Ch4. solubility and distribution phenomena

Bule Hora University
College of Health and Medical Sciences
Department Of Pharmacy
INTEGRATED PHYSICAL PHARMACY AND PHARMACEUTICS I
CHAPTER 4
Solubility and Distribution
Phenomena
By: Aliyi Gerina [BSc, B.pharm]
4/5/2022
Solubility & Distribution Phenomena by Aliyi Gerina
1

Solubility Phenomena
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Outline
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 Solubility Phenomena
 Terminologies (solute, solvent, solution, solubility)
 Solubility expressions
 Solute-solvent interactions
 Solubility of gases in liquids
 Solubility of liquids in liquids
 Solubility of solids in liquids
 Distribution Phenomena.

Introduction
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 A fundamental understanding of factors affecting solubility
 is important to the pharmacist,
 not only because many drugs are formulated as solution dosage
forms,
 but also because, regardless of dosage form a drug must be in
solution form to be biologically active.
 Thus an understanding of the forces responsible for
 solubility and the
 rate of dissolution are very important concepts in pharmacy.

Terminologies
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 Solute: is the dissolved agent(less abundant part of the solution ).
 Solvent : is the component in which the solute is dissolved (more
abundant part of the solution).

Cont’d,…
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Solubility:
 In a quantitative way: it is the concentration of
solute in a saturated solution at a certain temperature.
 It is intrinsic property of solute.
 In a qualitative way: it is the spontaneous interaction
of two or more substances (solute & solvent)
 to form a homogeneous molecular dispersion .

Cont’d,…
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 A Solution:
 is a mixture of two or more components that form a homogenous mix.
 The components are referred to the solute and/or solutes & the
solvent and/or solvents .
 An unsaturated solution:
 Sub - saturated solution is one containing the dissolved solute in a
concentration below that necessary for complete saturation at a
definite temperature.
 A saturated solution:
 is one in which an equilibrium is established between dissolved and un
dissolved solute at a definite temperature. Or
 A solution that contains the maximum amount of solute at a definite T.
 A supersaturated solution:
 contains more of the dissolved solute than it would normally contain in
a saturated state at a definite temperature.

Importance of Solubility
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 Solubility of a substance serves as a standard test for purity
 Select the best solvent for a drug or a mixture of drugs
 Overcome problems arising during preparation of pharmaceutical
solutions
 Drug molecules are required to present in dissolved form,
 in order to be transported across biological membranes.
 Direct administration of drug into the blood stream is desired
 Development of analytical methods for drug
– Reverse phase liquid chromatography
 Development of sustained release products, taste masking
and enhancement of chemical stability
Solubility reduction

Solubility Expressions
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 The solubility of a substance can be expressed in a number
of ways:
– Percentage, molarity and molality
 In the pharmaceutical field, three concentration terms are often
used these are:
 Percent weight by weight (%w/w)
 which is the number of grams of solute dissolved in 100 grams of
solution.
 Percent volume by volume (%v/v)
 which is the number of mL of solute dissolved in 100 mL of solution.
 Percent weight by volume (%w/v)
 which is the number of grams of solute dissolved in 100 mL of
solution.

Cont’d,…
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 Molarity
 is defined as the number of moles (or gram molecular
weight) of solute dissolved in 1liter(1000ml) of solution.
 Molality
 is defined as the number of moles of solute dissolved in
1kg (1000g) of solvent.
 The USP lists the solubility of drugs as:
 the number of ml of solvent in which 1g of solute will
dissolve.
E.g. 1g of boric acid dissolves in 18 mL of water and in 4 mL
of glycerin.

Table: Terms to approximate solubility
expressions
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Term Parts of solvent required for one
part of solute.
Very soluble less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10,000 parts
Practically insoluble or insoluble more than 10,000 parts

Solvent - Solute Interactions
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 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. Or
 two substances with similar intermolecular forces are likely
to be soluble in each others.
 Polar solutes dissolve in polar solvents.
E.g salts & sugar dissolve in water .
 Non polar solutes dissolve in non polar solvents.
Eg. Naphtalene dissolves in benzene.

Cont’d,…
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 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:
1. If A-A >> A-B. The solvent molecules will be attracted to each
other & the solute will be excluded. Example: Benzene & water,
where benzene molecules are unable to penetrate the closely
bound water aggregates.
2. 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.
3. If A-B >> A-A or B-B, or the three forces are equal .The solute
will form a solution. Example: NaCl in water.

