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Solubility and Distribution


Phenomena
Muhammaad Dzakwan
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Objectives of the Chapter

After completion of this chapter, the student should be able to:

1. Understand the various types of pharmaceutical solutions.

2. Define solubility, saturated & unsaturated solutions and polar & non
polar solvents.

3. Understand the factors controlling the solubility of strong & weak


electrolytes.

4. Define partition coefficient & its importance in pharmaceutical


systems.
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Importance of studying the
phenomenon of solubility
Understanding the phenomenon of solubility helps the pharmacist to:

1. Select the best solvent for a drug or a mixture of drugs.

2. Overcome problems arising during preparation of pharmaceutical


solutions.

3. Have information about the structure and intermolecular forces of the


drug.

4. Many drugs are formulated as solutions, or added as powder or solution


forms to liquids.

5. Drugs with low aqueous solubility often present problems related to their
formulation and bioavailability.
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Definitions

 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 .

 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).

 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 temperature

 An unsaturated solution: or subsaturated solution is one containing the


dissolved solute in a concentration below that necessary for complete
saturation at a definite temperature.
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Solubility

 A supersaturated solution: contains more of the dissolved solute


than it would normally contain in a saturated state at a definite
temperature.

Solubility:

 In a quantitative way: it is the concentration of solute in a saturated


solution at a certain temperature

 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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Degree of saturation

Unsaturated, Saturated or Supersaturated?

 How much solute can be dissolved in a solution?


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Solubility Curve

 Any solution can be made saturated, unsaturated, or


supersaturated by changing the temperature.
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Thermodynamic solubility of
drugs
 The thermodynamic solubility of a drug in a solvent is the maximum
amount of the most stable crystalline form that remains in solution
in a given volume of the solvent at a given temperature and pressure
under equilibrium conditions.

The equilibrium involves a balance of the energy of three interactions


against each other:

(1) solvent with solvent

(2) solute with solute

(3) solvent and solute


+

Steps of solid going into solution.

1. Step 1: Hole open in the solvent

2. Step 2: One molecule of the solid breaks away from the bulk

3. Step 3: The solid molecule is enter into the hole in the solvent
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Solubility process

A mechanistic perspective of solubilization process for organic solute


in water involves the following steps:

1. Break up of solute-solute intermolecular bonds

2. Break up of solvent-solvent intermolecular bonds

3. Formation of cavity in solvent phase large enough to


accommodate solute molecule

4. Transfer of solute into the cavity of solvent phase

5. Formation of solute-solvent intermolecular bonds


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Tree types of interaction in the
solution process
1. solvent – solvent interaction
2. solute – solute interaction
3. solvent solute interaction

ΔH sol = ΔH 1 + ΔH 2 + ΔH 3
+
Enthalpy

 The enthalpy change of solution refers to the overall amount


of heat which is released or absorbed during the dissolving
process (at constant pressure).

 The enthalpy of solution can either be positive (endothermic


reaction) or negative (exothermic reaction).

 The enthalpy of solution is commonly referred to as ΔH


solution.
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Expression Symbol Definition

Molarity M, c Moles (gram molecular weights) of solute in 1 liter

(1000 ml) of solution.

Molality m Moles of solute in 1000 gm of solvent.

Solubility expressions
Normality N Gram equivalent weights of solute in 1 liter of

solution

Mole Fraction x Ration of moles of solute to total moles of solute+

solvent

Percentage by % w/w gm of solute in 100 gm of solution

Weight

Percentage by %v/v ml of solute in 100 ml of solution

Volume

Percentage % w/v gm of solute in 100 ml of solution

Weight in Volume
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Solubility expressions

 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.

