Transcript Solutions and solubility

“Solubility of a substance may be defined as the
amount of solute dissolved in 100gms of a solvent to
form a saturated solution at a given temperature”.
The Solution Formation Process
 Therefore, the energy of solution formation, the enthalpy of solution, equals
the sum of the three steps:
 ΔHsoln = ΔH1 + ΔH2 + ΔH3.
 ΔH1 and ΔH2 are both positive because it requires energy to pull molecules
away from each other. When the expanded form of the solvent and the solute
are combined to form a solution, energy is released, causing ΔH3 to be
negative. This makes sense because the solute and solvent can interact through
the various types of intermolecular forces.
 solutions will form only when the energy of interaction between the solvent and
solute is greater than the sum of the solvent-solvent and solute-solute
interactions.
Factors Affecting solubility
Crystal
Characteristics
Molecular
structure of
Solute
Effect of
Temperature
on Solubility
Effect of Added
Substances on
Solubility:
Particle size of
Solid
The solubility of solutes is dependent on temperature.
CASE I: Decrease in solubility with
temperature:
CASE II: Increase in solubility with
temperature:


If the heat given off in the dissolving process is
greater than the heat required to break apart
the solid, the net dissolving reaction is
exothermic ΔH1negative value (energy given
off). The addition of more heat (increases
temperature) inhibits the dissolving reaction
since excess heat is already being produced by
the reaction.
If the heat given off in the dissolving reaction
is less than the heat required to break apart
the solid, the net dissolving reaction is
endothermic ΔH1positive value (energy
required). The addition of more heat
facilitates the dissolving reaction by providing
energy to break bonds in the solid. This is the
most common situation where an increase in
temperature produces an increase in solubility
for solids.
The solubility of solutes is dependent on
temperature.
 The solubility of a solute in a solvent is dependent on temperature, nature of
solute and nature of solvent.
 Heat of solution ΔH represents the heat released or absorbed when a mole of
solute is dissolved in a large quantity of solvent.
 Most of the substances are endothermic, absorbing heat in the process of
dissolution. For this substances, an increase in temperature results in an
increase in solubility.
 Exothermic substances give off heat in the process of dissolution. The solubility
of such substances would decrease with increase in temperature.
The solubility of solutes is dependent on
temperature.
 Why does solubility change with temperature? Consider a beaker that contains
a saturated solution of table sugar. The bottom of the beaker is covered with
sugar crystals. When a tiny amount of sugar dissolves, heat is absorbed. When
a tiny amount of sugar crystallizes out of solution, heat is released. We can
write:
 heat + solid sugar + water = dissolved sugar
 The equation represents two processes: dissolution going left to right, and
crystallization going right to left. When the sugar crystals are dissolving at
exactly the same rate that sugar is crystallizing out of solution, the system is at
equilibrium. The balance between dissolution and crystallization
can be changed by changing the temperature of the solution.
Adding heat will favor dissolution. Cooling the solution will
favor crystallization.
II Molecular structure of Solute:
Substituents
hydrophobic or
hydrophilic,
depending on their
Salts are usually more
soluble than their weak
acids or weak bases.
High degree of ionic
dissociation of the
compound when it
dissolves in water.
For simple molecules
solubility decreases with
increase of molecular
surface area.
The greater the number
of polar groups, the
greater is the solubility
in water; pyrogallol is
more soluble in water
than phenol.
In general, aqueous
solubility decreases with
increasing boiling point
and melting point.
Molecular structure of Solute:
 Substituents hydrophobic or hydrophilic, depending on their polarity:
 Polar groups such as –OH capable of hydrogen bonding with water
molecules impart high solubility.
 Non-polar groups such as –CH3 and –Cl are hydrophobic and impart low
solubility.
 Ionization of the substituent increases solubility, e.g. –COOH and –NH2
are slightly hydrophilic whereas –COO– and –NH3 are very hydrophilic.
III: Crystal Characteristics
 Crystal habit is description of outer appearance of crystal.
 Internal structure is molecular arrangement within the solid.
 Depending on internal structure compounds are classified as






