived from two dimensional chemical structures
 In order to express its influence on solubility of liquid hydrocarbons, alcohols,
ethers and esters in water, Kier and Hall used a structural index χ (chi), which
takes on values that depends on the structural features and functional groups of a
particular molecule
 Different order chi terms are used to describe a molecule. 1χ (First order) is
obtained by summing the bonds weighted by the reciprocal square root number of
each bond
 For alkanes at 250C, the relation between 1χ and solubility is given by
lnS = -1.505 – 2.5331χ
 Dissolving occurs at the surface of the solute, so, there is a direct correlation between
solute surface area and its solubility. As the surface area of the solute increases, the
solubility is increased because there will an increased contact between the solute and the
solvent
 The correlation for some compounds can be given by
Log (solubility) = 0.0168 (TSA) + 4.44 where TSA – Total surface area

32
  Total surface area can be divided into hydrocarbon surface area (HYSA) and functional
group surface area (FGSA) contribution. Based on these groups, the solubility of
hydrocarbons and alcohols in water at 250C is given by
ln (solubility) = -0.0430 (HYSA) – 0.0586 (FGSA) + 8.3003I + 4.420
Where FGSA is the surface area for the hydroxyl group
I – indicator variable (I = 1 if the compound is an alcohol and 0 if the
compound is hydrocarbon)

Solubility of solids in liquids

 Systems of solids in liquids include the most frequently encountered and probably the
most important type of pharmaceutical solutions.
 In ideal solution, the heat of solution is equal to the heat of fusion
 Ideal solubility is not affected by the nature of the solvent
 The molecules of an ideal solution exhibit complete freedom of motion and
randomness of distribution in the solution
 Ideal solutions are formed with no change in heat content
 For such solutions, solubility can be predicted from heat of fusion. The ideal solubility
solutes for an ideal solution of a solid in a liquid is
- log x2i = ∆Hf To-T
2.303R ToT
 Where x2i is the ideal solubility of the solute expressed in mole fraction
To - is the melting point of the solid solute in absolute degrees
T- is the absolute temperature of the solution
The superscript i in the symbol x2i refer to an ideal solution
The subscript 2 designates the mole fraction as that of the solute
∆Hf – is the molar heat of fusion of the solid state in cal/mole
R- is the gas constant (1.987cal/deg.mol)
 The formula can also be written as
log x2i = - ∆Hf × 1 + Constant
2.303R T
 The molar heat of fusion of various drugs can be obtained from their solubility in ideal
solution using this equation

33
  Plotting logarithm of solubility expressed in mole fraction, against the reciprocal
of the absolute temperature results in a straight line with a slope -∆Hf/2.303R for
an ideal solution
 In ideal solution, the solubility of the solute depends only on temperature, melting point
and heat of fusion
 The equation does not apply when T >To and at temperatures considerably lower than the
melting point
 At temperatures above the melting point, the solute is in the liquid state, and in an
ideal solution, the liquid solute is miscible in all proportions with the solvent
 At temperature well below melting point, the molar heat of fusion of the solid
state can no longer be used
 There are solid—liquid mixtures in which the two components are completely miscible in
the liquid state and completely immiscible as solids
 Examples of such systems are salol—thymol, salol—camphor and acetaminophen
—propyphenazone
 The phase diagram for such system can be constructed with the help of the ideal
solubility equation and conversely, if the points along the two lines of the phase diagram
are obtained experimentally, they can be used together with the ideal solubility equation
to calculate the heat of fusion
 The phase diagram for the salol—thymol system contains four regions:
I. A single liquid phase (region i)
II. A region containing solid salol and a conjugate liquid phase(region ii)
III. A region in which solid thymol is in equilibrium with a conjugate liquid
phase(region iii)
IV. A region in which both components are present as pure solid phases (region iv)

34
 Fig.15. Phase diagram of Tymol-Salol system
 Suppose we prepare a system containing 60% by weight of thymol in salol and raise the
temperature of the mixture to 50’C. Such a system is represented by point x. On cooling
the system, we observe the following sequence of phase changes.
 The system remains as a single liquid until the temperature falls to 29 C, at which
point a minute amount of solid thymol separates out to form a two-phase solid—
liquid system
 At 250C, system x (denoted as x1) is composed of a liquid phase, a1 (composition
53% thymol in salol), and pure solid thymol, b1, the weight ratio of the liquid
phase to pure solid thymol is
a1/b1 = (100 — 60)/(60 — 53) = 40/7 = 5.71:1
 Below 130C, the liquid phase disappears altogether and the system contains two solid
phases of pure salol and pure thymol.
 This point on the phase diagram is known as the eutectic point. At the eutectic
point, three phases (liquid, solid salol. and solid thymol) coexist

35
  The eutectic point is the point at which the liquid and solid phases have the same
composition (the eutectic position)
 Eutectic composition is the composition of two or more compounds that exhibits a
melting temperature lower than that of any other mixture of the compounds
 Examples of other substances that form eutectic mixture include:- camphor,
aspirin, chloral hydrate, menthol, betanaphthol, phenol, phenyl salicylate

Non-ideal solution

 This kind of solutions occurs when heat of solutions has positive value. Non ideal
solution is due to various attractive forces involved between solute, solvent and solute-
solvent molecules
 In this case, the activity of the solute must be considered
 The activity of a solute in a solution is expressed as the concentration multiplied by the
activity coefficient
a2 = X2γ2 Where γ2 - activity coefficient