 Substances whose solubility values are not known are described by


the following terms:
Term Parts of solvent required for 1
part of solute
Very soluble Less than 1 part
Freely soluble 1 to 10 parts
Soluble 10 to 30 parts
Sparingly soluble 30 to 100 parts
Slightly soluble 100 to 1000 parts
Very slightly soluble 1000 to 10 000 parts
Practically insoluble More than 10 000 parts
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Biopharmaceutics
Classification System (BCS)
 BCS is a scientific framework for classifying Drug substances
according to their aqueous solubility and their intestinal permeability
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Solubility expressions: BCS

High solubility

 The highest single unit dose is completely soluble in 250 ml


or less of aqueous solution at pH 1 - 6.8 (37 °C)

Xanax (alprazolam)
anxiety disorder
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Solvent - Solute 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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POLAR SOLUTE - POLAR
SOLVENT
Ammonia Dissolves in Water:

 Polar ammonia molecules dissolve in polar water molecules.

 These molecules mix readily because both types of


molecules engage in hydrogen bonding.

 Since the intermolecular attractions are roughly equal, the


molecules can break away from each other and form new
solute (NH3), solvent (H2O) hydrogen bonds.
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Alcohol Dissolves in Water:

 The -OH group on alcohol is polar and mixes with the polar
water through the formation of hydrogen bonds.

 A wide variety of solutions are in this category such as sugar


in water, alcohol in water, acetic and hydrochloric acids.
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Solute-Solvent interactions
 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.
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Classification of solvents & their
mechanism of action

1. Polar solvents

2. Non polar solvents

3. Semi polar solvents


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Polar solvents
 The solubility of a drug is due in large measure to the polarity of the solvent,
that is, to its dipole moment. Polar solvents dissolve ionic solutes and other
polar substances.

 The ability of the solute to form hydrogen bonds is a far more significant
factor than is the polarity as reflected in a high dipole moment

Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.
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Polar solvents
 The solubility of a substance also depends on structural features such
as the ratio of the polar to the nonpolar groups of the molecule.

 As the length of a nonpolar chain of an aliphatic alcohol increases, the


solubility of the compound in water decreases

 Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids


with more than four or five carbons cannot enter into the hydrogen-
bonded structure of water and hence are only slightly soluble.
+Polar solvents

 When additional polar groups are present in the molecule, as found


in propylene glycol, glycerin, and tartaric acid, water solubility
increases greatly.

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, whereas n-butyl alcohol
dissolves to the extent of about 8 g/100 mL of water at 20°C.

tert-Butanol n-Butanol
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Hydrogen bonding is the attractive


interaction of a hydrogen atom with an
electronegative atom, such as nitrogen,
oxygen

Dipole-dipole forces are electrostatic interactions of


permanent dipoles in molecules.
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Non polar solvents

 Non-polar solvents are unable to reduce the attraction between the


ions of strong and weak electrolytes because of the solvents' low
dielectric constants.

 They are unable to form hydrogen bonds with non electrolytes.

 Non polar solvents can dissolve non polar solutes through weak van der
Waals forces

 Example: solutions of oils & fats in carbon tetrachloride or benzene.

Polyethylene glycol 400

Castor oil
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Semi polar solvents

 Semi polar solvents, such as ketones can induce a certain degree of


polarity in non polar solvent molecules. For example, benzene, which
is readily polarizable, becomes soluble in alcohol

 They can act as intermediate solvents to bring about miscibility of


polar & non polar liquids.

Example: acetone increases solubility of ether in water.

Propylene glycol has been shown to increase the mutual solubility of


water and peppermint oil and of water and benzyl benzoate
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Polarity as Dielectric Constant of Solvent, ε
decrease , the solubility also decrease
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Polarity
 The solubility of the drug substance is attributable in large part to the
polarity of the solvent, often expressed in terms of dipole moment,
related to the dielectric constant.

 Solvents with high dielectric constants dissolve ionic compounds


(polar drugs) readily because of ion–dipole interactions,

 Solvents with low dielectric constants dissolve hydrophobic


substances (non-polar drugs)

 polar solvents, with examples such as water and glycerin;

 non-polar solvents, with example such as oils.

