Solubility of drugs

Solubility of drugs
By
Prof. Mirza Salman Baig
Department of Pharmaceutics
AIKTC School of Pharmacy

Solubility of drugs
• Solubility expressions,
• Mechanisms of solute solvent interactions,
• Ideal solubility parameters

• Solubility of drugs: Solubility expressions, mechanisms of solute
solvent interactions,
• ideal solubility parameters, solvation & association, quantitative
approach to the factors influencing solubility of drugs, diffusion
principles in biological systems.
• Solubility of gas in liquids, solubility of liquids in liquids, (Binary
solutions, ideal solutions)
• Raoult’s law, real solutions. Partially miscible liquids, Critical solution
temperature and applications.
• Distribution law, its limitations and applications

Definition
• Solubility is defined in quantitative terms as the
concentration of a solute in a saturated solution at a certain
temperature
• Saturated solution: It is a solution that contains the solute at
the limit of its solubility at any given temperature and
pressure.
• In qualitative terms it is defined as spontaneous interaction
between two or more substance to form a homogeneous
molecular dispersion.

SOLUBILITY EXPRESSIONS
• g/ml : Most commonly used method of expressing solubility. It
is the number of grams of solute that dissolves in one ml of the
solvent.
• Molarity : It is the number of moles (gram molecular weight) of
the solute in 1 litre of the solvent.
• Normality : It is the gram equivalent weight of the solute in
1litre of the solution.

SOLUBILITY EXPRESSIONS
• %w/w : It is the weight in grams of solute dissolved in 100 g of
solution.
• %w/v : It is the weight in grams of solute dissolved in 100 ml of
solution.
• %v/v : It is the volume of the solute in ml dissolved in 100 ml of the
solvent

SOLVENT-SOLUTE INTERACTIONS
• The interaction between the solute and the solvent depends on
the chemical, structural and electrical properties of both the solute
as well as solvent.
• Both, the attractive as well as the repulsive forces play a role in
these interactions.
• Repulsive forces : As two molecules are brought together,
opposite charges in the two molecules being closer than the like
charges, causes the molecules to attract each other. When both
the molecules come so close that their electronic clouds touch
each other, they repel each other like rigid elastic bodies.
• Attractive forces: Van der Waals force

(Hydrogen bond)
• Hydrogen bond is a strong type of dipole-dipole
interaction that occurs between a molecule
containing a hydrogen atom and a strongly
electronegative atom such as fluorine, oxygen, or
nitrogen
• In order to create the bond, the hydrogen atom
must be covalently attached to another
electronegative atom.
• A perfect example of hydrogen bond is water.
• Hydrogen bonds can also exist between alcohol
molecules, carboxylic acids, aldehydes, esters, and
polypeptides.

• In a water molecule, the hydrogen lone electron is pulled by
the covalently attached oxygen atom, creating a naked
nucleus on the side of the hydrogen atom facing away (partial
positive charge)
• This side of the hydrogen atom can get close to neighbouring
oxygen atom (with a partial negative charge) and interact
strongly with it.
(Hydrogen bond)

• “Like dissolves like.”
• Polar solvent dissolves polar solute
• Non-polar solvent dissolves non-polar solute

(Polar solvents)
• Polar solvents dissolve ionic solutes and other polar
substances.
• Accordingly, water mixes in all proportions with alcohol
and dissolves sugars and other polyhydroxy compounds.
• Ability of the solute to form hydrogen bonds is
responsible
• Water dissolves phenols, alcohols, aldehydes, ketones,
amines, and other oxygen- and nitrogen containing
compounds that can form hydrogen bonds with water
• When additional polar groups are present in the
molecule, as found in propylene glycol, glycerin, and
tartaric acid, water solubility increases greatly

SOLVATION
• The process of attracting and associating
the molecules of solvents towards
molecules or ions of the solute is called as
solvation.
• The larger the ion, the more solvent
molecules surround it and the more they
are solvated.
• Solvation depends on factors such as
hydrogen bonding and Van der Waals
forces.