Classification of solvents & mechanism of
action
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1. Polar solvents
2. Non polar solvents
3. Semi polar solvents

Cont’d,…
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A. Polar solvents
 Polar solvents (water, glycols, methyl and ethyl alcohol),
 dissolve other polar substances and ionic solutes.
 Polar solvents acts as a solvent according to the following
mechanisms:
A) Solvation through dipole interaction:
– Polar solvents are capable of solvating molecules and ions
through dipole interaction forces.
– The solute must be polar to compete for the bonds of the
already associated solvent molecules.

Cont’d,…
B) Hydrogen bond formation: Water dissolves phenols,
alcohols , aldehydes , ketones, amines, and other oxygen
and nitrogen containing compounds that can form
hydrogen bonds with water.
4/5/2022
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Cont’d,…
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C) Dielectric constant: due to their high dielectric constant,
 polar solvents reduce the force of attraction between oppositely
charged ions in crystals.
 The dielectric constant is a measure of the influence by a medium
on the energy needed to separate two oppositely charged bodies.
 main-qimg-5559dcebfed0d686870dea42cdeeca88.webp

Cont’d,…
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 The energy required to separate two oppositely charged bodies
is inversely proportional to the dielectric constant of the
medium.
E.g. H20 has a dielectric constant of 80.4 and Vacuum
arbitrarily given a dielectric constant of 1.
• It is much easier to separate charged molecules in
water than in vacuum.
– Example: water possessing a high dielectric constant
(>=80) can dissolve NaCl, while chloroform (>=5) and
benzene (>=2) can not.

Cont’d,…
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D)The ratio of polar to nonpolar groups:
 Solubility of substances in polar solvents depends also on
structural features:
– As the length of a nonpolar chain of an aliphatic alcohol increases,
=> solubility in water decreases .
• Straight chain monohydroxy alcohols, aldehydes & ketones
with » 4 Carbon can not enter into the hydrogen bonded structure
of water and hence slightly soluble in water.
– When additional polar groups are present in the molecule:
• Propylene glycol,
• Glycerin,and
• Tartaric acid,
=> Water solubility increase greatly.

Cont’d,…
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 Branching of the carbon chain reduces the nonpolar effect and
=> leads to increased water solubility.
• Tertiary butyl alcohol is miscible in all proportions with water,
where as n-butyl alcohol dissolves only to a small extent.
– More branching will reduce the size (or volume) of the molecule
and
 make it easier to be solvated with the molecules of solvent.
tert-Butanol n-Butanol

Cont’d,…
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B. Non polar solvents
 Ionic and polar solutes are not soluble or 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.

Cont’d,…
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 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.

Cont’d,…
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C. Semi-polar solvents
 Semi-polar solvents induce certain degree of polarity
in non-polar solvents
 Semi-polar solvents act as intermediate solvents that
generate miscibility between polar and nonpolar liquids.
e.g. Acetone increases the solubility of ether in water.

Some useful generalizations about
solubility
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1. The greater the structural similarity between solute and solvent,
the greater the solubility
( “Like dissolves like”)
2. Organic compounds containing polar groups capable of forming
hydrogen bonds with water are soluble in water,
 The polar groups OH, CHO, COH, CHOH, CH2OH, COOH, NO2, CO,
NH2, and SO3H
 tend to increase the solubility of an organic compound in water.
3. Non polar or very weak polar groups, such as the various
hydrocarbon radicals,
 reduce solubility in water;
 the greater the number of carbon atoms in the radical,
 greater the decrease in solubility.

Cont’d,…
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4. Introduction of halogen atoms (Cl,F) into a molecule in general
tends to decrease solubility in water
 because of an increased molecular weight without a
proportionate increase in polarity.
5.The greater the number of polar groups contained per molecule,
 the greater the solubility of a compound in water;
 provided that the size of the rest of the molecule is not altered;
thus pyrogallol is much more soluble in water than phenol.

Cont’d,…
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6.The relative positions of the groups in the molecule also
influence solubility;
 thus, in water resorcinol (m-dihydroxybenzene) is more soluble
than catechol(o-dihydroxybenzene), and the latter is more
soluble than hydroquinone (p-dihydroxybenzene).
7.Polymers and compounds of high molecular weight can be
poorly soluble.