 Solvents with intermediate dielectric constants are classified as


semipolar.
+ Types of solutions

Solutions of pharmaceutical importance include:

 Gases in liquids

 Liquids in liquids

 Solids in liquids
+ Solubility of gases in liquids

When the pressure above the


solution is released (decreases),
the solubility of the gas
decreases

As the temperature increases the


solubility of gases decreases
+Solubility of liquids in liquids

 Preparation of pharmaceutical solutions involves mixing of 2 or more liquids

 Alcohol & water to form hydroalcoholic solutions

 volatile oils & water to form aromatic waters

 volatile oils & alcohols to form spirits , elixirs

Liquid-liquid systems may be divided into 2 categories:

1. Systems showing complete miscibility such as alcohol & water, glycerin & alcohol,
benzene & carbon tetrachloride.

2. Systems showing Partial miscibility as phenol and water; two liquid layers are
formed each containing some of the other liquid in the dissolved state.

The term miscibility refers to the mutual solubility of the components in liquid-liquid
systems.
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Solubility of liquids in liquids

 Complete miscibility occurs when: The adhesive forces between


different molecules (A-B) >> cohesive forces between like molecules
(A-A or B-B).

 Polar and semipolar solvents, such as water and alcohol, glycerin


and alcohol, and alcohol and acetone, are said to be completely
miscible because they mix in all proportions.

 Nonpolar solvents such as benzene and carbon tetrachloride are


also completely miscible.
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Solubility of liquids in liquids

 Partial miscibility results when: Cohesive forces of the constituents of a mixture


are quite different, e.g. water (A) and hexane (B). A-A » B-B.

 When certain amounts of water and ether or water and phenol are mixed, two
liquid layers are formed, each containing some of the other liquid in the
dissolved state.

 The effect of temperature on the miscibility of two-component liquids is


expressed by phase diagrams.

 In the phase diagrams of two-component liquids, the mixture will have an upper
critical solution temperature, a lower critical solution temperature or both.
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Three-Component Systems

Polyethylene glycol

water
Peppermint oil
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Three-Component Systems
IPA

Methyl salicylate water


+

Solubility of solids in
liquids
+ Solubility of solids in liquids
Factors influencing solubility
1- Particle size (surface area) of drug particles

↓Particle size → ↑ surface area→ ↑Solubility


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Solubility of solids in liquids
Factors influencing solubility

o So is the solubility of large particles


o S is the solubility of fine particles
o γ is the surface tension of the particles
o V is molar volume
o T is the absolute temperature
o r is the radius of the fine particle
o R is the gas constant
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Example

 A solid is to be comminuted so as to increase its solubility by 10%,


that is s/so is to become 1.10

 What must be the final particle size, assuming that the surface
tension of the solid is 100 dynes/cm and the volume per mile is 50
cm3? The temperature is 27oC

Answer: 0.042µm
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Solubility of solids in liquids
Factors influencing solubility
2- 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
+ Solubility of solids in liquids
Factors influencing solubility
3- The boiling point of liquids and the melting point of
solids:

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 point and melting point.
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Solubility of solids in liquids
Factors influencing solubility

4-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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Influence of substituents on the
solubility

 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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Influence of substituents on the
solubility
 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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Solubility of solids in liquids
Factors influencing solubility
5-Temperature

 Temperature will affect solubility. 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.

 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.
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Solubility of solids in liquids
Factors influencing solubility
6-Crystal properties

Polymorphic Crystals, Solvates, Amorphous forms

Polymorphs have the same chemical structure but different physical properties,
such as solubility, density, hardness, and compression characteristics
A drug that exists as an amorphous form (non crystalline form) generally
dissolves more rapidly than the same drug in crystalline form
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Solubility of solids in liquids
Factors influencing solubility
7- PH

 is one of the primary influences on the solubility of most drugs that contain
ionizable groups

 Large number of drugs are weak acids or weak base.

 Solubility depends on the degree of ionization.

 Degree of ionization depends on the pH

About 85% of marketed drugs contain functional groups that are ionised
to some extent at physiological pH (pH 1.5 – 8).
+Carboxylic acids containing
more than five carbons are
relatively insoluble in water, carboxyl group (RCO2H)
they react with dilute sodium
hydroxide, carbonates and
bicarbonates to form soluble
salts.
As the number of carbons in a
carboxylic acid series becomes
greater, the boiling point
increases and the solubility in
water decreases.
+

Carboxylic acids with 12 to 20 carbon atoms are often referred to as fatty


acids
Fatty acids containing more than 10 carbon atoms form soluble soaps
with the alkali metals. They are soluble in solvents having low dielectric
constants; for example, oleic acid (C17H33COOH) is insoluble in water but
is soluble in alcohol and in ether.