Log a2 = log X2 + log γ2

 The activity coefficient depends on the nature of the solute, the solvent and the
temperature of the solution
 In ideal solution, a2 = X2 because γ2 is 1
 The mole fraction solubility of a solute in a non-ideal solution is given by
- log x2 = ∆Hf To-T + log γ2
2.303R ToT
 It usually provide poor predictions of solubility of drugs and other crystalline solids in
polar solvent
 Polar system are quite irregular involving self association of solute or solvent,
solvation of the solute by the solvent molecules or complexation of two or more
solute species in the solution
 The mole fraction solubility in various solvent in non-ideal solution is expressed as the
sum of the solubility in ideal solution and the logarithm of the activity coefficient of the
solute

36
 - log x2 = - log x2i + log γ2 where the superscript i is for ideal
 The activity coefficient can be expressed by
Log γ2 = (w22 + w11 – 2w12) × V2Φ12
2.303RT
 Where V2- is the molar volume or volume per mole of (supercooled) liquid solute
Φ1- is the volume fraction of the solvent (X1V1/ X1V1 + X2V2)
R- is the gas constant
T- is the absolute temperature of the solution
w22- is a net work for liberating a solute from a solute-solute interaction
w11- is work for creating a hole in the solvent molecules
w12- is the work needed to place the solute in the hole in the solvent
Subscript- 11 for solute-solute, 22- for solvent-solvent and 12 for solute-solvent
 w12 can be expressed as (w11× w22)1/2. When this is substituted in the formula
Log γ2 = (w22– 2(w11× w22)1/2 + w11) × V2Φ12
2.303RT
 The term in the bracket represent a perfect square, so
Log γ2 = [(w11)1/2 - (w22)1/2]2 × V2Φ12
2.303RT
 The (w)1/2 terms are known as solubility parameters and are designated by the symbols δ 1
and δ2 for solvent and solute respectively
Log γ2 = [δ1 - δ2]2 × V2Φ12
2.303RT
 Solubility parameter expresses the cohesion between like molecules and it is calculated
by
δ= ∆Hv - RT 1/2 Where ∆Hv- is heat of vaporization

V1 V1- molar volume of the liquid compound at the

desired temperature
R- Gas constant and T- Absolute temperature

37
  The extended Hilderbrand solubility approach allows one to calculate the solubility of
polar and nonpolar solutes in solvents ranging from nonpolar hydrocarbons to highly
polar solvents. The equation is
- log x2 = - log x2i + A (δ12 + δ22- 2W)
Where A stands for V2Φ12/2.303RT and W is used for w12

Solvation and association in solutions of polar compounds

 When the interaction between the solute and the solvent is higher than the interaction
between similar molecules (solute-solute and solvent-solvent), the solution will show a
negative deviation from Raoult’s law
 This applies when there is a specific interactions, such as hydrogen bonding
between the solute and the solvent
 Such specific combinations of the solvent with the solute are known as solvation
 When the interaction occurs between like molecules on one of the components in a
solution, the phenomena is referred to as association
 This type of interaction is exemplified by the dimerization of benzoic acid in
some nonpolar solvents or the interlinking of water molecules by hydrogen
bonding when mixed with a nonpolar solute
 Association leads to positive deviation from Raoult’s law

Solubility and the Heat of solution

 Solubility as a function of temperature for nonelectrolytes, weak electrolytes or strong
electrolytes in highly non-ideal solution can be calculated using the heat of solution,
∆Hsoln, instead of the heat of fusion
ln c’’ = ∆Hsoln (T’’ – T’)
c’ R (T’’T’)
Where c’’ - is the concentration and it corresponds to Kelvin temperature (T’’)
c’- is the concentration and it corresponds to Kelvin temperature (T’)
∆Hsoln- is the heat of solution in cal/mol
R- is the gas constant (1.987cal/mol.deg)- for strong electrolyte, R is replace by
vR, where v is the number of the ions produced in the dissociation

38
  By this equation, the solubility of a solute in a particular solvent at one temperature can
be determined if the heat of solution and the solubility at another temperature are known

Solubility of Strong Electrolytes

 A rise in temperature increases the solubility of a solid that absorbs heat when it dissolves
(Endothermic process)
 Most of the solids belong to this class
 A rise in temperature decreases the solubility of a solid that evolve heat when it dissolves
(Exothermic process)

Fig.16. The influence of temperature on the solubility of various salts

 Sodium sulfate exists in the hydrated form, NaSO 4. 10H20, up to a temperature of about
320C
 Until this point the dissolution is endothermic and the solubility increases with an
increase in temperature
 However above this temperature, the compound exists as the anhydrous salt,
NaSO4, and the dissolution is exothermic and the solubility decreases with an
increase in temperature
 Sodium chloride does not absorb or evolve an appreciable amount of heat when it
dissolves in water (slightly endothermic)
 Its solubility is not altered much by a change in temperature
 These correlation between temperature and solubility can be explained in terms of the
heat of solution, ∆H or the partial or differential heat of solution

39
  It is the heat absorbed per mole when a small quantity of solute is added to a large
quantity of solution or it is the rate of change of the heat of a solution per mole of
solute in a solution of any specified concentration
 The total or integral heat of solution is the heat absorbed when 1 mole of solute
is dissolved in enough solvent to produce a solution of specified concentration
 The heat of solution of a crystalline substance is the sum of the heat of sublimation of the
solid, as given by crystal lattice energy, and the heat of hydration or solvation of the ions
in solution
∆H (solution) = ∆Hsubl + ∆Hhyd
 The lattice energy is the energy required to separate 1 mole of a crystal into its ions in the
gaseous state or to vaporize the solid
NaClsolid → Na+gas + Cl-gas
 The heat of hydration is the heat liberated when the gaseous ions are hydrated
 It is influence by the radius of an ion
o For ions of the same valence, the smaller the ionic radius, the greater is the
electrostatic field surrounding the ion and the larger is the heat of
hydration
H20
+ -
Na gas + Cl gas Na+aq + Cl-aq