1. Crystalline
2. Amorphous
Crystalline compounds are characterized by repetitious spacing of constituent
atom or molecule in three dimensional arrays.
In amorphous form atoms or molecules are randomly placed.
Solubility & dissolution rate are greater for amorphous form than crystalline, as
amorphous form has higher thermodynamic energy.
E.g. Amorphous form of Novobiocin is well absorbed where as crystalline form
results in poor absorption.
Polymorphism
 It is the ability of the compound to
crystallize as more than one distinct
crystalline species with different






internal lattice.
Different crystalline forms are called
polymorphs.
Polymorphs differ from each other
with respect to their physical
property such as
Solubility
Melting point
Density
Hardness
 Chloromphenicol exist
in A,B & C forms, of
these B form is more
stable & most
preferable.
 2)Riboflavin has I,II &
III forms, the III form
shows 20 times more
water solubility than
form I.
Polymorphism
 Various polymorphic forms of a drug have identical chemical structure but different
crystalline structures & they show different physical properties such as Melting
points, Solubility & Dissolution rates, as we know having the same chemical
structure doesn’t mean to have the same orientation in 3D shapes in nature.
 At a given temperature only one crystalline form of the different polymorphs will
show a highly stable organized & strongly bonded crystals form, this is referred as to
the stable form, while the other crystal forms exhibit poorly organized & weakly
bonded crystal forms which will be referred to the Metastable forms.
 So the metastable form of the polymorphic drug as it shows a poorly organized
crystal form, which means weakly bonded also, will have a low melting point & thus
a higher solubility & high dissolution rate (as less energy is required to break its
bonds), While the stable form exhibits high melting point & low solubility &
dissolution rate (as being highly organized & strong bonded so more energy is
needed to break its bonds), Accordingly, in order to have high dissolution rates &
hence high absorption rates, that’s why the metastable form of polymorphic drug
might be always required & recommended over the stable form from absorption
point of view.
Polymorphism
 EXAMPLE 1
 Chloramphenicol palmitate exists in polymorphs having a stable & metastable
forms, the metastable form of the drug if formulated as a suspension was
always found to have higher solubility, dissolution rate & absorption compared
to the stable form.
 EXAMPLE 2
 Methylprednisolone exist as a metastable & stable form & if the drug is
formulated as a suspension for subcutaneous injection containing the 2
crystalline forms, then that means a sustained release of the drug can be
obtained where the metastable form (being highly soluble compared to the
stable form) can provide a rapid initial dose (loading dose), while the stable
form (being slowly dissolved) will provide the prolonged or sustained action
dose called the maintenance dose.
AMORPHISM
 In addition to different polymorphic forms,
a drug may exist in an amorphous form,
which is a non-crystalline or poorly
crystallized form.
 Since amorphous form is usually more
soluble & rapidly dissolving (but having
shorter duration of action) than the
corresponding crystalline form so it will
exhibit a higher dissolution rate &
absorption rate.

 EXAMPLE 1
 The amorphous form of novobiocin




(antibiotic) when taken orally as a
suspension, found to possess high
absorption while crystalline form of the
same drug was found to be poorly
absorbed.
EXAMPLE 2
Similarly the amorphous form of
chloramphenicol stearate is found to be
highly bioavailable, while the crystalline
form is therapeutically ineffective.
EXAMPLE 3
A mixture of amorphous & crystalline
forms of insulin taken subcutaneously or by
IM route provide an initial rapid action
dose due to the fast dissolving amorphous
form followed by a prolonged action
because of the slowly dissolving crystalline
form.
SOLVATION & ASOLVATION
SOLVATION
 During the process of crystallization, the
drug crystals may incorporate (include) one
or more molecules of the solvent used into
their internal structures & the result is
referred to as solvates.
 The effect of solvate & asolvate form
(hydration is used if the solvent was water
& salvation if it was any other organic
solvent)(asolvate means drug molecule
crystals containing no solvent molecules
trapped between them) on the dissolution
rate or permeation rate is great hence
effecting directly the total bioavailability of
the drug which will varies (the
bioavailability) greatly between different
drug forms & crystals forms depending on
the type of the solvent trapped.
ASOLVATION
 When the solvent is water, the
anhydrated form (the asolvate)
generally shows high dissolution rate
than their corresponding hydrates
(solvates) & hence shows higher
bioavailability. This is because the
anhydrous forms of the drug reacts
more extensively with water
compared to the already hydrated
form which is considered to have a
level of water saturation already. Some
examples of the effect of hydrates &
unhydrates on the dissolution & hence
bioavailability of the drug is shown as
the following:
SOLVATION & ASOLVATION