Cont’d,…
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8. High melting points frequently are indicative of low solubility
for organic compounds.
 One reason for high melting points is the association of molecules, and
this cohesive forces tends to prevent dispersion of the solute in the
solvent.
9. The cis form of an isomer is more soluble than trans form.
10. Acids, especially strong acids, usually produce water-soluble
salts when reacted with nitrogen-containing organic bases.

Types of solubility
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i. Solubility of Gases in liquids
ii. Solubility of Liquids in liquids
iii. Solubility of Solids in liquids

Solubility of Gases in
liquids
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 The solubility of a gas in a liquid
 is the concentration of the dissolved gas when it is in
equilibrium with some of the pure gas above the solution.
 Pharmaceutical solutions of gases include:
 hydrochloric acid and effervescent preparations containing
carbon dioxide that are dissolved & maintained in solution
under positive pressure.
 Aerosol products in which the propellant is either carbon
dioxide or nitrogen,
 some of which is dissolved under pressure.

Factors affecting the solubility of gases in liquids
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 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

Cont’d,…
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1. 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 forces between gas and solvent
molecules.

Cont’d,…
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2. Pressure
 When the pressure above the solution is released
(decreases), the solubility of the gas decreases.
 Increasing the pressure results in more collisions of the
gas molecules with the surface of the solvent (more
solvation); and
=> hence greater solubility.

Cont’d,…
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 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.

Henry's law
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 The effect of the pressure on the solubility of a gas is
expressed by Henry's law
 Henry's law states, ‘Solubility is directly proportional
to partial pressure of gas at a constant temperature’.
S= KP , k solubility coefficient

Cont’d,…
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3. Temperature
 Temperature also has a marked influence on the solubility of
a gas in a liquid.
 As the temperature increases, the solubility of gases decreases
 to the greater tendency of the gas to expand.
 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.

Cont’d,…
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 Solutions of gases are potentially dangerous when exposed to
warm temperature
 because of the libration and expansion of dissolved gas
 which may cause the container to burst.
 The pharmacist exercise caution in opening containers of
gaseous solutions in warm climates & under other conditions of
temperatures.
 A vessel containing a gaseous solution or a liquid with a high
vapor pressure such as ethyl nitrite and strong ammonia solution
 should be immersed in ice or cold water for some time
 to reduce the temperature & pressure of the gas
before opening the container.

Cont’d,…
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4. 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.
 The salting out effect can be demonstrated by adding a small
amount of salt to a “carbonated” solution,
example add salt in soft drinks like coca cola.

Cont’d,…
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 The resultant escape of gas is due to the attraction of salt ions or
the highly polar non electrolyte like sucrose for the water
molecules which reduces the density, structure and dynamics
of the aqueous environment adjacent to the gas molecules and
therefore,
Reduce the solubility of the gas.

Cont’d,…
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5. Effect of chemical reaction
 Henry’s law applies strictly to gases that are only slightly
soluble in solution & do not react in any way in the solvent.
 Gases such as hydrogen chloride, ammonia & carbon
dioxide show deviations as a result of chemical reaction
between the gas & solvent,
=> usually with a resultant increase in solubility.
 Accordingly, hydrogen chloride is about 10,000 times more
soluble in water than is oxygen.

Applications
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 Dissolved gases are removed by heating the solution.
 Distilled water is maintained at 80°C in order to make it
convenient for parenteral use,
 because gases cannot dissolve in water at that temp.
 Dissolved air influences boiling of liquids.
 Dissolution of gaseous anesthesia in blood influenced by
factors mentioned.

Solubility of liquids in
liquids
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 Frequently two or more liquids are mixed together in the
preparation of pharmaceutical solutions.
 For example:
 Alcohol is added to water to form hydroalcoholic solutions
 Volatile oils are mixed with water to form dilute solutions
known as aromatic waters
 Volatile oil are added to alcohol to yield spirits and elixirs
 Various fixed oils are blended into lotions, sprays and
medicated oils.

RAOULT’S LAW
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“The partial pressure (Pi) of each component in a solution
equal to the mole fraction of the component & the vapour
pressure of the pure component”.
Pi = Px
Or
P = PA
0 xA + PB
0 xB
Where PA and PB are the partial vapor pressures of the
constituents over the solution
 when the mole fraction concentrations are XA and XB.
 The vapor pressures of the pure components are PA
0 and
PB
0 respectively.