 If the heat of hydration is sufficient to provide the energy needed to overcome the lattice
forces and thus pull the ions away from the crystal, the salt will be soluble
 In ideal solution, no hydration occurs and the heat absorbed is only that required
to transform the crystals to the liquid state
 For this reason, only ∆Hf is included in the ideal solubility expression
 A positive value of ∆H indicates an absorption of heat and a negative value indicates
evolution of heat
 For solid systems, we follow a condensed system where the pressure is ignored and the
pressure is fixed to 1atm and the phase rule becomes
F= C - P + 1
 Example:- For subsaturated solution of sodium chloride in water, F= 2 and for saturated
solution, F=1

40
Solubility of slightly soluble Electrolytes
 Their solubility when they are dissolved to form a saturated solution is expressed by a
special constant, known as the solubility constant, Ksp of the compound
 In such systems, the excess solid is in equilibrium with the ions in a saturated solution at
a specific temperature. E.g. Silver chloride
AgClsolid ⇆ Ag+ + Cl-
 The equilibrium expression can be written in terms of concentration instead of activity
because of the low ionic strength and the salt dissolves only with difficulty
K = [Ag+][ Cl-] , the concentration of the solid phase is constant
[AgClsolid]
Ksp = [Ag+][ Cl-]
 The equation if only approximate for sparingly soluble salts or in the presence of other
salts, when activities rather than concentrations should be used
 It does not hold for salts that are freely soluble
 For aluminum hydroxide
Al(OH)3solid ⇆ Al3+ +3OH-
Ksp = [Al3+][ OH-]3
 The addition of a common ion to the solution of a slightly soluble electrolyte reduces its
solubility. However if the common ion form a complex with the salt, the solubility is
enhanced
 E.g. The addition of sodium chloride increases the concentration of chloride ions
in silver chloride solution
o Ksp ˂ [Ag+][ Cl-] and some of the silver chloride precipitated from the
solution until the equilibrium is reestablished
 Adding salts having no ion in common to the solution of a slightly soluble electrolyte , at
moderate concentration, increases the solubility because they lower the activity
coefficient
 Expressing the solubility constant using activity
Ksp = aAg+ × aCl-
 Because activities can be replaced by the product of concentration and activity coefficient

41
 Ksp = [Ag+][ Cl-] γAg+ γCl- = [Ag+][ Cl-] γ±2
Ksp = [Ag+][ Cl-]
γ±2
Solubility = [Ag+] = [ Cl-] = Ksp1/2
γ±
 The precipitation of a slightly soluble salt in water can be prevented by adding a
substance that will tie up and reduce the concentration of one of the ions
 More of the salt will then pass from the undissolved to the dissolved state until the
solubility product constant is reached and the equilibrium is reestablished
o E.g. If the ferric ion in a solution of the slightly soluble base Fe(OH) 3 can
be combined by complex formation with sodium citrate, more iron ion will
pass into solution so as to keep Ksp constant

Solubility of Weak Electrolytes

 Many important drugs belong to the class of weak acids and bases. They react with strong
acids and bases and, within definite ranges of pH, exist as ions that are ordinarily soluble
in water
 The solubility of weak electrolytes is influenced by the pH of the solution
 Carboxylic acids containing more than five carbons are relatively insoluble in water but
they react with dilute sodium hydroxide, carbonates, and bicarbonates to form soluble
salts
 The fatty acids containing more than 10 carbon atoms form soluble soaps with the alkali
metals and insoluble soaps with other metal ions
 They are soluble in solvents having low dielectric constants
o Oleic acid (C17H33C00H) is insoluble in water but is soluble in alcohol and
in ether
 Hydroxy acids, such as tartaric and citric acids, are quite soluble in water because they
are solvated through their hydroxyl groups.
 Most alkali metal salts of tartaric acid are soluble
o Potassium and ammonium bitartarates are not very soluble in water
 Sodium citrate is used sometimes to dissolve water-insoluble acetylsalicylic acid
because the soluble acetylsalicylate ion is formed in the reaction

42
 o The citric acid that is produced is also soluble in water
 Aromatic acids react with dilute alkalies to form water- soluble salts, but they can be
precipitated as the free acids if stronger acidic substances are added to the solution
 They can also be precipitated as heavy metal salts should heavy metal ions be
added to the solution
 Benzoic acid is soluble in sodium hydroxide solution, alcohol and fixed oils.
 Salicylic acid is soluble in alkalies and in alcohol
o The OH group of salicylic acid cannot contribute to the solubility because
it is involved in an intramolecular hydrogen bond
 Phenol is weakly acidic and only slightly soluble in water but is quite soluble in dilute
sodium hydroxide solution
C6H5OH + NaOH → C6H5O- + Na+ + H20
 Phenol is a weaker acid than H 2C03 and is thus displaced and precipitated by CO2
from its dilute alkali solution
 Many organic compounds containing a basic nitrogen atom in the molecule are important
in pharmacy. These include the alkaloids, sympathomimetic amines, antihistamines, local
anesthetics, and others.
 Most of these weak electrolytes are not very soluble in water but are soluble in
dilute solutions of acids
 E.g. Atropine sulfate and tetracaine hydrochloride are formed by reacting the
basic compounds with acids
o Addition of an alkali to a solution of the salt of these compounds
precipitates the free base from solution if the solubility of the base in
water is low
 The aliphatic nitrogen (—NH—SO2—) of the sulfonamides is sufficiently negative so
that these drugs act as slightly soluble weak acids rather than as bases
 They form water-soluble salts in alkaline solution by the following mechanism
o The oxygens of the sulfonyl (—SO 2—) group withdraw electrons, and the
resulting electron deficiency of the sulfur atom results in the electrons of
the N:H bond being held more closely to the nitrogen atom. The hydrogen

