College of Medicine and Health Sciences

Department of Pharmacy

Solubility and Distribution Phenomena

By: Tsegaye N. (B. Pharm, MSc in Pharmaceutics)

[email protected]
4/5/2022

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Solubility Phenomena

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Outline
3

 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.

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Introduction

 A fundamental understanding of factors affecting solubility is important,

 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.

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Terminologies

 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).

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Cont…

 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 .

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Cont…

 A Solution:
 Is a mixture of two or more components that form a homogenous mixture.
 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.

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Cont…

 A saturated solution:
 Is one in which an equilibrium is established between dissolved and
undissolved solute at a definite temperature. Or
 A solution that contains the maximum amount of solute at a definite To.
 A supersaturated solution:
 Contain more of the dissolved solute than would normally contain in a
saturated state at a definite temperature

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Importance of Solubility
 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

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Solubility Expressions

 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.

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Cont…
 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.

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Table: Terms to approximate solubility

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

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Solute – Solvent Interactions
 In pre or early formulation, selection of the most suitable solvent is based on
the principle of
 “like dissolves like”
 That is, a solute dissolves best in a solvent with similar chemical properties.
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.
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Cont…

 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
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Classification of solvents & mechanism of action
14

1. Polar solvents
2. Non polar solvents
3. Semi polar solvents

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Cont…
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:
 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.

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Cont…
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.

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Cont…
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.

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Cont…
 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.

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Cont…
 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 => Water solubility increase greatly.
 Tartaric acid,

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Cont…
 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

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Cont…

 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.

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Cont…
 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.

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Cont…

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.

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Some useful generalizations about solubility
 The greater the structural similarity between solute and solvent, the greater the
solubility
 ( “Like dissolves like”)
 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.
 Non polar or very weak polar groups, such as the various hydrocarbon radicals,
 Reduce solubility in water; the greater number of Carbone atom in radically greater the
decrease in solubility

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Cont…
 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.
 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.

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Cont…
 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).

 Polymers and compounds of high molecular weight can be poorly soluble.

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Cont…
 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.
 The cis form of an isomer is more soluble than trans form.

 Acids, especially strong acids, usually produce water-soluble salts when reacted
with nitrogen-containing organic bases.
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Types of solubility

I. Solubility of Gases in liquids

II. Solubility of Liquids in liquids

III. Solubility of Solids in liquids

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Solubility of Gases in liquids

 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.

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Factors affecting the solubility of gases in liquids

 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

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Cont…
 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.

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Cont…
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.

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Cont…
 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.

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 Henry's law

 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

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Cont…
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.

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 Cont’d,…

 Solutions of gases are potentially dangerous when exposed to warm temperature

 Because of the liberation 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.

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Cont…

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.

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Cont…
 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.

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Cont…

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.

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Applications

 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.

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Solubility of liquids in liquids
 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.

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Raoult’s Law

 “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 = PA0 XA + P0B X B

 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 PB0 respectively
.

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Ideal and Real solution

 Ideal solutions
 Is no attraction between solute and solvent molecules. Or
 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.

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Cont…

 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.

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Cont…
 Real (Non ideal) solutions
 Is the "cohesive“ force of attraction between A for A exceeds the "adhesive" force
of attraction existing between A and B . Or,
 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”.

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Solubility of solid in liquid

 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.

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Ideal solution
 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”

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Cont…
 Ideal solution: has ∆Hsoln = 0 and Interactions b/n solvent molecules A-
certain properties are predictable from the A; solute molecules B-B; solvent and
properties of the solution components. solute molecules A-B.
 In general, ideal solutions are rare. Solute

 Solutions of non-polar solutes in non-

polar solvents
 Usually come close to being ideal.

Solvent
All same

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Non-Ideal solution
49

 If the IMFs of attraction b/n unlike  Interactions b/n solvent molecules A-

molecules exceed those of like a molecules A; solute molecules B-B; solvent
solution, and solute molecules A-B
=>A non-ideal solution results.
 Non-ideal solution: here
 ∆Hsoln < 0 (exothermic) and the Force dominates Solute

properties of the solution components

cannot easily predicted.

Solvent

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Cont…

 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.

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Cont…
 If the IMFs of attraction b/n unlike molecules Interactions b/n solvent molecules
A-A; solute molecules B-B;
is some what weaker than those of like
solvent and solute molecules A-B
molecules, a non-ideal solution may still result
 Non ideal solution: here ∆Hsoln > 0, Stronger
(endothermic) and the properties of the
solution components cannot easily predicted.

Weaker

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Cont…
 If the IMFs of attraction b/n unlike Interaction b/n solvent molecules A-
molecules is significantly weaker than A; solute molecules B-B; solvent and
solute molecules A-B
those of like molecules,
 The components remain segregated in a
heterogeneous mixture.
 Dissolution does not occur to any
significant extent.
 Think: Water and gasoline

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Solubility and Heat of solution

 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

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Cont…
 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.