Solubility parameter
• Solvent power of a liquid is influenced by its intermolecular cohesive
forces and that the strength of these forces can be expressed in terms
of a solubility parameter
• The solubility parameter is a numerical value that indicates the
relative solvency behavior of a specific solvent.
• It is derived from the cohesive energy density of the solvent, which in
turn is derived from the heat of vaporization

Dielectric constant
• Dielectric constant of solvent is also
responsible for solubility
• The dielectric constant is a measure of
the ability of molecule to resist charge
separation.
• Water (78.5), chloroform (4.8)
• The capacitance of the condenser filled
with some material, Cx , divided by the
reference standard, C0, is referred to as
the dielectric constant, ε:
• ε = Cx/C0

ASSOCIATION
• When specific interactions occur
between like molecules of one of
the components in a solution, the
phenomenon is called as
association
• e.g. dimerisation of benzoic acid
where two molecules of benzoic
acid undergo association in a non-
polar solvent (benzene) to form a
dimer.

Polar solvents
• Due to high dielectric constant, polar solvent decrease force of
attraction between oppositely charged ions in crystals such as sodium
chloride.
• Polar solvents break covalent bonds of potentially strong electrolytes
by acid base reactions.
• Polar solvents are capable of solvating molecules and ions through
their hydrogen bond formation leading to solubility of a solute.

Non-Polar solvents
• Non-polar solvents are unable to reduce the attractions of ions between
strong and weak electrolytes.
• Because these solvents have a low dielectric constant. Nor can they break
covalent bonds and ionise weak electrolytes, since they are aprotic
solvents (don’t release H+ ion).
• Hence ionic or polar solutes are not soluble or slightly soluble in non-polar
solvents.
• However non-polar solvents dissolve non-polar solutes through induced
dipole-induced dipole interactions. The solute molecules are kept in
solution by weak Van der Waals type or London type of forces
• Example: Oils and fats dissolve in carbon tetrachloride, benzene

ideal solutions vs non-ideal solutions
• Mixing substances with similar properties forms ideal solutions. For
example, when 100 mL of methanol is mixed with 100 mL of ethanol,
the final volume of the solution is 200 mL, and no heat is evolved or
absorbed. The solution is nearly ideal.
• When 100 mL of sulfuric acid is combined with 100 mL of water,
however, the volume of the solution is about 180mL at room
temperature, and the mixing is attended by a considerable evolution
of heat; the solution is said to be nonideal, or real.

FACTORS AFFECTING SOLUBILITY
Temperature
• Temperature: If the process of
dissolution is exothermic then
increase in temperature decreases
the solubility.
• If the process of dissolution is
endothermic then increase in
temperature increases the solubility.
• Solubility curves are used to indicate
effect of temperature on solubility
• Generally solubility curves are straight
curves except in a few cases like
Na2SO4

Temperature
• Solubility curve of Na2SO4
• Its solubility therefore increases with
rise in temperature until 32.5°C is
reached. Above this temperature the
solid is converted into the anhydrous
form Na2SO4, and the dissolution of
this compound is an exothermic
process.
• The solubility therefore exhibits a
change from a positive to a negative
slope as the temperature exceeds the
transition value.

Nature of the solvent
• Nature of the solvent The solubility of the solute in the solvent
depends on the polarity of both the solvent as well as the solute
• 'Like dissolves like', i.e. a polar substance will dissolve in a polar
solvent and a non-polar solute will dissolve in a non-polar solvent.
• Such a generalization should be treated with caution, because the
• intermolecular forces involved in the process of dissolution are
influenced by factors other than the polarity of a molecule;
• For example, the possibility of intermolecular hydrogen-bond
formation between solute and solvent may be more significant than
polarity.