43
 therefore is bound less firmly and, in alkaline solution, the soluble
sulfonamide anion is readily formed
 The sodium salts of the sulfonamides are precipitated from solution by the
addition of a strong acid or by a salt of a strong acid and a weak base such as
ephedrine hydrochloride.
 The barbiturates (OC—NH—CO), like the sulfonamides are weak acids because the
electronegative oxygen of each acidic carbonyl group tends to withdraw electrons and to
create a positive carbon atom
 The carbon in turn attracts electrons from the nitrogen group and causes the
hydrogen to be held less firmly. Thus, in sodium hydroxide solution, the hydrogen
is readily lost, and the molecule exists as a soluble anion of the weak acid
o Although the barbiturates are soluble in alkalies, they are precipitated as
the free acids when a stronger acid is added and the pH of the solution is
lowered

Calculating the solubility of weak electrolytes as influenced by pH

 To ensure a clear and homogenous solution and maximum therapeutic effectiveness, the
preparation should be adjusted to an optimum pH
 For substance having acidic nature, the equilibria in a saturated solution of this slightly
soluble weak electrolyte is given as
HAsolid ⇆ HAsol
HAsol + H20 ⇆ H30+ + A- Where HA- the free acid form
A--The soluble ionized form of the acid
 The concentration of the unionized form in the solution is essentially constant and the
electrolyte is weak and does not dissociate appreciably, the solubility of the acid in water
is
S0 = [HAsoln] where S0 is molar solubility of the free acid
 The equilibria for acid base reaction is given by
Ka = [H30+] [A-]
[HA]
[A-] = Ka [HA]
[H30+]

44
  The total solubility, S, of the acid consists of the undissociated acid, [HA], and that of
the conjugate base or ionized form, [A-]
S = [A-] + [HA]
 Substitution gives
S = S0 + Ka S0
[H30+]
S - S0 = K a × S0
[H30+]
log (S-S0) = log Ka + log S0 - log[H30+]
- log [H30+] = - log Ka + log (S-S0) - log S0
pHp = Pka + log S- S0
S0
Where pHp is the PH below which the drug separated from the solution as the undissociated
acid
 For bases the equation will be
pHp = Pkw - PKb + log S0
S-S0
 Where S- is the concentration of the drug initially added as a salt
S0- is the molar solubility of the free base in water
pHp- is the pH above which the drug begins to precipitate from solution as the free
base

The influence of solvents in the solubility of drugs

 Weak electrolytes can behave like strong electrolytes or like nonelectrolytes in solution
depending on the pH
 When the solution is of such a pH that the drug is entirely in the ionic form, it
behaves as a solution of a strong electrolyte
 However, when the pH is adjusted to a value at which un-ionized molecules are
produced in sufficient concentration to exceed the solubility of this form,
precipitation occurs
 Frequently, a solute is more soluble in a mixture of solvent than in one solvent alone.

45
  This phenomenon is known as cosolvency and the solvents that, in combination,
increase the solubility of the solute are called cosolvents
 Enhanced solubility is achieved in pharmaceutical formulations by using
cosolvents such as ethanol or propylene glycol, which are miscible with water and
which act as better solvents for the solute in question
 For example, the aqueous solubility of metronidazole is about 100 mg in 10mL,
however, the solubility of this drug can be increased exponentially by the
incorporation of one or more water-miscible cosolvents, so that a solution
containing 500 mg in 10mL can be obtained

Combined effect of pH and solvents

 The same equation used for calculating the solubility of weak electrolyte as influenced by
pH is used
pHp = Pka + log S- S0
S0
 The added cosolvent usually changes the Pka and the solubility of the drug

 Because of this, the pH below which the drug separates from the solution as the
undissociated form will also change

Influence of surfactants
 Weakly acidic and basic drugs can be brought into solution by the solubilizing action of
the surfactants
 In the presence of surfactant, the total solubility, DT, of an acidic drug is expressed as the
sum of the concentration of species in solution
DT = (D) + (D-) + [D] + [D-]
Where (D) and (D -) are non-ionized acid and ionized acid, respectively, not in the
micelles
[D] and [D-] are non-ionized and ionized acid, respectively, present in the micelles
 The drug is considered to partition between the aqueous solution and the surfactant
micelles according to the expression
K’ = [D]0 for the non-ionized acid
(D)0