EXAMPLE 1
The anhydrous forms of the following drugs exhibits higher dissolution rates compared to their
corresponding hydrated form such as caffeine, theophylline & glutethimide
EXAMPLE 2
The anhydrous form of ampicillin, when taken orally in a hard gelatin capsule formulation was found
to possess higher dissolution rates & higher absorption rates than ampicillin trihydrate, which is
obviously the hydrated form of ampicillin.
On the other hand, when organic solvates are used (other than water), the drug will exhibit higher
bioavailability when it is in the solvate form rather than the other asolvate form.This may be due to
the fact that organic solvates has higher lipophilicity (partition coefficient) due to their non-aqueous
or Lipophilic environment in general surrounding the drug molecule & hence will increase the rate of
permeation of the drug via the GIT leading to general enhanced absorption & bioavailability rate.
EXAMPLE 3
The ethanol & acetone solvates of hydrocortisone & prednisolone show higher absorption rates than
the non-solvated forms.
EXAMPLE 4
The chloroform solvates of griseofulvin (anti-fungal) is better absorbed than the same drug asolvate.
So in general we see that crystal formation & the trap of any solvent molecule between the drug
crystals will highly & directly affect the whole process of absorption & bioavailability in different
manners.
IV-
Particle size of Solid:-
 The Solubility of a substance increases with decreasing particle size.
 The particle size and surface area of a drug exposed to a medium can affect actual solubility as










indicated by equation:
Where
S is the solubility of the small particles,
S0 is the solubility of the large particles,
γ is the surface tension,
V is the molar volume,
R is the gas constant,
T is the absolute temperature, and
r is the radius of the small particles.
The equation can be used to estimate the decrease in particle size required to increase
solubility.The size of the solid particle influences the solubility because as particle becomes
smaller, the surface area to volume ratio increases the surface area, which allows a greater
interaction with the solvent.
This effect may be significant in the storage of pharmaceutical suspensions, as the smaller
particles in such a suspension will be more soluble than the large ones. As small particles
disappear, the overall solubility of the suspended particles will decrease and the large particles
will grow. The occurrence of crystal growth is of importance in the storage of parenteral
suspensions.
V-
Effect of Added Substances on Solubility:
 1.Effect of salts on the solubility of nonelectrolyte
 2. Effect of common ion
 3-Effect of semipolar solvents on the solubility of nonpolar solutes
 4-Effect of semipolar solvents on the solubility of sparingly soluble
electrolyte
 5-Effect of surface active agent
 6-Complex formation
 7- pH and solubility
1- Effect of salts on the solubility of nonelectrolyte
 . Most commonly, the solubility of the nonelectrolyte is decreased, the effect is referred to as"
salting - out", less commonly it is increased, and is described as "salting. - in".
 "Salting - out" occurs because the ions of the added electrolyte require water for their
hydration, thereby reducing the amount of water available for solution of the nonelectrolyte.
The greater the degree of hydration of the ions, the more the solubility of the nonelectrolyte is
decreased If, for example, one compares the effect of equivalent amount of lithium chloride,
sodium chloride, potassium chloride, rubidium chloride and cesium chloride (all of which
belong to the family of alkali metals and are of the same valence type), it is observed that,
lithium chloride decreases the solubility of a non-electrolyte to the greatest extent and
that, the salting out effect decreases in the order given. This is also the order of the degree of
hydration of the cations. Lithium ion, being the smallest ion and therefore having the
greatest density of positive charge per unit of surface area is the most extensively
hydrated of the cation. (Electro negativity value are Li = 1, Na = 0.9, K = 0.8, Rb = 0.8 and Cs
= 0.7)( Example of salting out (addition of electrolytes to aromatic water).
 "Salting in" commonly occurs when either the salts of various organic acid or organic substituted ammonium salts are added to aqueous solutions of nonelectrolyte. The solubility
increases as the concentration of added salt is increased. The phenomenon is known as
"hydrotropy"
& the salt is known as "hydrotropic salt".
2. Effect of common ion

The solubility of slightly soluble electrolyte is decreased by the addition of a second electrolyte that possesses a similar ion to the first. This is
known as the common ion effect.
 In a saturated solution in contact with undissolved solid, the equilibrium may be
represented as follows for a compound AB:
 AB(s)
AB
A+ + B  Undissolved
undissociated
ions
 Solid
molecules
 KSP = [A+] [B-]