Ideal and Real solution
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Ideal solutions
 An ideal solution is a solution in which:
 there is no attraction between solute and solvent molecules.
 there is no change in the properties of the components, other
than dilution, when they are mixed to form the solution.
 No heat is evolved or absorbed during the mixing process,
and the final volume of the solution represents and additive
property of the individual constituents.
Stated another way, no shrinkage or expansion occurs
when the substances are mixed.

Cont’d,…
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 Uniformity of intermolecular forces.
 Irrespective of the volume of the solute and solvent they are
miscible to each other
 Obey Raoult’s law over the whole range of composition.
 Mixtures of
 benzene + ethylene chloride and
 ethyl bromide + ethyl iodide are commonly mentioned
systems that exhibit ideal behavior.

Cont’d,…
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Real (Non ideal) 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 adhere to Raoult’s law over entire range of
composition”.

Solubility of solid in liquid
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 Systems of solids in liquids include the
 most frequently encountered and
 probably the most important type of pharmaceutical
solutions.
 Pharmaceutical solutions consists of a wide variety of
 solutes and
 solvents.

Ideal solution
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 Ideal solubility is approached when solute and solvent
are involved in similar intermolecular interactions.
 If the IMFs of attraction are the same type and equal
strength,
 the solvent and solute molecules randomly mix.
 A homogeneous solution results, and
=> an ideal solution.
– “like dissolves like”

Cont’d,…
 Ideal solution: has ∆Hsoln = 0
and certain properties are
predictable from the properties
of the solution components.
 In general, ideal solutions are
rare.
 Solutions of non-polar solutes in non-
polar solvents
 usually come close to being ideal.
Interactions b/n solvent
molecules A-A; solute
molecules B-B; solvent and
solute molecules A-B.
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Solute
Solvent
All same

Non-Ideal solution
 If the IMFs of attraction b/n
unlike molecules exceed those
of like molecules, a solution still
forms.
=>A non-ideal solution results.
 Non-ideal solution: here
∆Hsoln < 0 (exothermic) and
the properties of the solution
components cannot easily
predicted.
 Interactions b/n solvent
molecules B-B; solvent
and solute molecules A-B.
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Solvent
Solute
Force dominates

Cont’d,…
 If the IMF of attraction b/n unlike
molecules exceed those of like
molecules,
 a non-ideal solution results.
 H-bonding b/n CHCl3 (chloroform)
and (CH3)2CO (acetone) molecules
 produces forces of attraction b/n unlike
molecules that exceed those b/n like
molecules.
4/5/2022
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Cont’d,…
 If the IMFs of attraction b/n unlike
molecules is some what weaker than
those of like molecules,
 a non-ideal solution may still result.
 Non ideal solution: here ∆Hsoln > 0
(endothermic) and the properties of
the solution components cannot
easily predicted.
and solute molecules A-B
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Stronger
Weaker

Cont’d,…
 If the IMFs of attraction b/n unlike
molecules is significantly weaker
than those of like molecules,
 the components remain segregated in a
heterogeneous mixture.
 Dissolution does not occur to any
significant extent.
Think: Water and gasoline
and solute molecules A-B.
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Solubility and Heat of solution
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 As a solid solute dissolves,
 it takes in energy to break apart the crystal lattice structure
and
 separate it into ions or molecules to get to the individual ion or
molecule necessary to form a solution.
 The solvent-water-takes in energy to break apart its
hydrogen bonds
 to allow the solute to come in contact with adjacent
molecules of water.
 When the solute and the solvent come together,
 energy is released.

Cont’d,…
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 The overall energy exchange is called the Heat of solution
– The amount of heat energy absorbed or released
when a solute dissolves in a specific amount of a solvent.