46
 K’’= [D-]0 for the ionized acid
(D-)0
 The subscript zero represents concentration expressed relative to individual phase
volumes rather than the total volume of the system. In terms of the total volume, it will
become
K’ = [D][1-(M)]
(D)(M)
K’’= [D-][1-(M)]
(D-)(M)
 (M) is the volume fraction of surfactant as micelles in solution: the amount in true
solution would be small and can be neglected
 Because it is small, 1-(M) = 1
[D] = K’(D)(M)
[D-] = K’’(D-)(M)
 The total solubility, DT*, in a solution at definite pH and in the absence of the
surfactant(DT* = S) is defined as
DT* = (D) + (D-) and
 The fraction (D)/ DT*, of un-ionized drug in the aqueous phase is
(D) = (H+)
DT* Ka + (H+)
DT* = (D)× Ka + (H+)
(H+)
DT = 1+ (M) (H+) K’ + Ka K’’
DT* Ka +(H+)
Where DT is total drug solubility in the presence of surfactant
 By using this equation, it is possible to calculated total drug solubility in a
solution of a definite pH and having a volume fraction (M) of surfactant present in
the form of micells
 The expression for the calculation of the solubilization of a weakly basic drug in aqueous
solution of a micellar solubilizing agent is given by
DT = 1+ (M) (H+) K’’ + Ka K’

47
 DT* Ka + (H+)
 The total solubility of a basic drug corresponding to that for an acidic drug, in a solution
containing a micellar surfactant is
DT = (D) + (D+) + [D] + [D+]
Where (D) is the non-ionizable free base not in the micelle, (D+) is the cationic acid,
conjugate to the molecular base, not in the micelle

Influence of Complexation in Multicomponent systems

 Many liquid pharmaceutical preparations consist of more than a single drug in a solution.
 When several drugs together with pharmaceutical adjuncts interact in solution to form
insoluble complexes, simple solubility profiles of individual drugs cannot be used to
predict solubility in mixtures of ingredients
 The specific multicomponent systems must be studied to estimate the
complicating effects of species interactions
 In some cases, it may be possible to interact a poorly soluble drug with a soluble material
to form a soluble intermolecular complex. Complexation is sometimes used to increase
drug solubility, particularly of poorly water-soluble drugs
 One class of complexing agents that is increasingly being employed is the
cyclodextrin family
o Cyclodextrins are enzymatically modified starches

Influence of other factors on the solubility of solids

 The size and shape of small particles (those in the micrometer range) also affect
solubility.
 Solubility increases with decreasing particle size according to the approximate
equation
log s = 2Vγ
s0 2.303RTr
Where s- is the solubility of the fine particles;
s0- is the solubility of the solid consisting of relatively large particles
γ- is the surface tension of the particles (for solids-extremely difficult to
obtain)

48
 V-is the molar volume (volume in cm3 per mole of particles)
r-is the final radius of the particles in cm
R-is the gas constant (8.314 x 107 ergs/deg mole)
T-is the absolute temperature.
 The equation can be used for solid or liquid particles such as those in suspensions or
emulsions
 The increase in solubility with decrease in particle size ceases when the particles have a
very small radius, and any further decrease in size causes a decrease in solubility
 This change arises from the presence of an electrical charge on the particles and
that the effect of this charge becomes more important as the size of the particles
decreases
 The configuration of a molecule and the type of arrangement in the crystal also has some
influence on solubility and a symmetric particle can be less soluble than an unsymmetric
one.
 This is because solubility depends in part on the work required to separate the
particles of the crystalline solute
 If the molecules form a compact crystal with high lattice energy, they will have
low solubility
 If the molecules pack less efficiently in the crystal partly because of the projecting
side chains, and the crystal energy is reduced, the solubility will be high
 The addition of a non-electrolytes also affects the solubility of electrolytes
 The solubility of electrolytes depends on the dissociation of dissolved molecules
into ions. The ease of this dissociation is affected by the dielectric constant of the
solvent
 If a water-soluble non-electrolyte such as alcohol is added to an aqueous solution
of a sparingly soluble electrolyte, the solubility of the latter is decreased because
the alcohol lowers the dielectric constant of the solvent and ionic dissociation of
the electrolyte becomes more difficult
 The effect of adding electrolytes on the solubility of non-electrolytes
 Non-electrolytes do not dissociate into ions in aqueous solution, and in dilute
solution the dissolved species therefore consists of single molecules. Their

49
 solubility in water depends on the formation of weak intermolecular bonds
(hydrogen bonds) between their molecules and those of water
 The presence of a very soluble electrolyte, the ions of which have a marked
affinity for water, will reduce the solubility of a non-electrolyte by competing for
the aqueous solvent and breaking the intermolecular bonds between the non-
electrolyte and the water

Rules of solubility
For Inorganic molecules
a. If both the cation and anion of an ionic compound are monovalent, the solute–solute
attractive forces are usually easily overcome, and, therefore, these compounds are
generally water soluble (e.g., NaCl, LiBr, KI, NH4NO3, and NaNO2)
b. If only one of the two ions in an ionic compound is monovalent, the solute–solute
interactions are also usually easily overcome and the compounds are water soluble (e.g.,
BaCl2, MgI2, Na2SO4, and Na3PO4)
c. If both the cation and anion are multivalent, the solute–solute interaction may be too
great to be overcome by the solute–solvent interaction, and the compound may have poor
water solubility (e.g., CaSO4, BaSO4, and BiPO4; exceptions: ZnSO4, FeSO4)
d. Common salts of alkali metals (e.g., Na, K, Li, Cs, and Rb) are usually water soluble
(exception: Li2CO3)
e. Ammonium and quaternary ammonium salts are water soluble
f. Nitrates, nitrites, acetates, chlorates, and lactates are generally water soluble (exceptions:
silver and mercurous acetate)
g. Sulfates, sulfites, and thiosulfates are generally water soluble (exceptions: calcium and
barium salts)
h. Chlorides, bromides, and iodides are water soluble (exceptions: salts of silver and
mercurous ions)
i. Acid salts corresponding to an insoluble salt will be more water soluble than the original
salt
j. Hydroxides and oxides of compounds other than alkali metal cations and the ammonium
ion are generally water insoluble
k. Sulfides are water insoluble except for their alkali metal salts