Benzoic acid is soluble in sodium hydroxide solution

Phenol is weakly acidic and only slightly soluble in water but quite
solution in dilute NaOH solution.
Organic compounds containing a basic nitrogen atom
Most of these weak electrolytes are not very soluble in water but are
soluble in dilute solutions of acids
+  
HP  H 2O  H 3O  P

[ H 3O  ][ P  ] [ P 
]
Ka  
log K a  log[ H 3O ]  log( )
[ HP ] [ HP ]

 [ P ]
 log[ H 3O ]   log K a  log( )
[ HP ]
S The total solubility of drug ( un-ionized + ionized) S  [ HP ]  [ P  ]

S solubility of the un-ionized form of drug in solution S  [HP ]


S  S
pH p  pK a  log
S
+ The equation relating the solubility, S, of an
acidic drug to the pH of the solution is:

Acidic drugs
Henderson-Hasselbalch S  S
pH  pK a  log
S
S The total solubility of the drug (un-ionized + ionized)
S The solubility of the un-ionized form of the drug

pH is the pH below which the drug separates from solution as the undissociated
acid.
From equation we can calculate:
If the pH of the solution is known then we can calculate the solubility of an acidic drug at
that pH.
minimum pH that must be maintained in order" to prevent precipitation from a solution
of known concentration.
+ -
+ B+H 2O«BH +OH

  [ BH ]
Kb 
[ BH ][OH ] log Kb  log[ OH  ]  log( )
[ B]
[ B]
[ BH ]  [ BH  ]

 log[ OH ]   log Kb  log( ) pOH  pKb  log( )
[ B] [ B]

[ BH  ] K b dissociation constant or basicity


14  pH  14  pK a  log( ) constant for a weak base
[ B]
[ B]
pH  pK a  log( 
)
[ BH ]

S The total solubility of (phenobarbital) un-ionized + ionized S  [ B]  [ BH ]
S concentration of the un-ionized form in solution S  [B]
S
pH  pK a  log
S  S
+ The equation relating the solubility,
pKS,
a
of an basic drug to the pH of the solution
is:
Henderson-Hasselbalch
Basic drugs
S
pH  pK a  log
S  S
S The total solubility of the drug (un-ionized + ionized)
S The solubility of the un-ionized form of the drug

The pH is the pH above which the drug begins to 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 basic drug at
that pH.
minimum pH that must be maintained in order" to prevent precipitation from a solution
of known concentration.
Ionization of drugs
+
For acidic drug For basic drug

HP  H 2O  H 3O   P  B  H 2O  BH   OH 
S  S S
pH  pK a  log pH  pK a  log
S S  S
S  [ HP ]  [ P  ] S  [ B]  [ BH  ]
S  [HP ] S  [B]
[P ] [ B]
pH  pK a  log( ) pH  pK a  log( )
[ HP ] 
[ BH ]
pH = pKa + log [ionized drug] pH = pKa + log [un-ionized drug]
[ionized drug]
[un-ionized drug]
+
+Below what pH will phenobarbital begin to separate from a solution
having an initial concentration of 5% (w/v)?
The molar solubility of phenobarbital, So, is 0.005 and the pKa is 7.41 at
25°C.
The molecular weight of sodium phenobarbital is 254.

S  S
pH p  pK a  log
S
5 gm 
    50 gm / Liter
0.1L 1L

Weight 50
Molarity    0.1968mole / Liter
Molecular .Weight 254

0.1968  0.005
pH p  7.41  log  7.41  log 38.36  7.41  158  5.826
0.005
+ Calculate the pHp of a 1% sodium phenobarbital solution.
From Merck Index:
S  S
pH p  pK a  log
S

(i.e. 1% phenobarbital will precipitate at or below a pH of 8.3)


Example
+
What is the pH below which sulfadiazine (pKa = 6.48) will begin to
precipitate in an infusion fluid, when the initial molar
concentration of sulfadiazine sodium is 4X 10 -2 mol/ dm 3 and
the solubility of sulfadiazine is 3.07X 10 -4 mol/ dm 3 ?

