Solubility and Distribution

Solubility and Distribution
Phenomena

Introduction
• A solution is a system in which
molecules of a soluteare dissolved in a
solvent.
• Solubility is defined concentration of
solute in a saturated solution at certain
temperature. It is intrinsic property of
solute.
• Saturated solution is one in which solute
in solution is in equilibrium with solid
phase

Solute-Solvent Interactions
“Like dissolves Like”
• Polar substances tend to dissolve in polar solvents, while
nonpolar substances tend to dissolve in nonpolar solvents.
• The more similar the Intermolecular attractions are, the more
likely one substance is to be soluble in another.
Types of solvents:
• Polar solvents
• Nonpolar solvents
• Semipolar solvents

Factors affecting solubility
The solubility of a substance depends on
• Polarity
• Dielectric constant
• Association
• Solvation
• Internal pressures
• Acid-base reactions
• Chemical, electrical, and structural effects that lead to mutual
interactions between the solute and solvent

Polar Solvents
Polar solvents dissolve ionic solutes and polar substances. The
solubility of a drug in polar solvent depends on:
1.The polarity of the solute and the solvent.
2.The ability of the solute to form hydrogen bonds.
• Water dissolves phenols, alcohols, aldehydes, ketones, amines,
and other oxygen- and nitrogen-containing compounds that can
form hydrogen bonds with water.

Polar Solvents
3. The ratio of polar to nonpolar groups of the molecule
When additional polar groups are present in the molecule (e.g.
propylene glycol, glycerin, and tartaric acid), water solubility
increases greatly.
As the length of a nonpolar chain of an aliphatic alcohol
increases, the solubility in water decreases (e.g. Straight
chain monohydroxy alcohols, aldehydes, and acids with
more than 4 carbons cannot enter into the hydrogen-
bonded structure of water and hence are slightly soluble).
7

Polar Solvents
• Branching of the carbon chain reduces the nonpolar
effect and leads to increased water solubility (e.g.
Tertiary butyl alcohol is miscible in all proportions with
water, whereas n-butyl alcohol dissolves only to a
small extent).

9
Non-polar Solvents
Ionic and polar solutes are not soluble or are only slightly in nonpolar
solvents (e.g. hydrocarbons) because:
• Nonpolar solvents are unable to reduce the attraction between the
ions of strong and weak electrolytes because of the solvents' low
dielectric constants.
• Nonpolar solvents cannot break covalent bonds and ionize weak
electrolytes, because they are aprotic (no hydrogen).
• Nonpolar solvents cannot form hydrogen bridges with
nonelectrolytes.
Non polar solvents dissolve non polar solutes with similar attractive
forces through induced dipole interactions (London forces) (e.g. CCl4
can dissolve oils and fats).

Semi-polar Solvents
• Semipolar solvents induce certain degree of
polarity in non-polar solvents
• Semipolar solvents act as intermediate solvents
that generate miscibility between polar and non-
polar liquids (e.g. Acetone increases the solubility
of ether in water).

Ideal and real solutions
Ideal Solution
• Ideal Solution is one in which there is
no attraction between solute and
solvent molecules.
• Ideal solution is one in which there is
no change in the properties of the
components, other than dilution.
• They obey Raoult’s law
Real Solutions
• In real solutions the "cohesive“ force
of attraction between A for A exceeds
the "adhesive" force of attraction
existing between A and B.
• Alternatively, the attractive forces
between A and B may be greater than
those between A and A or B and B.
This
• may occur even though the liquids
form solution in all proportions. Such
mixtures are real or non-ideal
• They do not obey Raoult's law

Raoult’s law
• In ideal solutions partial vapor pressure of each volatile constituent is
equal to the vapor pressure of the pure constituent multiplied by its
mole fraction in the solution.
• Thus, for two constituents A and B
• in which ƤA and ƤB are the partial vapor pressures of the constituents
over the solution when the mole fraction concentrations are XA and
XB respectively

Vapor pressure-
composition curve
for an ideal solution
(binary mixture)

Deviation from Raoult’s Law
(Henry's law)
• Negative
• Positive

Negative deviation
from Raoult’s Law
• Negative deviation: When the
"adhesive" attractions between
molecules of different species
exceed the "cohesive" attractions
between like molecules, the vapor
pressure of the solution is less
than that expected from Raoult's
ideal solution law, and negative
deviation occurs
• E.g. Chloroform + Acetone