Steps of solid going into
solution
1. Step 1: Hole open in the solvent.
Pure solvent => separated solvent molecules,
ΔHa > 0 (endo)
2. Step 2: One molecule of the solid breaks
away from the bulk. Molecule solute =>
separated solute molecules,ΔHb > 0 (endo)
3. Step 3: The solid molecule is enter into the
hole in the solvent.
Separated solvent and solute molecules
dissolve => solution, ΔHc < 0 (exo)
Overall: Pure solvent + pure solute = > sol. ΔH
= ΔHa + ΔHb + ΔHc 4/5/2022
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Solubility of strong electrolytes
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 A rise in T increases the solubility of a solid that
absorbs heat (endothermic process) when it dissolves
and the flask gets cold (more common).
Eg KNO3 , KBr
 The reaction may be exothermic when heat is released
as a result of solubility process, and the flask gets
warm (less common).
Eg Calcium hydroxide , calcium acetate ,
=> in this case solubility decreases as T rises.

Cont’d,…
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 NaCl does not absorb or evolve an appreciable amount
of heat when it dissolves in water;
 thus, its solubility is not altered much by a change of T.
 Sodium sulfate exists in hydrated form, Na2SO4 .
10H2O, up to a T of 32oC
 the solution process is endothermic and
 solubility increases with increase in T.
 Above this point the compound exists as anhydrous
salt, Na2SO4 ,
 the dissolution is exothermic and
 solubility decreases with an increase in T

Cont’d,…
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 Plots of solubility versus temperature, which are referred
to as solubility curves,
 are often used to describe the effect of temperature on a given
system.

Cont’d,…
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32 oC

Solubility of slightly soluble electrolyte
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 When slightly soluble electrolytes are dissolved to
form saturated solution,
 the solubility is described by a special constant, Ksp,
solubility product.
Eg: Silver chloride (AgCl), aluminum hydroxide(Al(OH)3).
 At specific T:
AgCl solid ↔Ag+ + Cl- ; Ksp= [Ag+ ] [Cl-]
Al(OH)3 solid ↔ Al3+ +3OH- ; Ksp = [Al3+] [OH-]3

Cont’d,…
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Common ion effect
 Common ion effect
 can reduce the solubility of slightly soluble electrolytes.
 If an ion in common with AgCl,
 Ag+ or Cl-, is added to the solution of silver chloride,
 the equilibrium is altered.
Eg: the addition of NaCl increases the concentration of Cl-
 so that momentarily [Ag+ ] [Cl-] > Ksp And
 some of the AgCl precipitates from the solution until
equilibrium is , [Ag+ ] [Cl-] =Ksp, re-established

Solubility of weak electrolytes
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 A weak electrolyte forms only a few ions (< 1 %) in solution
with most of the compound staying in a non-ionic form (> 99
%).
 Many important drugs belong to the class of weak acids and
bases.
 The solubility of weak electrolytes is strongly influenced by
 pH of the solution.
 The solubility of a compound, at a given pH,
 is a function of the solubility of the ionized form and
 the limiting solubility of the neutral molecule.

Cont’d,…
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 If the pH of a solution of either a weakly acidic drug or a salt
of such a drug is reduced then the proportion of unionized
acid molecules in the solution increases.
 Precipitation may therefore occur because the solubility of the
unionized species is less than that of the ionized form.
 Conversely, in the case of solutions of weakly basic drugs or
their salts precipitation is favoured by an increase in pH.
 Example: 1% solution of phenobarbital sodium is soluble at
pH values high in the alkaline range.
 The soluble ionic form is converted into molecular
phenobarbital as the pH is lowered, and below 9.3,
 the drug begins to precipitate from solution at room temperature.

Cont’d,…
HA  H2O  H3O A-
pH= pKa + log [(S - So)/So]
S  [HA][A-]
S0 [HA]
pH is the pH below which the drug separates
from solution as the undissociated acid.
B  H2O  BH  OH-
pH= pKa + log [So/(S - So)]
S  [B][BH+ ]
S0  [B]
pH is the pH above which the drug begins to
precipitate from solution as the free base .
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For Weakly acidic drug For weakly basic drug
From equation we can calculate:
 If the pH of the solution is known then we can calculate the solubility of an
acidic/basic drug at that pH.
 Minimum pH that must be maintained in order" to prevent precipitation from a
solution of known concentration".
So= Solubility of unionized free drug
S = Total solubility of drug (un-ionized + ionized).