The pH below which the drug will precipitate is calculated using


equation
S  S
pH  pK a  log
S
Example
+ Example:
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.

S
pH  pK a  log
S  S
S = 8.66 mg/ml
pka = 8.05

S = 1gm/ 200ml = 1000mg/200 ml =5 mg/ ml


pH = 8.05 + log (5/ 8.66 – 5)
pH = 8.05 + log 1.37
pH = 8.19
This is maximum pH and 7.4 is less than 8.19, therefore solution is
stable and no ppt. occurs.
+
Ionization and pH

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 nonionized 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

 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 [P ]


pH  pK a  log( )
log(ionized/unionized) = pH - pKa, or [ HP ]
ratio of ionized to unionized is 10X / 1, where
X = pH – pKa
+
Computing ionization ratios

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

[P ] [ B]
pH  pK a  log( ) pH  pK a  log( )
[ HP ] 
[ BH ]
Acidic drugs Basic drugs
+ [P ]
pH  pK a  log( [ B]
) pH  pK a  log( 
)
[ HP ] [ BH ]
Lipoid diffusion- weak acids and weak
+
bases
Henderson-Hasselbalch equation
 Determines extent of ionization
pKa = pH at which 50% of drug is ionized.

[P ]
 WEAK ACIDS: pH  pK a  log( )
[ HP ]
log (ionized form/nonionized form)= pH – pKa

 WEAK BASES: [ B]
pH  pK a  log( 
)
[ BH ]
log (nonionized form/ionized form)= pH – pKa
+ PASSIVE DIFFUSION

•water soluble drug


(ionized or polar) is
readily absorbed via
aqueous channels or
pores in cell
membrane.
•Lipid soluble drug
(nonionized 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.
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.
+
But look what happens…

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.
P will be subject to ion trapping.
+
+ pKa of Aspirin [weakPercent Ionization of Aspirin [Stomach]
acid] = 3.4 (50% HA and A- at pH 3.4)
pH stomach = 1.4 pH blood = 7.4
pH = pKa + log (A-)/(HA) [ H-H equation]
pH - pKa = log (A-)/(HA)
1.4 – 3.4 = - 2 log of 0.01= -2 (stomach)
A- / HA= 0.01/ 1 so HA is 100 fold greater than A
HA moves from the stomach into the blood (good absorption)

Percent Ionization of Aspirin [Blood]


Stomach (pH=1.4) Blood (pH=7.4)

pH - pKa = log (A-)/(HA)

7.4 – 3.4 = 4 log of 10,000 = 4 (blood)


A- / HA= 10,000/ 1
so A- is 10,000 fold greater than HA
+
Another example
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.

unionized/ionized = 10-4/1= 1/10,000

In the stomach, M will be mostly ionized, and not very fat soluble.
+
But…
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.


+
Percent Ionization of Codeine
[Stomach]

• CODEINE (weak base) pKa = 7.9


• Stomach pH=1.9 Blood pH =7.4

pH - pKa = log(B)/(BH+) [H-H equation]

1.9 - 7.9 = -6 log 0.0000001 = -6 [Stomach]

B/ BH+ = 0.000001/1 so BH+ is 1,000,000 fold greater than B.

Little B (codeine) is absorbed into the blood (poor absorption)


+
An oddity

Caffeine is a base drug, but it has a pKa of 0.5


pH – pKa = 3.5 – 0.5 = 3
Since caffeine is a base drug, we use the ratio backwards:
unionized/ionized.
unionized/ionized = 103/1= 1000/1
 In
the stomach, caffeine will be mostly unionized, and fat
soluble!
 In
the blood, caffeine will be even more unionized and fat
soluble:
pH – pKa = 7.5 – 0.5 = 7, ratio = 107/1= 10,000,000/1.
+
WEAK ACIDS
log (ionized form/nonionized form)= pH – pKa

 A drug is a weak acid.

 pKa is 3.5.