Negative deviation from Raoult’s Law
• The vapor pressure-composition relationship of the
solute(Chloroform) cannot be expressed by Raoult's law, but instead
by an equation known as Henry's law (Chloroform + Acetone)
• Ƥsolute = ksolute Xsolute
• Henry’s law applies to the solute and Raoult's applies to the solvent in
dilute solutions of real liquid pairs

Positive deviation from
Raoult’s Law
• When the interaction between A and B
molecules is less than that between
molecules of the pure constituents (A-A
or B-B), the presence of B molecules
reduces the interaction of the A-A
molecules correspondingly reduce the B-
B interaction.
• Accordingly, the dissimilarity of polarities
or internal pressures of the constituents
results in a greater escaping tendency of
both the A and the B molecules. The
partial vapor pressure of the constituents
is greater than that expected from
Raoult's law, and the system is said to be
positive deviation.
• E.g. Benzene + Ethyl Alcohol

Azeotropic binary mixture
• It is the mixture of liquids that has a constant boiling point because
the vapour has the same composition as the liquid mixture.
• The boiling point of an azeotropic mixture may be higher or lower
than that of any of its components.
• The components of the solution cannot be separated by simple
distillation

Solubility of Liquid in Liquid
19
Frequently two or more liquids are mixed together in the
preparation of pharmaceutical products (e.g. aromatic
waters, spirits, elixirs, lotions, sprays, and medicated oils).
Liquid–liquid systems can be divided into two categories
according to the solubility of the substances in one another:
1. Complete miscibility
2. Partial miscibility.

20
Complete Miscibility
Polar and semipolar solvents, such as water and alcohol,
alcohol and acetone, are said to be completely miscible
because they mix in all proportions.
Nonpolar solvents such as benzene and CCl4 are also
completely miscible.
These liquids are miscible because the broken attractive
forces in both pure liquids are re-established in the mixture.

21
Partial Miscibility
When water and phenol are mixed, two liquid layers are
formed each containing some of the other liquid in the
dissolved state.
It is possible to calculate the composition of each component
in the two conjugate phases and the relative amount of
each phase from the tie lines that cut the binodal curve.

Phenol Water
System
phase
diagram

Partial Miscibility
Partially miscible liquids are influenced by temperature. The
two conjugate phases changed to a homogenous single
phase at the critical solution temperature (or upper
consolute temperature).
Some liquid pairs (e.g.
trimethylamine and water)
exhibit a lower consolute
temperature, below which
the two members are
soluble in all proportions
and above which two
separate layers form.
23

Partial Miscibility
Few mixtures (e.g. nicotine
and water) show both an
upper and a lower consolute
temp. with an intermediate
temp. region in which the
two liquids are only partially
miscible.
A final type exhibits no critical
solution temperature (e.g.
ethyl ether and water shows
partial miscibility over the
entire temperature range at
which the mixture exists.
24

Two component
containing solid
and liquid
phases:
Eutectic mixture
Salol+ thymol
phase diagram

Salol –thymol system
• (i) a single liquid phase;
• (ii.) a region containing solid salol and a conjugate liquid phase;
• (iii) a region in which solid thymol is in equilibrium with a conjugate liquid
phase;
• (iv) a region in which both Components are present as pure solid phases
• 25 C ….. X1 --- conjugate liquid phase a1 consist 53% thymol and solid
phase (b1) 100% solid thymol
• 15 C … X2 … conjugate liquid phase a1 consist 37% thymol and solid phase
(b1) 100% solid thymol
• Below 13 C .. Two solid phases … Thymol and Salol
• Lowest temperature at which liquid phase can exist in system is 13 C.
mixture contain 34% of thymol in salol … this is eutectic point (F=3-1+2 =0)

3component system
diagram (ternary diagram)

3component
system diagram
(ternary phase
diagram)

Solubility of Gas in Liquid
29
The solubility of gases in liquids depends on:
1. The mass of gas molecules
2. Pressure
3. Temperature
4. Presence of salt
5. Chemical reactions with solvent

The Mass of Gas Molecules
• The solubility of gas molecules typically increases with
increasing mass of the gas molecules.
• The larger the mass of gas molecules, the stronger London and
Debye forces is between gas and solvent molecules.