50
 l. Phosphates, carbonates, silicates, borates, and hypochlorites are water insoluble except
for their alkali metal salts and ammonium salts

For Organic molecules

i. Molecules having one polar functional group are usually soluble to total chain lengths of
five carbons
ii. Molecules having branched chains are more soluble than the corresponding straight-chain
compound
iii. Water solubility decreases with an increase in molecular weight
iv. Increased structural similarity between solute and solvent is accompanied by increased
solubility

Solution dosage forms

 In pharmaceutical terms, solutions are liquid preparations that contain one or more
chemical substances dissolved in a suitable solvent or mixture of mutually miscible
solvents
 Solutions may be prepared from any combination of solid, liquid, and gas, the three states
of matter
 The most common type of solution contain either solid or liquid as a solute and
liquid as a solvent
 Because of a particular pharmaceutical solution’s use, it may be classified as oral, otic,
ophthalmic, or topical
 Still other solutions, because of their composition or use, may be classified as other
dosage forms
 Syrups- aqueous solutions containing a sugar sweetened
 Elixirs- hydroalcoholic solutions
 Spirits- solutions of aromatic materials containing alcohol as solvent
 Aromatic waters - solutions of aromatic materials containing water as solvent
 Tinctures- solutions prepared by extracting active constituents from crude drugs
 Injections- solutions prepared to be sterile and pyrogen free and intended for
parenteral administration

51
Preparation of solutions
 Most pharmaceutical solutions are unsaturated with solute. Thus, the amounts of solute to
be dissolved are usually well below the capacity of the volume of solvent employed
 The strength of pharmaceutical solutions are usually expressed in terms of percent
strength, although for very dilute preparations, expressions of ratio strength may be used
 The dissolution of a given substance can be enhanced several techniques, such as
applying heat, reducing the particle size of the solute, using a solubilizing agent, and/or
subjecting the ingredients to vigorous agitation
 Most solutions are prepared by simple mixing of the solutes with the solvent. On an
industrial scale, solutions are prepared in large mixing vessels with ports for mechanical
stirrers
 When heat is desired, thermostatically controlled mixing tanks may be used

Solutions taken orally

 Most solutions intended for oral administration contain flavorants and colorants to make
the medication more attractive and palatable.
 They may also contain stabilizers to maintain the chemical and physical stability
of the medicinal agents and preservatives to prevent the growth of
microorganisms in the solution
 Liquid pharmaceuticals for oral administration are usually formulated such that the
patient receives the usual dose of the medication in a conveniently administered volume,
as 5 (one teaspoonful), 10, or 15 mL (one tablespoonful)
 Liquid pharmaceuticals for oral administration include syrups, elixirs, drops, tinctures
and others
 These dosage forms can come in either in formulated solution form or dry powder for
reconstitution
 The dry powder mixture like the solutions contains all of the formulative
components, including drug, flavorant, colorant, buffers, and others, except for
the solvent
 Once reconstituted, the solution remains stable when stored in the refrigerator for
the labeled period, usually 7 to 14 days, depending on the preparation

52
Syrups
 Syrups are concentrated aqueous preparations of a sugar or sugar substitute with or
without flavoring agents and medicinal substances
 Syrups containing flavoring agents but not medicinal substances are called
nonmedicated or flavored vehicles (syrups)
o Serve as pleasant tasting vehicles for medicinal substances
 Syrups provide a pleasant means of administering a liquid form of a disagreeable-tasting
drug
 They are particularly effective in the administration of drugs to children
 Most syrups contain the following components in addition to the purified water and any
medicinal agents present
 Sugar, usually sucrose, or sugar substitute used to provide sweetness and viscosity
o Usually 60-80% (make it also more resistant to microorganism)
 Antimicrobial preservatives
 Flavorants
 Colorants
 Solubilizing agents, thickeners, or stabilizers
 Syrups can be preserved by
 Storage at low temperature
 Adding preservatives such as glycerin, benzoic acid, sodium benzoate, methyl
paraben, or alcohol in the formulation
 The maintenance of a high concentration of sucrose as a part of the formulation
 The solubility of sucrose in water is 1g for 0.5ml of water. However, 46.3 g or ml of
purified water is used to dissolve 85 g of sucrose
 Only a very slight excess of water (about 3.8mL per 100mL of syrup) is employed
in the preparation of syrup
o This excess water makes the syrup more resistant to crystallization and
hence makes it more resistant to microbial growth
 Frequently, small amount of alcohol is used to enhance the solubility of the drug or the
inactive ingredients

53
Preparation of syrups
 Syrups are most frequently prepared by one of four general methods, depending on the
physical and chemical characteristics of the ingredients
 Solution of the ingredients with the aid of heat
o It is used when it is desired to prepare the syrup as quickly as possible and
when the syrup’s components are not damaged or volatilized by heat
o In this method, the sugar is generally added to the purified water, and heat
is applied until the sugar is dissolved. Then, other heat-stable components
are added to the hot syrup, the mixture is allowed to cool, and its volume
is adjusted to the proper level by the addition of purified water
 If heat-labile agents or volatile substances are to be added, they are
generally added to the syrup after the sugar is dissolved by heat,
and the solution is rapidly cooled to room temperature
o Using of heat hydrolyzes sucrose into monosaccharides, dextrose
(glucose), and fructose (levulose)
 When heat is applied in the preparation of sucrose syrup, such
inversion of the sucrose is almost certain and the speed of
inversion is greatly increased by the presence of acids
 Should inversion occur, the sweetness of the syrup is altered
because invert sugar is sweeter than sucrose, and the normally
colorless syrup darkens because of the effect of heat on the
levulose portion of the invert sugar
 When the syrup is greatly overheated, it becomes amber
colored as the sucrose caramelizes
 Syrups so decomposed are more susceptible to
fermentation and to microbial growth than the stable,
undecomposed syrups
 Solution of the ingredients by agitation without the use of heat, or the simple
admixture of liquid components
o It is used to avoid heat-induced inversion of sucrose