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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

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Solubility of strong electrolytes

 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.

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Cont…
 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 decrease with increase in To

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Cont…
 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.

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Cont…

32 oC

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Solubility of slightly soluble electrolyte

 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

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Cont…

 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
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Solubility of weak electrolytes

 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.

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Cont…
 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 be precipitation of solution at room temp.
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Cont…

For Weakly acidic drug For weakly basic drug

HA  H2O  H3O A- B  H2O  BH  OH-
pH= pKa + log [(S - So)/So] pH= pKa + log [So/(S - So)]
S  [HA][A-]
S  [B][BH+ ]
S0 [HA] S0  [B]
pH is the pH below which the drug pH is the pH above which the drug begins to
separates solution as the undissociated acid .from precipitate from solution as the free base

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).

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Example

 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

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Strong vs. weak acids and bases

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.

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Computing Ionization Ratios

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

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Determines extent of ionization

Henderson-Hasselbalch equation
 pKa = pH at which 50% of drug is ionized.
Weak Acids: Weak Bases:
pH= pKa + log[A-] pH= pKa + log[B]
[HA] [BH+]
pH – pKa=log (Ionized/Unionized)
pH – pKa)=log (Unionized/Ionized

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Passive Diffusion

 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.

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Examples
 P weak acid, has a pKa of 5.5.  The highly fat soluble P readily
 Takenorally, it is in a stomach solution of crosses the stomach membranes and
pH 3.5. enters blood plasma, which has a pH
of 7.5. pH – pKa = 7.5 – 5.5 = 2
 pH – pKa = 3.5 – 5.5 = -2
 Ionized/unionized =102/1
 Since it is an acid drug, we use the
alphabetical formula:- = 100/1
Ionized/unionized = 10-2/1  For every 100 molecules of P that
 = 1/100 are ionized, only 1 is unionized.
 P in the blood is not very fat
 For every 1 molecule of P that is
ionized, 100 are unionized. soluble.

 P in the stomach is highly fat soluble.

4/27/2025 Solubility & Distribution Phenomena 71
Cont…
 M, a weak base with a pKa of 7.5  If we inject M intravenously into
 is dissolved in the stomach, pH 3.5. the blood, with a pH of 7.5, pH –
pKa = 7.5 – 7.5 = 0
 pH – pKa = 3.5 – 7.5 = -4
 unionized/ionized = 100= 1/1
 Since M is a base drug, we use the ratio
backwards:  In the blood, M will be
equally ionized and unionized.
 unionized/ionized = 10-4/1= 1/10,000
 In the stomach, M will be mostly
ionized, and not very fat soluble.

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Quiz 5%
72

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

4/27/2025 Solubility & Distribution Phenomena 73

Factors influencing solubility
1-Temperature
 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.

4/27/2025 Solubility & Distribution Phenomena 74

2- PH
 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.

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3- Particle size (surface area)

 As the particle size 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.

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4- Crystal properties

 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).

4/27/2025 Solubility & Distribution Phenomena 77

Cont…
 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

4/27/2025 Solubility & Distribution Phenomena 78

Cont…

 General there is a correlation between the melting point of the different

polymorphs and solubility.
 Polymorph with high melting point have low solubility
 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.

4/27/2025 Solubility & Distribution Phenomena 79

Cont…

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Cont…
 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.

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5- Boiling and Melting Point

 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.

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6- Molecular size

 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

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7-The influence of substituents

 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.

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Cont…
 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…
 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

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8-The influence of Surfactants

 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
 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

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Cont…
 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.

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Cont…
 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 from a solution

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9-Complexation as solubility enhancing mechanism

 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.

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Cont…
 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

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Cont…

 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.
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 10- The influence solvents on the solubility of drugs

 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.

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Cont…

 This technique is mainly used in the formulation of parenteral.

 Commonly used co-solvents are
 Ethanol, Sorbitol, Glycerin, Polyethylene glycol, propylene glycol etc.
 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 .

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Cont…

 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.
 Co-solvents increases the solubility by reducing the difference between the polarity
of the drug and water system

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Cont…
 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.

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 Distribution Phenomena

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Partition Coefficient (K)

 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.

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Cont…

 Co is molar conc. in organic layer

 Cw is molar conc. in aqueous layer
 Kd is partition coefficient , distribution
constant or distribution ratio.

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Example for distribution coefficient

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Partition Coefficient (K)
 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.
𝐶𝑜𝑛𝑝𝑜𝑢𝑛𝑑 𝑜𝑐𝑡𝑎𝑛𝑜𝑙
P= 𝐶𝑜𝑛𝑝𝑜𝑢𝑛𝑑 𝑤𝑎𝑡𝑒𝑟

[Un−ionized Cpd]𝑜𝑟𝑔
Log P = [Un−ionized Cpd]aq. or log P=log10(P)

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Cont…
 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.

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

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Application of distribution concepts

 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!!!!
Q???

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