Particle size
• Smaller the particle size of the solute, more will be the surface
area available for dissolution and hence more will be the
solubility.
• The solubility of a substance to increase with decreasing particle
size due to increase interfacial free energy as per equation
• 𝑙𝑜𝑔
𝑆
𝑆0
=
2𝛾𝑀
2.303 𝑅𝑇𝜌𝑟
• Where,
• S is the solubility of small particles of radius r,
• S0 is the normal solubility (i.e. of a solid consisting of fairly large particles),
• y is the interfacial energy,
• M is the molecular weight of the solid, p is the density of the bulk solid,
• R is the gas constant and
• T is the thermodynamic temperature

Crystal structures & polymorphism
• Crystal structures : The amorphous forms of drugs are more soluble than
the crystalline forms.
• The different crystalline forms of the same substance are known as
polymorphs
• The more soluble polymorphs are metastable but they convert to the
stable form; the rate of such conversion is often slow hence metastable
form are useful in pharmaceutical point of view.
• Crystalline material may be altered by incorporation of solvent molecules.
The processes is solvation and the resultant solid is known as solvates. If
the solvent is water then the it is termed as hydrate. These hydrated
crystals show lower aqueous solubility than their unhydrated forms

Molecular structures
• Molecular structures : Presence of hydrophilic or hydrophobic groups
within the molecular structure greatly affects the solubility of the
compound.
• Introduction of a hydrophilic hydroxyl group can produce a large
improvement in water solubility
• Phenol is 100 times more soluble than benzene

Reduction in solubility may provide a suitable method for:
• Masking the taste of a parent drug, e.g. chloramphenicol palmitate is
used in paediatric suspensions rather than the more soluble and very
bitter chloramphenicol base;
• Protecting the parent drug from excessive degradation in the gut, e.g.
erythromycin propionate is less soluble and consequently less readily
degraded than erythromycin;
Molecular structures

pH
• pH : pH has a great influence on the solubility of ionic compounds for
e.g. in case of acidic drugs higher the pH (in alkaline range) more will
be their ionization.
• Acidic drugs are unionised in acidic pH. Hence, precipitation may
occur if pH is reduced of the solution of acidic drug.
• But the acedic drug undergo ionisation if pH is increased (to basic
range i.e. above 7)
• Henderson Hasselbalch equation
• pH = pKa + log
[𝑆𝑎𝑙𝑡]
[𝐴𝑐𝑖𝑑]

Common ion effect
• Whenever a solution of an ionic substance added to another ionic
compound with a common ion, the solubility of the ionic substance
decreases significantly
• The common ion effect can be explained by Le Chatelier’s principle of
chemical equilibrium

Diffusion principles in biological systems
• Diffusion is the process of movement of the solute from a region of
higher concentration to the region of a lower concentration.
• The transport of a drug across a biological membrane can occur by
two processes, passive diffusion and active transport, of which
passive diffusion is the predominant mechanism.
• Thus absorption of the drug through the GI tract, skin etc. occur by
the process of diffusion.

Diffusion
• Diffusion is spontaneous movement of
molecules from higher concentration region to
lower concentration region till equilibrium is
established

Diffusion through biological membranes

• Diffusion through lipoidal membrane (BBB) is known as transcellular
diffusion
• Paracellular diffusion occurs through the space between cells
• In addition to drugs, nutrients also pass through biological
membranes

• Membrane transporters are specialized proteins that facilitate drug
transport
• Active transport
• Facilitated diffusion

• Energy dependent carrier mediated diffusion through biological
membrane (Active transport)
• Energy independent carrier mediated diffusion through biological
membrane (Facilitated diffusion)

• GASTROINTESTINAL DRUG ABSORPTION :
• A drug taken orally must dissolve first in the GI fluid followed by its
absorption into the blood stream.
• For drug absorption, it needs to pass through the GI membrane at
various locations.
• The GI membrane acts as a barrier and it is composed of double layer
of phospholipids surrounded by protein molecules.
• Drug absorption through this membrane occurs by passive diffusion,
pore transport, facilitated diffusion, active transport, etc.
• Passive diffusion : It is a process in which molecules spontaneously
diffuse from a region of higher concentration to a region of lower
concentration.