Where KSP is a constant and known as the apparent solubility product of compound AB,
If ksp is exceeded by the product of the concentration of the ions, i.e. [A+][B-] then the equilibrium shown above, moves towards the left in
order to restore the equilibrium, and solid AB is precipitated. The product [A +] [B-] will be increased by the addition of more A+ ions
. AX  A+ + X Where A+ is the common ion. Solid AB will be precipitated and the solubility of this compound is therefore
produced by the dissociation of another compound, e.g




decreased. This is known as the common ion effect.
The addition of common B- ion would have the same effect.
Note that: The solubility product principle is valid for aqueous solutions of slightly soluble salts, provided the concentration of added salt is
not too great.
When the concentrations are high, deviations from the theory occur. Deviations may also occur as the result of the formation of complexes
between the two salts. A pharmaceutical example of increased solubility by virtue of complex-ion formation is seen in the effect of solutions
of soluble iodide on mercuric iodide. According to the solubility product principle it might be expected that, soluble iodides would decrease
the solubility of mercuric iodide, but because of the formation of the more soluble complex salt K 2 Hg l4 which dissociate as follow:
K2Hgl4
2 K+ + (Hgl4)-
 The iodide ions no longer function as a common ion.
3-Effect of semipolar solvents on the solubility of
nonpolar solutes
 To enhance the solubility of poorly soluble materials, the water miscible solvents are







used in which the drug has good solubility. This process of improving solubility is
known as co-solvency.Solvents used to increase the solubility is known as cosolvents.
The mechanism for solubility enhancement by co-solvency is not clearly
understood. But it is proposed that, solubility is increased may be by reducing the
interfacial tension between the solvent and hydrophobic solutes and
decreasing dielectric constant of solvent.
The commonly used and acceptable cosolvents in formulation of aqueous liquids
for oral solutions are Ethanol, Sorbitol, Glycerin, Several members of PEG series.
Some characteristics of cosolvent, which are used in preparation:
1. It must be non-toxic. Non-irritating.
2. It should be able to solubilize the drug in given solvent.
3. It should be able to cross the membrane.
Apart from increasing solubility, they are also used to improve the solubility of
volatile constituents used to impart a desirable flavor and odor to the product.
4-Effect of semipolar solvents on the solubility of
sparingly soluble electrolyte
 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, which is a measure of the polar nature of the solvent.
Liquid with a high dielectric constant (DEC=80) like water is able to reduce the
attractive forces that operate between oppositely charged ions produced by
dissociation of an electrolyte. To determine the dielectric constant of the
solute, dioxane-water blend having known dielectric constants are used and the
dielectric constant at which maximum solubility is attained is noted.
 If alcohol is added to an aqueous solution of a sparingly soluble electrolyte,
the solubility of the latter is decreased because the alcohol (DEC=25) lowers
the dielectric constant of the solvents & ionic dissociation of the electrolyte
becomes more difficult. The DEC of glycerin is 46 close to the 60% alcohol
mixture, therefore, a salt like sodium chloride to have about the same solubility
in glycerin as in 60% alcohol.
5-Effect of surface active agent
Air
Oil
Water
Water
5-Effect of surface active agent
 Solubilization has been defined as the spontaneous passage of poorly
water-soluble solutes into an aqueous solution of a surface active agent
(or surfactant) in which a thermodynamically stable solution is formed.
When surfactants are added to a liquid at low concentration they
tend to orient at the air-liquid interface. As additional surfactant is
added, the interface becomes fully occupied and the excess molecules
are forced into the bulk of the liquid. At still higher concentrations, the
molecules of surfactant in the bulk of the liquid begin to form oriented
aggregates or micelles: this change in orientation occurs rather
abruptly, and the concentration of surfactant at which micelle is
formed is known as the critical micelle concentration or CMC.
Solubilization
 Solubilization is thought to occur by virtue of the
solute dissolving in or being absorbed onto the
micelle. Thus, the ability of surfactant solution to
dissolve or solubilize water-insoluble materials starts
at the critical micelle concentration and increases with
the concentration of the micelles. Example, phenol is
markedly more soluble in aqueous soaps than in pure
water. Cresol in aqueous solution is known as LYSOL.
Surfactant based solution of Taxol, that is solubilized in
50% solution of Cremophor.
6-Complex formation
 The apparent solubility of a solute in a particular liquid
may be increased or decreased by the addition of a third
substance which forms an intermolecular complex with
the solute. For example, the formation of the complexes
between 3-aminobenzoic acid and various dicarboxylic
acids has been shown to increase the apparent water
solubility of the former compound. Also, p-aminobenzoic
acid increases the apparent solubility of caffeine, while
gentisic acid decreases the solubility of caffeine.
7- pH and solubility
 Many drugs are weak organic acids (for example, acetylsalicylic
acid) or weak organic bases (for example, procaine) or their salts
(for example, ephedrine hydrochloride). A weak acid or base is
only slightly ionized in solution, unlike a strong acid or base,
which is completely ionized. The degree to which weak acids and
bases are ionized in solution is highly dependent on the pH. The
exceptions to this general statement are the nonelectrolyte, such as the
steroids, and the quaternary ammonium compounds, which are completely
ionized at all pH values and in this respect, behave as strong electrolytes.
Acids ionize in alkaline medium, while bases ionize in acidic medium. The
ionized drug is more soluble in water, while the neutral drug is more soluble in
other organic solvents e.g., alcohol, chloroform, acetone.
pH and solubility
 Example: Phenobarbital (acidic drug)
 Increased pH leads to increased ionization leads to increased water solubility
and decreased solubility in other organic solvents.
 Example: Procaine HCl (basic drug)
 Increased pH leads to decreased ionization leads to decreased water solubility
and increased solubility in other organic solvents.
 Let’s begin with a definition of the term pH. The p comes from the word power.
The H, of course, is the symbol for hydrogen. Together, the term pH means the
hydrogen ion exponent.
 The pH of a substance is a measure of its acidity, just as a degree is a measure of
temperature.
 Weak electrolytes undergo ionization and are more soluble when in
ionized form. The degree of ionization depends on dissociation constant
(pKa) and the pH of the medium. The pKa is the pH at which concentration
of ionized and non-ionized forms is equal.
Henderson Hasselbach equation:
 pH = pKa + log S –S0/ S0
 S =St= total solubility.