13
Pressure
• Gases increase in solubility with an increase in
pressure.
• Increasing the pressure results in more collisions
of the gas molecules with the surface of the
solvent (more solvation); and hence greater
solubility.

Henry's law
• The effect of the pressure on the solubility of a gas is expressed by
Henry's law
• Henry's law states, “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.
• If C2 is the concentration of the dissolved gas in grams per liter of
solvent and p is the partial pressure in millimeters of the undissolved
gas above the solution,
• Henry's relationship may be written as C2 = σp
• σ=1/k solubility coefficient

Temperature
• Gases decrease in solubility with an increase in temperature.
• Increasing temperature causes an increase in kinetic energy of
gas molecules which leads to breakdown of intermolecular
bonds and gas escaping from solution.
• E.g. Carbon dioxide gases escape faster from a carbonated
drink as the temperature increases.

34
Presence of Salts
• Dissolved gases are often liberated from solutions
by the introduction of an electrolyte (e.g. NaCl)
and sometimes by a non electrolyte (e.g. sucrose)
• This phenomenon is known as SALTING OUT.

Solubility of Solid in Liquid
pH
• Systems of solids in liquids include the
most frequent and important type of pharmaceutical
solutions.
• Most drugs belong to the class of weak acids and bases.
They react with strong acids or bases to form water soluble
salts.
• Acidic drugs (e.g. NSAIDs), are more soluble in
solutions where the ionized form is the predominant.
• Basic drugs(e.g. ranitidine), are more soluble in acidic
solutions where the ionized form of the drug is predominant.
35

pH
Carboxylic acids containing more than 5 carbons are relatively
insoluble in water; however, they react with dilute NaOH,
carbonates, and bicarbonates to form soluble salts.
The fatty acids (> 10 carbon) form soluble soaps with the alkali
metals and insoluble soaps with other metal ions.
Phenol is weakly acidic and only slightly soluble in water
but is quite soluble in dilute sodium hydroxide.
36

pH
• Drug (HP) is weak electrolyte ( salt of weak acid ), and dissociate
• HP + H2O <=> H3O+ + P-
• log (S-S0) = log Ka + log S0 – log [H3O+]
• pHp = pKa + log S−S 𝟎
S 𝟎
• Where,
• pHp is the pH below which drug separate
• S= Total solubility of drug (Dissociated + undissociated)
• S0= molar solubility (of un dissociated form of drug) is constant
37

Substituents
Substituents can influence solubility by affecting the solute
molecular cohesion and its interaction with water molecules.
Polar groups such as –OH are capable of hydrogen bonding
(high solubility).
E.g. Hydroxy acids, such as tartaric and citric acids, are quite
soluble in water because they are solvated through their
hydroxyl groups.
Non-polar groups such as –CH3 and –Cl are hydrophobic (low
solubility).
38

Substituents
• The position of the substituent on the molecule can affect
the solute molecular cohesion and its interaction with water
molecules, and hence its solubility.
• E.g. the OH group of salicyclic acid cannot contribute to the
solubility because it is involved in an intramolecular
hydrogen bond.
39

Substituents
E.g. the aqueous solubility of o-, m- and p-dihydroxybenzenes
are 4, 9 and 0.6 mol/L, respectively.
particles (p-dihydroxybenzenes) can be lessSymmetric
soluble than asymmetric ones (m-dihydroxybenzenes)
because they form a compact crystals (which require more
work to separate the particles), while the asymmetric
particles pack less efficiently in crystals.
40

Solvent
• Frequently solute is more soluble in mixture of solvents than
in single solvent.
• The solvent, which in combination with the main solvent
increases solubility is known as cosolvent.
41

42
Crystal Characteristics
• Different crystalline forms of the same substance (known as polymorphs)
possess different lattice energies.
• The polymorphic form with the lowest free energy will be the most stable.
• Less stable (metastable) forms with the highest energy will be the most
soluble one. They tend to transform into the most stable form over time.
• The solubility of a crystalline material and its rate of dissolution can be
increased by using a metastable polymorph.
• Many drugs exhibit polymorphism, e.g. steroids, barbiturates and
sulphonamides.