• Drug moves down the concentration gradient.
• The transport process depends on the surface area of the GI
membrane. Thus more drug is absorbed from the intestine than the
stomach.
• It depends on partition coefficient of the drug. Thus drugs that have
high value of K are lipophilic and diffuse easily across the lipoidal GI
membrane.
• Unionised forms, being lipoidal, diffuse easily as compared to the
ionic form.

• PERCUTANEOUS DRUG ABSORPTION :
• Percutaneous penetration, or absorption through skin, involves: (i)Drug
dissolution in its vehicle. (ii)Drug diffusion from vehicle to skin surface.
(iii)Drug penetration through skin layers.
• The skin consists of three layers: the epidermis, dermis and subcutaneous fat
layers.
• The epidermis consists of outermost layer of stratum corneum which is
composed of dead, keratinized cells.
• The stratum corneum is the main barrier to drug diffusion and once it is
overcome, it can easily enter the dermis and the systemic circulation.
• The process of drug penetration in the stratum corneum is passive diffusion,
which depends on different factors such as hydration of the stratum corneum,
drug properties such as its partition coefficient, pH, etc.

SOLUBILITY OF GAS IN LIQUIDS
• Solubility of gas in liquids is the concentration of dissolved gas in the
liquid when it is in equilibrium with the pure gas above the solution.
• The example of gas in liquid includes effervescent preparations
containing dissolved carbon dioxide, ammonia water and
hydrochloride gas.
• Aerosol products containing nitrogen or carbon dioxide as propellant
are also considered to be solution of gases in liquids.

Factors Affecting Solubility of Gas in Liquids:
The solubility of gas in liquids depends on
• Pressure,
• Temperature,
• Concentration of Salt
• Chemical reaction
• Micellar solubilization.

Pressure:
• Liquids and solids do not show
any change of solubility with
changes in pressure.
• But, solubility of gases in liquids,
depends on the pressure of the
gas in contact with the liquid
• At higher gas pressure, more gas
is dissolved in liquids
Solubility of Gases at Different Pressures

Pressure:
• For example, the soda bottle is packed at high pressure of
carbon dioxide before sealing.
• When the cap of bottle is opened, the pressure above the
liquid is reduced to 1 atm and the soda fizzes.
• This fizzing is just carbon dioxide that was dissolved in soda,
is getting released.
• Therefore, if lower is the pressure less carbon dioxide is
soluble

Pressure:
• The effect of pressure on the solubility of gas is given Henry’s law which
states that in dilute solution the mass of gas which dissolves in each
volume of liquid solvent at constant temperature is directly
proportional to partial pressure of gas.
Henry law
Sg = KHPg
Where,
• Sg is solubility of gas, expressed as mol/L;
• KH is Henry law constant which is different for each solute-solvent
system
• Pg is partial pressure of the gas in mmHg

Temperature :
• Temperature : As the temperature increases the solubility of most
gases decreases due to increased tendency of gas to expand.

Salting out
• Salting out : Gases are liberated from the solution in which they are
dissolved by the introduction of an electrolyte such as sodium
chloride and non electrolyte such as sucrose.
• This phenomenon is called as “salting out”.
• The resultant escape of gas is due to attraction of salt ions or highly
polar non electrolytes for water molecules which decreases the
density of aqueous environment adjacent to gas molecules.

Effect of chemical reaction
• Effect of chemical reaction : Henry’s law applies to gases that are
slightly soluble in solution and does not react in anyway with the
solvent.
• Gases such as HCl, ammonia show deviations from this law due to
their chemical interaction with the solvent.

Raoult’s law &
Azeotropic binary
solutions (mixture)

Concept
• Mole fraction
• Solution = 20% component A + 80%
component B
• Solution = 0.2 A + 0.8 B
• Partial pressure = Pressure exerted by
one component (e.g. component A)
when it is in solution
• Vapour pressure = Pressure exerted by
one component (e.g. component A)
when it is 100% pure

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
Negative
deviation
Positive
deviation

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 solutions (mixture)
• It is the mixture of liquids that has a
constant boiling point because the vapor
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 liquids in liquids,
(Binary solutions, ideal solutions)

Solubility of Liquid in Liquid
59
• 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).