Example
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 Below what pH will free phenobarbital begin to separate from
a solution having an initial concentration of 0.0393.The molar
solubility of phenobarbital, So, is 0.005 and the pKa is 7.41 at
25°C.
 S=0.0393
 So=0.005
 Pka=7.41
pH = 7.41 + log (0.0393-0.005/0.005)
pH = 7.41 + log 6.86
pHp = 8.24

Strong vs. weak acids and bases
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1. Strong – ionized at all pHs.
2. Weak – only ionized at certain pHs (most drugs are weak acids
or weak bases.
3. Ionized drugs are not very lipid soluble
- only non ionized form of drug crosses membrane readily.
4. Percent ionization is pH dependent
5. pKa is the negative log of the ionization constant and
is equal to the pH at which a drug is 50% ionized.
6. Weak acids become highly ionized as pH increases.
7. Weak bases become highly ionized as pH decreases.

Computing Ionization Ratios
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 According to the Henderson-Hasselbalch equation,
 the difference between the pH of the solution and the pKa of
the drug is the common logarithm of the ratio of ionized to
unionized forms of the drug.
 For acid drugs
log(ionized/unionized) = pH – pKa , OR
ratio of ionized to unionized is 10X/ 1, where
X = pH – pKa
 For basic drugs,
• everything is the same except that the ratio reverses:
Log(unionized/ionized) = pH – pKa, or
Ratio of unionized to ionized is 10X/ 1, where
X = pH – pKa

Determines extent of ionization
WEAK ACIDS:
pH= pKa + log[A-]
[HA]
 pH – pKa=log (Ionized/Unionized)
WEAK BASES:
pH= pKa + log[B]
[BH+]
 pH – pKa)=log (Unionized/Ionized
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Henderson-Hasselbalch equation
 pKa = pH at which 50% of drug is ionized.

PASSIVE DIFFUSION
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 Water soluble drug (ionized or
polar) is readily absorbed via
 aqueous channels or pores in cell
membrane.
 Lipid soluble drug (non ionized or
non polar) is readily absorbed via
 cell membrane itself.

Examples
 P weak acid, has a pKa of 5.5. Taken
orally, it is in a stomach solution of
pH 3.5.
pH – pKa = 3.5 – 5.5 = -2
 Since it is an acid drug, we use the
alphabetical formula:-
Ionized/unionized = 10-2/1
= 1/100
 For every 1 molecule of P that is
ionized, 100 are unionized.
 P in the stomach is highly fat soluble.
 The highly fat soluble P
readily crosses the stomach
membranes and enters blood
plasma, which has a pH of 7.5.
pH – pKa = 7.5 – 5.5 = 2
Ionized/unionized=102/1
= 100/1
 For every 100 molecules of P
that are ionized, only 1 is
unionized.
 P in the blood is not very fat
soluble.
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Cont’d,…
 M, a weak base with a pKa of 7.5
is dissolved in the stomach, pH
3.5.
pH – pKa = 3.5 – 7.5 = -4
 Since M is a base drug, we use the
ratio backwards:
unionized/ionized = 10-4/1= 1/10,000
 In the stomach, M will be mostly
ionized, and not very fat soluble.
 If we inject M
intravenously into the
blood, with a pH of 7.5,
pH – pKa = 7.5 – 7.5 = 0
unionized/ionized = 100= 1/1
 In the blood, M will be
equally ionized and
unionized.
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# Quiz 5%
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1. If 8.66 mg/ml procaine solution stable (i.e., no ppt.) at
pH 7.4 given that 1 gm dissolves in 200 ml water and
pka = 8.05. Justify it.1 pt
2. pKa of Aspirin [weak acid] = 3.4
pH stomach = 1.4 pH blood = 7.4
A. What is the percent ionization of Aspirin in
the Stomach and justify it? 2 pt
B. What is the percent ionization of Aspirin in
the Blood and justify it? 2pt

Factors influencing solubility
1-Temperature
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 Generally, an increase in the temperature of the solution
increases the solubility of a solid solute.
 A few solid solutes are less soluble in warm solutions.
 For all gases, solubility decreases as the temperature of the
solution increases.
 For effect of T on solubility we have to take consider two
criteria:
 If the solution process absorbs energy then the solubility will be
increased as the temperature is increased.
 If the solution process releases energy then the solubility will
decrease with increasing temperature.

2- PH
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 is one of the primary influences on the solubility of most
drugs that contain ionizable groups.
 Solubility depends on the degree of ionization.
 Degree of ionization depends on the Ph.
 1. Non ionizable substances
– Little effect of pH on non ionizable substances
– Solubility can be increased by change of dipole moment
2. Ionizable substances
– Depends on HEDERSON-HESSELBALCH equation.