 If stomach pH is 1.5, what percentage of drug will be in absorbable form?

 pH – pKa = 1.5 – 3.5 = - 2

pH = pKa + log [ionized drug] / [un-ionized drug]

(pH) – (pKa) -2 -1 0 1 2
Weak acid 99 90 50 10 1
% nonionized
+
Remember – absorbable means
nonionized !
 pH – pka = -2

 This (-2) in the table for weak acid matches to 99%.

 And this is supposed to be the nonionized form, which is


same as “absorbable form” that is asked in this problem.

 Hence the absorbable form is 99%.


+
Weak bases
log (nonionized form/ionized form)= (pH) – (pKa)

 A drug is a weak base.

 pKa is 8.

 At pH 6, what percentage of drug will be in the ionized form?

pH – pKa = 6 – 8 = - 2

(pH) – (pKa) -2 -1 0 1 2
Weak base 1 10 50 90 99
% nonionized
+
Please remember – ionized means
nonabsorbable !

 pH – pka has come as -2.

 In the table for weak base, -2 matches with 1%. But this 1% is
nonionized form. What is asked is – ionized.

 So, ionized is 100 – 1 = 99%.


+
Co-solvent effect on 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.

 The presence of a co-solvent can increase the


solubility of hydrophobic organic chemicals
 Co-solvents can completely change the solvation
properties of “water”
+
Fig. 9-5. The influence of
alcohol concentration on
the dissociation constant
of phenobarbital.
+
Distribution of Solutes between Immiscible
Solvents
 States that a solute will distribute itself between two
immiscible solvents so that the ratio of its concentration in
each solvent is equal to the ratio of its solubility in each one

CO
Kd = ---------
CW

Co= molar conc in organic layer


Cw= molar conc in aqueous layer
Kd= distribution constant, distribution ratio, distribution
coefficient, or partition coefficient
Partition coefficients
P
Xaqueous Xoctanol

Partition coefficient P (usually expressed as log10P or logP) is defined as:

[X]octanol
P=
[X]aqueous

P is a measure of the relative affinity of a molecule for the lipid and aqueous phases
in the absence of ionisation.

1-Octanol is the most frequently used lipid phase in pharmaceutical research.


This is because:

 It has a polar and non polar region (like a membrane phospholipid)


 Po/w is fairly easy to measure
 Po/w often correlates well with many biological properties
+
Application
 Extraction

 Preservative action of weak acids in o/w systems

 Drug absorption/distribution/action
+
Application

Extraction

 it is
used to determine the efficiency with which one
solvent can extract a compound from a second solvent
 extract natural drugs from a solvent with several
portions of an immiscible solvent
+
Application

Preservative action

 the concentration of preservative to be used in an emulsion can be


calculated from the distribution law to give the effective antimicrobial
concentration in the water phase
+
Drug
Absorption/Distribution/Action

 Hydrophobic drugs (high partition coefficients) are preferentially


distributed to hydrophobic compartments such as lipid bilayers of
cells

 Hydrophilic drugs (low partition coefficients) preferentially are found


in hydrophilic compartments such as blood serum.
Example
+ What is the solubility of benzylpenicillin G at a pH
sufficiently low to allow only the nondissociated form of
the drug to be present?
The pKa of benzylpenicillin G is 2.76 and the solubility of
the drug at pH 8.0 is 0.174 mol/ dm 3
(From R. E. Notari, Biopharmaceutics and Pharmacokinetics, 2nd edn, Marcel Dekker, New York, 1978.)

If only the undissociated form is present at low pH then we need to find


S0.
S  S
pH  pK a  log
S
0.174  S
8.0  2.76  log  5.24
S
S 0  110 6 mol / dm 3
+
In general

 solubility increases exponentially as cosolvent fraction


increases.

 need 5-10 volume % of cosolvent to see an effect.

 extent of solubility enhancement depends on type of cosolvent


and solute
 effect is greatest for large, nonpolar solutes
 more “organic” cosolvents have greater effect
propanol>ethanol>methanol