S0 =Ks= molar solubility of the undissociated form.




(A) Solubility of a weak acid:
pH = PKa + log [salt (ionized) / acid (unionized)
This pH is called precipitation pH and defined as the minimum pH at which a weak acid at a
given total concentration will remain in solution without precipitation i.e., solution
stable. pKa is defined as pH at which drug is half ionized, that is, the ratio of concentration of
ionized Vs unionized is 1 i.e.
pH – pka = log [1]

 pH – pKa = 0
 or pH = pka
 Therefore, drugs like phenobarbital, a weakly acidic drug with pKa 7.4, will be in ionized as
well as unionized state in equal concentration in blood plasma (pH 7.4), provided the drug is
directly in contact with the blood.
 Example: look to book

(B) Solubility of a weak base:
 pH = PKw -pkb+ log [base (unionized) / salt (ionized)]
 Where PHp is the pH above which the drug begins to
precipitate from solution as the free base.

Prediction of solubility of a solute in specific
solvent
The general statement: "Like
dissolve like" Likeness may be
 Polarity as measured by the
dielectric constant. Polar and weak
polar solutes will dissolve in polar
solvents.
 For non-polar and non-interacting
substances, solubility can be
predicated by solubility parameter.
 Solubility Parameter is a measure
of the intermolecular forces in the
solvent and is commonly expressed
in hildebrand units where 1
hildebrand = (calories / cm3)1/2
 Chemical structure: Phenol will
dissolve in glycerin both having OH
group.
RATE OF SOLUTION (DISSOLUTION RATE)
 By Fick's first law of diffusion:
 Where D is the diffusion coefficient, A the surface area, Cs the




solubility of the drug, Cb the concentration of drug in the bulk
solution, and h the thickness of the stagnant layer. If Cb is much
smaller than Cs then we have so-called "Sink Conditions" and the
equation reduces to:
According to Fick's Law. The rate of solution is also directly
proportional to the area of the solid, A in cm2, exposed to solvent and
inversely proportional to the length of the path(h) through which the
dissolved solute molecule must diffuse.
Where:
D is the proportionality constant called diffusion coefficient
(cm2/sec).
(Cs) saturation solubility.
RATE OF SOLUTION (DISSOLUTION RATE)
 Small particles go into solution faster than large particles. For a given mass of