3- Particle size (surface area)
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 As the PS decreases solubility increases
 due to increase in the surface area
 meaning more of the solid is in contact with the solvent.
 But after very small PS decrease in PS will decreases solubility
 due to formation of agglomerates.

4- Crystal properties
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 Solids exist as either
 Non crystalline or amorphous compounds or
 Crystalline compounds depending on internal structure of
the compounds.
 Crystalline compounds are characterized by repetitious
spacing of constituent atom or molecule in three dimensional
array( lattice).

Cont’d,…
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 When substances exists in more than one crystalline form, the
different form are designated as polymorphs and the phenomenon
as polymorphism.
 Polymorphs are two crystals that have the same composition , but
different arrangement of molecules or crystal packing.
 Polymorphs have the same chemical structure but different
physical properties, such as
 Melting point
 Solubility
 Density and
 Stability
 General there is a correlation between the melting point of
the different polymorphs and solubility.
 Polymorphs with high melting points have low solubility.

Cont’d,…
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 Amorphous forms are, by definition, non-crystalline materials,
 i.e., they do not have well defined molecular structure.
 In amorphous form atom or molecule are randomly placed.
 A drug that exists as an amorphous form (non crystalline form)
 generally dissolves more rapidly than the same drug in
crystalline form.

Cont’d,…
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Cont’d,…
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 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 un-solvated crystals will dissolve faster.

5- Boiling and Melting Point
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 Both reflect the strengths of interactions between the
molecules in the pure liquid or the solid state.
 In general, aqueous solubility decreases with
 increasing boiling and melting point.

6- Molecular size
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 Molecular size will affect the solubility.
 The larger the molecule or the higher its molecular weight the
less soluble the substance.
 Larger molecules are more difficult to surround with solvent
molecules in order to solvate the substance.
 In the case of organic compounds the amount of carbon
branching will increase the solubility
 since more branching will reduce the size (or volume) of the molecule
and make it easier to solvate the molecules with solvent

7-The influence of substituents
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 The influence of substituents on the solubility of
molecules in water
 can be due to their effect on the properties of the solid or
liquid
 for example, on its molecular cohesion, or to the effect of
the substituent on its interaction with water molecules.
 Substituents can be classified as either
 hydrophobic or
 hydrophilic, depending on their polarity.

Cont’d,…
 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.
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Cont’d,…
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 The position of the substituent on the molecule can
influence its effect on solubility,
 for example the aqueous solubilities of o-, m- and p
dihydroxybenzenes

8-The influence of Surfactants
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 Surfactants are termed as surface-active agents also wetting
agents, emulsifying agents or suspending agents depending on its
properties and use.
 Surface-active agents are substances which, at low
concentrations, adsorb onto the surfaces or interfaces of a system
and
 alter the surface or interfacial free energy and the surface or interfacial
tension.
 Surfactants are monomers, it has a characteristic structure
possessing both
 hydrophobic groups / non-polar regions (their "tails") and
 hydrophilic groups / Polar Regions(their heads).
 Therefore, they are soluble in both organic solvents and water, so
they called amphiphilic.

Cont’d,…
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 The functional groups such as
 alcoholic (-OH), carboxylic acid (-COOH), sulphate (-SO4) &
quaternary ammonium(NH4+) contribute to hydrophilic
portion.
 alkyl chains contribute to lipophilic nature of molecules
 The polar end is oriented towards the water and the non polar end
is projected upwards to space.

Cont’d,…
Surfactants can work in three different
ways:
(a)Roll-up mechanism:
 The surfactant lowers the oil/solution
and fabric/solution interfacial tensions
and
 in this way lifts the stain of the fabric.
(b)Emulsification:
 The surfactant lowers the oil/solution
interfacial tension and
 makes easy emulsification of the oil.
(c)Solubilization :
 Through interaction with the micelles of
a surfactant in a solvent (water),
 a substance spontaneously dissolves to
form a stable and clear solution. 4/5/2022
88

9-Complexation as solubility enhancing
mechanism
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 It is reversible association of a substrate and ligand molecule.
 The most common complexing ligands are
 cyclodextrins , caffeine, urea, polyethylene glycol, N -methyl
glucamide.
 Cyclodextrins are unique
 since they increase the water solubility of poorly soluble drugs
 by fitting them into the hydrophobic cavity of the cyclodextrin
molecule.
 These cyclodextrins have the ability to form molecular inclusion
complexes with
 hydrophobic drugs having poor aqueous solubility.