54
 o On a small scale, sucrose and other formulative agents may be dissolved
in purified water by placing the ingredients in a vessel larger than the
volume of syrup to be prepared, permitting thorough agitation of the
mixture
 This process is more time consuming than the use of heat, but the
product has maximum stability.
o On large scale, huge glass lined or stainless steel tanks with mechanical
stirrers or agitators
o When solid agents are to be added to syrup, it is best to dissolve them in
minimal amount of purified water and incorporate the resulting solution
into the syrup
 If added directly, they dissolve slowly because the viscous nature
of the syrup does not permit the solid substance to distribute
readily throughout the syrup to the available solvent and also
because a limited amount of available water is present in
concentrated syrups
 Addition of sucrose to a prepared medicated liquid or to a flavored liquid
o Occasionally a medicated liquid, such as a tincture or fluidextract, is
employed as the source of medication in the preparation of a syrup
o If the alcohol-soluble components are desired medicinal agents, some
means of rendering them water soluble is employed
o However, if the alcohol-soluble components are undesirable or
unnecessary, they are generally removed by mixing the tincture or
fluidextract with water, allowing the mixture to stand until separation of
the water-insoluble agents is complete, and filtering them from the
mixture
 The filtrate is the medicated liquid to which the sucrose is added in
preparation of the syrup.
o If the tincture or fluidextract is miscible with aqueous preparations, it may
be added directly to simple syrup or to a flavored syrup
 Percolation of either the source of the medicating substance or the sucrose

55
 o In the percolation method, either sucrose may be percolated to prepare the
syrup or the source of the medicinal component may be percolated to form
an extractive to which sucrose or syrup may be added
 Sometimes a syrup is prepared by more than one of these methods, and the selection may
simply be a matter of preference on the part of the pharmacist

Elixirs
 Elixirs are clear, sweetened hydroalcoholic solutions intended for oral use and are usually
flavored to enhance their palatability
 Nonmedicated elixirs are employed as vehicles, and medicated elixirs are used for the
therapeutic effect of the medicinal substances they contain
 Compared with syrups, elixirs are usually less sweet and less viscous because they
contain a lower proportion of sugar and consequently are less effective than syrups in
masking the taste of medicinal substances
 However, because of their hydroalcoholic character, elixirs are better able than
aqueous syrups to maintain both water soluble and alcohol-soluble components in
solution
 They are preferred to syrups because of their stable characteristics and the ease
with which they are prepared (by simple solution), from a manufacturing
standpoint
 The proportion of alcohol in elixirs varies widely because the individual components of
the elixirs have different water and alcohol solubility characteristics
 Elixirs containing more than 10% to 12% of alcohol are usually self-preserving and do
not require the addition of an antimicrobial agent.
 Because of their usual content of volatile oils and alcohol, elixirs should be stored in
tight, light-resistant containers and protected from excessive heat

Preparation of Elixirs
 Elixirs are usually prepared by simple solution with agitation and/or by admixture of two
or more liquid ingredients

56
  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, rather than the reverse
 This is done to maintain the highest possible alcoholic strength at all times so that
minimal separation of the alcohol-soluble components occurs
 The presence of glycerin, syrup, sorbitol, and propylene glycol in elixirs generally
contributes to the solvent effect of the hydroalcoholic vehicle, assists in the dissolution of
the solute, and enhances the stability of the preparation
 However, these materials adds to the viscosity of the elixir and slows the rate of
filtration
 Nonmedicated elixirs can be used as pleasant-tasting vehicle and for dilution of an
existing medicated elixir
 Most official and commercial elixirs contain a single therapeutic agent. The main
advantage of is that the dosage of that single drug may be increased or decreased by
simply taking more or less of the elixir
 However, if more therapeutic agents are present, it is impossible to increase or
decrease the dose of one without an automatic and corresponding adjustment in
the dose of the other

Tinctures
 Tinctures are alcoholic or hydroalcoholic solutions prepared from vegetable materials or
from chemical substances
 Depending on the preparation, tinctures contain alcohol in amounts ranging from
approximately 15% to 80%.
 The alcohol content protects against microbial growth and keeps the alcohol-
soluble extractives in solution.
 Tinctures cannot be mixed successfully with liquids too diverse in solvent character
because the solute may precipitate.
 Because of the alcoholic content, tinctures must be tightly stoppered and not exposed to
excessive temperatures

57
  Also, because many of the constituents found in tinctures undergo a
photochemical change upon exposure to light, many tinctures must be stored in
light-resistant containers and protected from sunlight