solute, as we make the particle size smaller, the surface area increases, the rate must
proportionally increase. Hence when the pharmacist wishes to increase the rate of solution of a
drug, he should decrease its particle size.
Stirring of a solution increases the rate at which a solid dissolves. This is because the
thickness of the stagnant layer depends on how fast the bulk solution is stirred; as stirring rate
increases, the length of the diffusion path decreases. Since the rate of solution is inversely
proportional to the diffusion path, the faster the solution is stirred, a faster the solute will go
into solution.
The larger the saturation solubility, the faster the dissolution rate. Different polymorphs
of the same drug may have different solubility, the metastable polymorph usually
have higher solubility (as riboflavin can exist in three different polymorphic forms, having a
solubility in water at 25° of 60 mg., 80 mg., and 1200 mg. per liter respectively). It is evident
that the most soluble form of this vitamin can be particularly useful in certain pharmaceutical
products, such as powdered parenteral formulations that are constituted before use by addition
of water.
Solubility of weak acids or bases can be highly increased; up to-1000 fold, by the use of their
respective salts, e.g.Atropine sulfate, sodium phenobarbital and sodium sulfadiazine.
With a viscous liquid, the rate of solution is slowed. This is because the diffusion
coefficient is inversely proportional to the viscosity of the medium.
Modified Noyes-Whitney equation which is:
 DA/dt = K S (Cs - C)
 Where A is the amount of the drug in solution, K is the intrinsic dissolution
rate constant, S is the surface area, Cs is the concentration of a saturated
solution of the drug, and C is the concentration of the solution at time t.
RATE OF SOLUTION (DISSOLUTION RATE)
 Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from



the solid surface to the liquid phase.
Rate of dissolution is the amount of drug substance that goes in solution per unit time under
standardized conditions of liquid/solid interface, temperature and solvent composition.
Solubility plays important role in controlling dissolution from dosage form.
From Noyes-Whitney equation it shows that aqueous solubility of drug which determines its
dissolution rate.

Particle size and effective surface area of the drug .Particle size and
related to each other.
surface area are inversely

Greater the effective surface area, more intimate the contact between the solid surface and the aqueous
solvent and faster the dissolution. Amorphous form of drug which has no internal crystal structure
represents higher energy state and greater aqueous solubility than crystalline forms.

E.g. - amorphous form of novobiocin is 10 times more soluble than the crystalline form.

Thus, the order for dissolution of different solid forms of drug is amorphous
stable.



> metastable >
Dissolution rate of weak acids and weak bases can be enhancing by converting them into their salt form.
With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and
sulfonamides.
With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal
drugs.
The Distribution of Solutes between Immiscible Liquids:












If a substance, which is soluble in both components of a mixture of immiscible liquids, is dissolved in
such a mixture, then, when equilibrium is attained at constant temperature it is found that the solute
is distributed between the two liquids in such a way that the ratio of the activities of the substance in
each liquid is a constant, which can be expressed by equation:-. This is known as the Nernst
distribution law
aA/ab = constant (1)
Where aA and aB are the activities of the solute in solvent A and B, respectively.
As the concentration of the solution is increased, the ratio becomes less than unity . When the
solutions are dilute or when the solute behaves ideally, the activities may be replaced by
concentrations (CA and CB),
Ca/Cb = K (2)
Where the constant K is known as the distribution or partition coefficient. In the case of sparingly
soluble substances, K is approximately equal to the ratio of the solubility (SA and SB) of the solute in
each liquid; i.e.
Sa/Sb = K (3)
If the solute exists as monomers in solvent A and as dimers in solvent B, the distribution coefficient is
given by Eq. (4), in which the square root of the concentration of the dimeric form is used:
Ca/ Cb = K (4)
If the dissociation into ions occurs in the aqueous layers, B of a mixture of immiscible liquids, then
the degree of dissociation (α) should be taken into account as indicated by Eq. (5).
Ca/Cb1-α= K (5)
Applications of Distribution Law:

(1) Extraction:

Extraction of substances from one phase into another is often used in analytical and organic chemistry and in the removal of
active principles from crude drugs. Application of the distribution law to the process of extraction shows that it is more
efficient to divide the extracting solvent into a number of smaller volumes that are used in
successive extraction rather than to use the total amount of solvent in one single process.

(2) Release of Drugs from Certain Dosage Forms:
 Suppositories and ointments are often formulated in water-immiscible bases. The rate of
release of medicaments from these dosage forms into aqueous body fluids will depend
mainly on partition coefficient of the medicament between the base and the body fluid.