43
Crystal Characteristics
• Incorporation of solvent molecules into the lattice structure
of crystalline material during crystallization will result in
solids that are called solvates. If water is the solvating
molecule, the solids are called hydrate.
• The interaction between the substance and water that
occurs in the crystal phase reduces the amount of energy
liberated when the solid interact with the solvent (water).
• Therefore unsolvated crystals will dissolve faster.

44
Complexation
• Complexation can increase or decrease the solubility of
drugs depending whether the formed complex is water
soluble or insoluble.
• e.g. Cyclodextrin can form water soluble complexes with
most drugs, thus increasing their water solubility.
• e.g. Tetracycline can form water insoluble complexes with
various metal cations. Therefore tetracycline solubility is
decreased in the presence of those metals.

45
Boiling and Melting Point
• In general, aqueous solubility decreases with increasing
boiling and melting point.
• This is because the higher the boiling point of liquids and
melting point of solids, the stronger the interactions between
the molecules in the pure liquid or the solid state.
Particle Size
• Solubility increases with decreasing particle size, due to the
increased particle surface area; meaning more of the solid
is in contact with the solvent.

Partition Coefficient (K)
Definition
If a liquid or solid substance is added to a
mixture of two immiscible liquids, it will
become distributed between the two
layers in a definite concentration ratio.
If C1 and C2 are the equilibrium
concentrations of the substance in
Solvent1 and Solvent2, respectively, the
equilibrium expression becomes:
C1 / C2 = K
The equilibrium constant, K, is known as
the distribution ratio, distribution
coefficient, or partition coefficient.
47

Partition Coefficient (K)
48
Example
When boric acid is distributed between water and amyl
alcohol at 25°C, the concentration in water is found to
be 0.0510 mole/liter and in amyl alcohol it is found to be
0.0155 mole/liter. What is the distribution coefficient?
K(w/o) = CH2O / Cal = 0.0510 / 0.0155 = 3.29
No convention has been established with regard to whether
the concentration in the water phase or that in the organic
phase should be placed in the numerator. Therefore, the
result can also be expressed as:
K(o/w) = Cal / CH2O = 0.0155 / 0.0510 = 0.304
One should always specify, which of these two ways the
distribution constant is being expressed.

Partition Coefficient (P)
49
Definition
• Partition coefficient (P) is a parameter that characterizes the relative affinity
of a compound in its unionized form for water and an immiscible model lipid
solvent (octanol).
• Octanol was chosen as the model lipid phase because it most closely
simulates the properties of biological membranes.
• Determination of P (or log P) values involves the placing of a drug
compound along with the two immiscible solvents in a separation funnel.
• Molecules of the solute will distribute in each phase until equilibrium is
established.
• The ratio of the two concentrations is the partition coefficient or
distribution coefficient P, i.e. P = Co /Cw.

50
Interpretation
• P > 1 or Log P > 0 implies that the drug has affinity for lipid
membranes
• P = 1 or Log P = 0 there is equal distribution between the
water and oil layer.
• P < 1 or Log P < 0 the drug has affinity for water or hydrophilic
layer.
• Structure affect the value of partition coefficient P
• Thesubstituent that increase P value are -alkyl, -aryl, -halogens
• The substituent that decrease P value are -COOH, -NH2, -O, -CO , -OH

51
Pharmaceutical Applications
Knowledge of partition is important to the pharmacist
because the principle is involved in several areas
of current pharmaceutical interest. These include:
1. Preservation of oil–water systems.
2. The absorption and distribution of drugs
throughout the body.
3. Extraction of active ingredients from crude
drugs.

Apparent Partition Coefficient (Papp)
52
When association and dissociation of drugs occur, the
situation becomes more complicated, e.g. benzoic acid
associates in the oil phase and dissociates in the aqueous
phase.
Drugs that are weak acids or weak bases ionize in water,
depending on their pka and on the pH of the aqueous
phase.
In general, ionized structures cannot partition in octanol or
other hydrophobic solvents.
P value cannot be used to assess the true distribution of the
ionizable drug in the two immiscible phases, simply
because its value is dependent on the ionic state of the
drug (which in turn depends on pH).

Apparent Partition Coefficient (Papp)

Reference
• Sinko, Martin's physical pharmacy and pharmaceutical sciences:
physical chemical and biopharmaceutical principles in the
pharmaceutical sciences, Philadelphia, Lippincott Williams &
Wilkins.

Solubility and Distribution

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