Spirits
 Spirits are alcoholic or hydroalcoholic solutions of volatile substances.
 Generally, the alcoholic concentration of spirits is rather high, usually over 60%
 Because of the greater solubility of aromatic or volatile substances in alcohol than in
water, spirits can contain a greater concentration of these materials than the
corresponding aromatic waters.
 When mixed with water or with an aqueous preparation, the volatile substances
present in spirits generally separate from the solution and form a milky
preparation.
 Spirits may be used pharmaceutically as flavoring agents and medicinally for the
therapeutic value of the aromatic solute
 When taken orally, they are generally mixed with a portion of water to reduce the
pungency of the spirit
 Depending on the materials, spirits may be prepared by simple solution, solution by
maceration or distillation

Topical solutions
 Solution used topically include colloidons, lotions, sprays, tinctures, liniments
 Generally, the topical solutions employ an aqueous vehicle, whereas the topical tinctures
characteristically employ an alcoholic vehicle.
 As required, cosolvents or adjuncts to enhance stability or the solubility of the
solute are employed
 Most topical solutions and tinctures are prepared by simple dissolving. However, certain
solutions are prepared by chemical reaction
 Because of the nature of the active constituents or the solvents, many topical solutions
and tinctures are self-preserved. Those that are not may contain suitable preservatives

58
  Topical solution used in small volume, such as the anti-infectives, are usually packaged
in glass or plastic bottles with an applicator tip as a part of the cap assembly or in plastic
squeeze bottles that deliver the medication in drops
 In contrast to aqueous solutions, when the alcoholic tinctures are applied to
abraded or broken skin, they sting
Sprays
 Sprays may be defined as aqueous or oleaginous solutions in the form of coarse droplets
or as finely divided solids to be applied topically, most usually to the nasopharyngeal
tract or to the skin
 Many commercial sprays are used intranasally to relieve nasal congestion and
inflammation and to combat infection
o Throat sprays- to relieve conditions such as halitosis, sore throat, and
laryngitis
 Externally on the skin-To treat fungal infections like athlete’s foot, sun burn
 To break up a solution into small particles so that it may be effectively sprayed or to
facilitate the spraying of a powder, several mechanical devices are commonly employed
 The plastic spray bottle, gently squeezed to issue a spray of its contents, is
familiar
 Medicinal atomizers, which emit medication in the form of fine droplets are also
used
Liniments
 Liniments are alcoholic or oleaginous solutions or emulsions of various medicinal
substances intended to be rubbed on the skin
 Liniments with an alcoholic or hydroalcoholic vehicle are useful when rubefacient,
counterirritant, or penetrating action is desired and oleaginous liniments are employed
primarily when massage is desired
 Oleaginous liniments are less irritating to the skin than alcoholic liniments.
 Liniments are not applied to skin areas that are broken or bruised because excessive
irritation might result
 The vehicle for a liniment is selected based on

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  The type of action desired (rubefacient, counterirritant, or massage)
 On the solubility of the desired components in the various solvents
 Liniments that are emulsions or that contain insoluble matter must be shaken thoroughly
before use to ensure even distribution of the dispersed phase, and these preparations
should be labeled shake well.
 Liniments should be stored in tight containers
Collodions
 Collodions are liquid preparations composed of pyroxylin dissolved in a solvent mixture
usually composed of alcohol and ether with or without added medicinal substances.
 One part of pyroxylin is slowly but completely soluble in 25 parts of a mixture of 3
volumes of ether and 1 volume of alcohol. It is also soluble in acetone and glacial acetic
acid.
 Pyroxylin is precipitated from solution in these solvents upon the addition of
water.
 Pyroxylin, like collodions, is exceedingly flammable and must be stored away from flame
in well-closed containers, protected from light at a temperature not exceeding 30 0C
 Collodions are intended for external use. When applied to the skin with a fine camel’s
hair brush or glass applicator, the solvent rapidly evaporates, leaving a filmy residue of
pyroxylin
 This provides an occlusive protective coating to the skin, and when the collodion
is medicated, it leaves a thin layer of that medication firmly placed against the
skin
o The film is useful in holding the edges of an incised wound together
 Naturally, collodions must be applied to dry tissues to adhere to the skin’s surface
 In order to make colloidons suitable for use in areas of the body subjected to movement
like the joints, camphor (it also makes it waterproof) and castor oil are added to make
them more flexible

Solutions instilled into body cavities

 Solutions instilled Into the body cavities include douches, enemas, ear drops, nasal sprays
Vaginal Douches

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  Douche is an aqueous solution, which is directed against a part or into a cavity of the
body
 Powders are used to prepare solutions for vaginal douche, i.e., for irrigation cleansing of
the vagina (for hygienic purpose)
 They may also contain anti-infective agents
 The powders themselves may be prepared and packaged in bulk or as unit packages
 These powders are added to the appropriate volume of warm water and stirred
until dissolved prior to use
Enemas
 They are aqueous, liquid, oily solutions or suspensions for rectal route administration
 They are used to evacuate and cleanse the bowel (evacuation enemas) or influence
the general system by absorption (retention enemas)

Solutions in mouth and throat

 Solution of this type include gargles, mouthwashes, throat sprays
 Gargles are aqueous solutions frequently containing antiseptics, antibiotics and/or
anesthetics used for treating the pharynx (throat) and nasopharynx by forcing air from the
lungs through the gargle, which is held in the throat; subsequently, the gargle is
expectorated.
 Many gargles must be diluted with water prior to use
 Mouthwashes can be used for therapeutic & cosmetic purposes
 Therapeutic mouthwashes can be formulated to reduce plaque, gingivitis, dental
caries and stomatitis
 Cosmetic mouthwashes may be formulated to reduce bad breath through the use
of antimicrobial and/or flavoring agents


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