(3) Passage of Drugs through Membranes:
The cell membrane consists of a bimolecular lipid sheet (hydrophobic) interspersed with protein molecules (hydrophilic), and
contains minute aqueous pores which allow passage of small hydrophilic substances.

The partition coefficient of the drug is therefore important in all processes that involve the transport
and distribution of drugs throughout the body; e.g. the absorption of drugs from the gastrointestinal
tract, and distribution of drugs between various tissues.

(4) Preservation of Emulsions and Creams:

An emulsion consists of two immiscible liquids one of which is uniformly dispersed through the other as droplets of diameter
greater than 0.1 m. Preservatives should have a wide spectrum of activity against a range of bacteria, yeasts and moulds. Since
microorganisms usually multiply in the aqueous phase of this type of system, and preservatives must
therefore be capable of exerting their activity in this phase. The selective preservative should have
high water solubility and a low oil/water partition coefficient.

Solubility of gases in liquids
 Henry's Law
 Liquids and solids exhibit practically no change of solubility with changes in pressure.
Gases as might be expected, increase in solubility with an increase in pressure.
Henry's Law states that: The solubility of a gas in a liquid is directly proportional
to the pressure of that gas above the surface of the solution (at constant
temperature). “the partial pressure of the gas in vapour phase (p) is proportional
to the mole fraction of the gas (x) in the solution” and is expressed as:

p = KHx
 Here KH is the Henry’s law constant.
 If the pressure is increased, the gas molecules are "forced" into the
solution since this will best relieve the pressure that has been applied.
The number of gas molecules is decreased. The number of gas molecules
dissolved in solution has increased as shown in the graphic on the left.

Solubility of gases in liquids







The solubility of a gas in a liquid depends on temperature, the partial pressure of the gas over the liquid, the
nature of the solvent and the nature of the gas. The most common solvent is water. Carbonated beverages are an
example of Henry's law in everyday life. The dissolved carbon dioxide stays in solution in a closed pop bottle or can
where the partial pressure of carbon dioxide was set at a high value during bottling. When the can or bottle is opened
the partial pressure of CO2 is much lower and the dissolved carbon dioxide will gradually escape from the pop. When
the cap is removed, the decreased pressure above the solution results in the decreased solubility of the carbon
dioxide—the carbon dioxide escapes the solution.
The concentration of dissolved gas depends on the partial pressure of the gas. The partial pressure controls the number
of gas molecule collisions with the surface of the solution. If the partial pressure is doubled the number of collisions
with the surface will double. The increased numbers of collisions produce more dissolved gas.
Gases are usually more soluble at colder temperatures. For example, oxygen is more soluble in cold water
than in hot water. The decrease in oxygen solubility with increased temperature has serious consequences
for aquatic life. Power plants that discharge hot water into rivers can kill fish by decreasing the dissolved
oxygen concentration.
The same sort of analysis can be applied to solutions of gases. Dissolving oxygen in water releases a small
amount of heat:
Gaseous O2 + nearly saturated O2 solution = saturated O2 solution + heat
Le Chatelier's principle predicts that heating the solution shifts the equilibrium to the left- less oxygen
dissolves at higher temperature.
A molecular model of gas solubility. The solubility of gases, like other solubility's, can increase or decrease
with temperature. A simple model can be used to explain why gases can behave either way, depending on the
gas and the solvent. The heat absorbed or released when a gas dissolves in liquid has essentially two
contributions:
Solubility of gases in liquids
 Energy is absorbed to open a pocket in the solvent. Solvent molecules attract each other.