60
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.

Complete Miscibility
61
• 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.

Partial Miscibility
62
• When water and phenol are mixed, two liquid layers are formed
each containing some of the other liquid in the dissolved state.

Partial Miscibility
• Miscibility is the common solubilities of the components in liquid-
liquid systems.
• Partial miscibility occurs is when the substances only mix partially.
• When mixed, there are two layers formed each layer containing some
of both liquids.
• Of these two mixed layers, each layer contains some of both the
liquids for example, phenol and water

Partial Miscibility
Conjugate solutions
• If water be added to phenol and the mixture shaken, solution will form
up to a certain point; beyond this point further addition of water
result in the formation of two liquid layers,
• one consisting of a saturated solution of water in phenol and the other
a saturated solution of phenol in water.
• These two mutually saturated solutions in equilibrium at a
temperature are called conjugate solutions
• A conjugate system has two partially miscible liquids in contact with
each other

Partial Miscibility
Conjugate solutions
• Phenol-water solution is characterized by increasing mutual solubility
with rise of temperature.
• Thus, when phenol is added to water at the ordinary temperature, a
homogeneous liquid is produced.
• When the concentration of the phenol in the solution has risen to
about 8 %, the addition of more phenol results in the formation of a
second liquid phase, which may be regarded as a solution of water in
phenol

Partial Miscibility
Consulate temperature
• The temperature at which the two layers become identical in
composition and are in fact one layer is known as the critical solution
temperature or the consulate temperature of the system.
• Upper consulate temperature
• Lower consulate temperature

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.
68

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.
69

Distribution
Partition coefficient

Distribution law
• When an excess amount of solute is added to two immiscible liquid
phases, it distributes itself between these phases until saturation, if
mixed by shaking vigorously.
• If insufficient amount of solute is added it distributes in a definite ratio.
• The term partition coefficient is commonly refers to the equilibrium
distribution of single substance between two immiscible solvent
phases separated by a boundary.

Partition coefficients
• Partition coefficients’ are sometimes
called distribution coefficient
• Partition coefficient is a measure of
drugs lipophilicity
• It is commonly determined using
octanol (oil) and water (aq.)

Partition
coefficient
• The partition coefficient is defined as
the ratio of unionized drug distributed
between organic phase and aqueous
phase at equilibrium.
• Ko/w = Co/Cw

Limitations of Distribution Law
• The selected solvent liquid pair must immiscible with each other. Any mutual
solubility must not affect distribution of solute if left aside for enough time to
separate.
• The experimental temperature must be maintained constant. As temperature
has effect on solubility of solute, any change in temperature during
determinations may change the findings.
• The solute in question should be in same molecular state in both the solvents.
If any chemical change is observed the concentration of species common to
both solvents only should be considered.
• Solute must present in both the solvent at low concentrations. At high
concentrations of solutes Nernst’s distribution law does not hold good.
• Samples should be withdrawn for analysis only after achievement of
equilibrium. Early equilibrium attainment can be possible by vigorous shaking.

Applications
• Drug absorption, bioavailability, toxicity, bioaccumulation and
metabolism.
• Since biological membranes are lipoidal in nature the rate of drug
transfer for passively absorbed drugs is directly related to the
lipophilicity of the molecule.
• Effect on dissolution rate, pKa and solubility on absorption
• hydrophobic drug receptor interactions.
• preservative action of weak acids and determination of its optimum
concentration for the effectiveness of action.

Applications
• extraction of drugs from mixtures such as blood, urine and crude
plant extracts
• drug separation by partition chromatography
• structure activity relationship for series of compounds
• To study release of drug from gels, ointments and creams partition
coefficient is a very important consideration.

Solubility of drugs

Solubility of drugs

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