Cont’d,…
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90
 These are formed by the insertion of the non polar molecule or
the non polar region of one molecule into the cavity of another
molecule or group of molecules.
 The most commonly used host molecules are cyclodextrins .
 Cyclodextrins are non- reducing, crystalline , water soluble,
cyclic, oligosaccharides.
 Cyclodextrins consist of glucose monomers arranged in a
donut shape ring. Hydrophillic
Hydrphobic

Cont’d,…
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 Complexation of drugs with cyclodextrins
 has been used to enhance aqueous solubility and drug stability.
 Cyclodextrins of pharmaceutical relevance
 contain 6, 7 or 8 dextrose molecules (α, β, γ-cyclodextrin) bound in a
1,4-configuration to form rings of various diameters.
 The ring has a hydrophilic exterior and lipophilic core in which
appropriately sized organic molecules can form non covalent inclusion
complexes
 resulting in increased aqueous solubility and chemical stability.
 Complexation relies on relatively weak forces
 such as London forces, hydrogen bonding and hydrophobic
interactions.

10- The influence solvents on the
solubility of drugs
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 Substances like weak electrolytes and non-polar molecules are
poorly soluble in water
 The solubility of these substances can be enhanced by the addition of
water miscible solvents in which the drug has good solubility.
 The nonelectrolytes and the undissociated molecules of weak
electrolytes more soluble in a mixture of solvents than in one
solvent alone.
 This phenomenon is known as cosolvency, and
 the solvents that, in combination, increase the solubility of the
solute are called cosolvents.
 This technique is mainly used in the formulation of parenterals.
 Commonly used co-solvents are
 Ethanol, Sorbitol, Glycerin, Polyethylene glycol, propylene glycol etc

Cont’d,…
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 The solubilizing effect by co-solvency depends on the polarity
of the drug with respect to solvent and co-solvent.
 That means more non-polar the solute the greater is the solubilization
achieved by the added solvents .
 Mechanism responsible for solubility enhancement through co-
solvency is
 by reducing the interfacial tension predominantly between the
aqueous solution and hydrophobic solutes and
 by reducing the contact angle between the solid and liquid.

Cont’d,…
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 Co-solvents increases the solubility by reducing the difference
between the polarity of the drug and water system
Ex. For co-solvency
 The solubility of Diazepam can be increased by using 10% ethanol
and 40% propylene glycol.
 Phenobarbitone is relatively insoluble in water but its solubility can be
increased by using mixture of solvents like water, alcohol and glycerin.

Distribution Phenomena
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Partition Coefficient (K)
Definition
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 If a substance which is soluble in both components of a
mixture of immiscible liquids is dissolved in such a
mixture
 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 concentration of the substance in
each liquid is a constant.
 This is known as the Nernst distribution law or partition law.

Cont’d,…
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• Co is molar conc. in organic layer
• Cw is molar conc. in aqueous layer
• Kd is partition coefficient ,
distribution constant or distribution
ratio.

Example for distribution coefficient
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Partition coefficient(p)
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 Partition Coefficient (oil/ water) is a measure of a drug’s
lipophilicity and
 an indication of its ability to cross cell membranes.
 Molecules of the solute will distribute in each phase until
equilibrium is established.
 It is defined as the ratio of unionized drug distributed
between the organic and aqueous phases at equilibrium.
Log P =[Un-ionized Cpd]org
[Un-ionized Cpd]aq.

Cont’d,…
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 The most common method for determining partition and
distribution coefficients is the shake flask method.
 In this technique, the candidate drug is shaken between
 octanol (previously shaken together to pre saturate each
phase with the other) and
 water layers, from which an aliquot is taken and analyzed
using UV absorption, HPLC or titration.
 Octanol was chosen as the model lipid phase because it most
closely simulates the properties of biological membranes.

Interpretation
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 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
 The substituent that increase P value are -alkyl, -aryl,
halogens
 The substituent that decrease P value are -COOH, -NH2, -
O, -CO , -OH

Application of distribution concepts
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 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 crud drugs.

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Thank You!!!!

Ch4. solubility and distribution phenomena

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