Pulling them apart to make a cavity will require energy, and heat is absorbed in this step for
most solvents. Water is a special case- it already contains open holes in its network of loose
hydrogen bonds around room temperature. For water, very little heat is required to create
pockets that can hold gas molecules.
Energy is released when a gas molecule is popped into the pocket. Intermolecular attractions
between the gas molecule and the surrounding solvent molecules lower its energy, and heat is
released. The stronger the attractions are, the more heat is released. Water is capable of
forming hydrogen bonds with some gases, while organic solvents often can't. A larger amount
of heat is released when a gas molecule is placed in the pocket in water than in organic
solvents.
There is usually net absorption of heat when gases are dissolved in organic solvents, because
the pocket-making contribution is bigger. Le Chatelier's principle predicts that when heat is
absorbed by the dissolution process, it will be favored at higher temperature. Solubility is
expected to increase when temperature rises.
There is usually net release of heat when gases are dissolved in water, because the
pocket-filling contribution is biggest. Solubility is expected to decrease when
temperature rises.
The reason for this gas solubility relationship with temperature is an increase in
kinetic energy. The higher kinetic energy causes more motion in molecules which
break intermolecular bonds and escape from solution.
Applications
 Carbonated beverages provide the best example of this phenomenon. All
carbonated beverages are bottled under pressure to increase the carbon dioxide
dissolved in solution. When the bottle is opened, the pressure above the solution
decreases. As a result, the solution effervesces and some of the carbon dioxide
bubbles off.
 Deep sea divers may experience a condition called the "bends" if they do not
readjust slowly to the lower pressure at the surface. As a result of breathing
compressed air and being subjected to high pressures caused by water depth, the
amount of nitrogen dissolved in blood and other tissues increases. If the diver
returns to the surface too rapidly, the nitrogen forms bubbles in the blood as it
becomes less soluble due to a decrease in pressure. The nitrogen bubbles can cause
great pain and possibly death.To alleviate this problem somewhat, artificial
breathing mixtures of oxygen and helium are used(11.7% helium, 56.2% nitrogen
and 32.1% oxygen). Helium is only one-fifth as soluble in blood as nitrogen. As a
result, there is less dissolved gas to form bends".
 At high altitudes the partial pressure of oxygen is less than that at the
ground level. This leads to low concentrations of oxygen in the blood and
tissues of people living at high altitudes or climbers. Low blood oxygen causes
climbers to become weak and unable to think clearly, symptoms of a condition
known as anoxia.
Solubility of solids in solids
 If two solids are either melted together and then cooled or dissolved in a suitable solvent,which













is then removed by evaporation,the solid that is redeposited from the melt or the solution will
either be a one-phase solid solution or a two-phase eutectic mixture.
Solid – Dispersion System
Definition:
Solid dispersion is defined as dispersion of one or more active ingredients in an inert
carrier or matrix at solid state prepared by the melting, solvent or melting solvent method.
Classification
Simple Eutectic Mixtures
Solid Solutions
Glass Solutions and Glass Suspensions
A. Eutectic Mixtures
When two or more substances are mixed together they liquefy due to the lowering of melting
point than their individual melting point. Such substances are called as eutectic substances.
e.g. paracetamol-urea, griseofulvin-urea
Simple binary phase diagram showing eutectic point E.
The eutectic composition at point E of substance A and B represents the melting point.
TA and TB are melting point of pure A and pure B.
Solubility of solids in solids

















B. Solid Solutions
It is made up of a solid solute dissolved in a solid solvent. It is often called a “mixed crystal” because
the two components crystallize together in a homogenous phase system.
It is prepared by fusion method.
A solid solution of poorly soluble drug in a rapidly soluble carrier achieves a faster dissolution because
particle size of drug is reduced to molecular size.
Classification
According to extent of miscibility :
Continuous (iso-morphous, unlimited, complete) solid solution.
Discontinuous (limited, restricted, incomplete) solid solution.
According to crystalline structure of solid solutions :
Substitutional solid solutions.
Interstitial solid solutions.
Continuous Solid Solutions :The two components are miscible or soluble at solid state in all proportions.
No established solutions of this kind have been shown to exhibit fast release dissolution properties.
The faster dissolution rate would be obtained if the drug is present as a minor compartment.
Discontinuous Solid Solutions :There is only limited solubility of a solute in a solid solvent in this group of solid solutions.
Solubility of solids in solids
 C. Glass Solutions and Glass Suspensions
 A glass solution is a homogenous, glassy system in which a solute is usually








obtained by abrupt quenching of the melt.
Many compounds have been shown to be able to form glasses readily upon cooling
from liquid state.
These compounds include sucrose, glucose, ethanol and 3- methyl hexane.
It is presumably due to their strong hydrogen bonding which may prevent their
crystallization.
Polymers possessing linear, flexible chains can freeze into a glass state to
transparency and brittleness.
The strength of chemical binding in a glass solution is much less compared to that
in a solid solution.
Hence, dissolution rate of drugs in the glass solution is faster than in solid solution.
E.g. Glass solution of citric acid.
The enhancement of poorly soluble drug solubility's through solid solutions
and or eutectic mixtures leading to enhancing bioavailability.