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SOLUBILITY AND PARTITION PHENOMENA Chapter. 9

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SOLUBILITY AND PARTITION PHENOM-ENA

Chapter. 9

CONTENTS

Solubility

• Definitions• Factors influencing solubility• The effect of pH on solubility• The effect of pressure• Influence of solvents on solubility

CONTENTS

Partition Phenomena

• Partition concepts• For weak electrolytes as solutes• Drug absorption• pH partition hypothesis• Site of drug partitioning

DEFINITIONS

Solubility is the concentration of a solute when the solvent has dissolved all the solute that it can at a given temperature

• Martin’s Physical Pharmacy & Pharmaceutical Sciences 6th editionPatrick J. Sinko

FACTORS INFLUENCING SOLUBILITY

Dissolution of a crystal

1. A solute (drug) molecule is removed from its crystal

2. A cavity for the molecule is created in the solvent

3. The solute molecule is in-serted into this cavity

* Physicochemical Principles of Pharmacy 4th editionAlexander T Florence and David Attwood

FACTORS INFLUENCING SOLUBILITY

Temperature

Solubility is an equilibrium value that is dependent on a given temperature and pressure

Solubility does not depend on how fast a substance dissolves in the solvent

FACTORS INFLUENCING SOLUBILITY

Temperature

Heat of solution (ΔHsoln)

The enthalpy change associ-ated with the dissolution of a substance in a solvent

* Applied Physical Pharmacy Mansoor M.Amiji, Beverly J.Sandmann

Solute ΔHsoln (25 ) kcal/mole℃

HCl - 17.96

NaOH - 10.6

CH3COOH - 0.36

NaCl + 1.0

KMnO4 + 10.4

Mannitol + 5.26

KI + 4.3

Table. Heat of solution*

FACTORS INFLUENCING SOLUBILITY

Temperature

If ΔHsoln is negative, increasing the temperature of the solvent will decrease the solubility of the solute

S exp∝ (-ΔHsoln/RT)

FACTORS INFLUENCING SOLUBILITY

Chemical structure

Dipole moment

A measure of polarity Molecules that have a

high dipole moment are more soluble in polar solvents such as water

FACTORS INFLUENCING SOLUBILITY

Chemical structure

Dielectric proper-ties

Related to the ability to store charge

How a substance inter-acts with solvents

Solvent Dieletric con-stant

Water 78.5

Glycerin 40.1

Propylene glycol 32.01

Methanol 31.5

Acetone 19.1

PEG 400 12.5

Cottonseed oil 6.4

Ether 4.3

Table 6-5 Dielectric Constants of Some Solvents at 25℃

* Applied Physical Pharmacy Mansoor M.Amiji, Beverly J.Sandmann

*

FACTORS INFLUENCING SOLUBILITY

Chemical structure

Hydrogen bonding

The attractive interac-tion of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine

Major factor on solubil-ity in water

• Amines with small alkyl groups are very soluble in water. This is because hydrogen bonding occurs between the amine and water molecules

FACTORS INFLUENCING SOLUBILITY

Chemical structure

Hydrogen bonding

The attractive interac-tion of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine

Major factor on solubil-ity in water

• The presence of hydroxyl groups or nitro groups can markedly in-crease the solubility.

* Physicochemical Principles of Pharmacy 4th editionAlexander T Florence and David Attwood

*

FACTORS INFLUENCING SOLUBILITY

A high melting point means low water solubil-ity

cis (z) Isomer is more soluble than trans (e) isomer

* Physicochemical Principles of Pharmacy 4th editionAlexander T Florence and David Attwood

*

# Kirk-Othmer Encyclopedia of Chemical Technology18 OCT 2001

THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA)

Total saturation solubility of drug S, the solubil-ity of the undissociated species HA S0

S = S0 + (concentration of ionised species)

* Physicochemical Principles of Pharmacy 4th editionAlexander T Florence and David Attwood

THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA)

The dissociation constant Ka

According to previous page, [HA] = S0, [A-] = S – S0

THE EFFECT OF PH ON SOLUBILITY

Acidic drugs (HA) Taking logarithms,

[A-] = S – S0, S0 = [HA]

<Henderson-Hasselbalch Equation>

THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2)

Total saturation solubility of drug S, the solubil-ity of the undissociated species RNH2 S0

S = S0 + (concentration of ionised species)

* Physicochemical Principles of Pharmacy 4th editionAlexander T Florence and David Attwood

THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2)

The dissociation constant Kb

According to previous page, [RNH2] = S0, [RNH3+]

= S – S0

THE EFFECT OF PH ON SOLUBILITY

Basic drugs (RNH2) Taking logarithms,

[RNH3+] = S – S0, S0 = [RNH2]

<Henderson-Hasselbalch Equation>

Henry’s Law

C2= σp

C2= concentration of the dissolve gas (g/l)

p = partial pressure (mm of the undissolvegas)

σ= inverse of the Henry’s law constant, K

In a dilute solution at constant temperature, the concentration of dissolved gas is propor-tional to the partial pressure of the gas above the solution at equilibrium

THE EFFECT OF PRESSURE

INFLUENCE OF SOLVENTS ON SOLU-BILITY

Strong electrolytes

Strong acids and bases and all salts are sol-uble in water

The polar nature of water attracts the ions

Weak electrolytes

Weak acids and bases with high molecular weight are not soluble in water

Cosolvents such as alcohol, propylene glycol and polyethylene glycol are required for sol-ubility

INFLUENCE OF SOLVENTS ON SOLU-BILITY

Cosolvents

Solubility enhance-ments caused by co-solvent addition occur because of changes in the bulk properties of the isotropic solution

PARTITIONING CONCEPTS

A solute distributes itself between two im-miscible solvents so that the ratio of its con-centration in each solvent is equal to the ra-tio of its solubility in each one

C0 = molar concentration in organic layer Cw = molar concentration in aqueous layer P = partition coefficient or distribution constant

FOR WEAK ELECTROLYTES AS SOLUTES

The partition law for weak electrolytes de-pends on pH

Kd1 = the apparent partition coefficient and its

value depends on pH

FOR WEAK ELECTROLYTES AS SOLUTES

Using the Ka expression, an equation can be developed that gives the hydrogen ion de-pendency

Substitution in Kd1 gives

FOR WEAK ELECTROLYTES AS SOLUTES

Substitution of Kd for (HA)0/(HA)w gives

This equation can be made linear

FOR WEAK ELECTROLYTES AS SOLUTES

The partition law for weak electrolytes de-pends on pH

Kd1 = the apparent partition coefficient and its

value depends on pH

FOR WEAK ELECTROLYTES AS SOLUTES

Using the Ka expression, an equation can be developed that gives the hydrogen ion de-pendency

Substitution in Kd1 gives

FOR WEAK ELECTROLYTES AS SOLUTES

Substitution of Kd for [B:]0/[B:] gives

This equation can be made linear

DRUG ABSORPTION

Drug absorption occurs by partitioning through the mucosal membrane of an epithelial cell of the gas-trointestinal tract and then moving through the cell and partitioning through the serosal mem-brane

DRUG ABSORPTION

Factors influencing drug absorption

Lipid/water partition coefficient (P) Water solubility Molecular weight Chemical structure

DRUG ABSORPTION

SMEDDS (Self-microemulsifying drug delivery system)

Lipid/water partition coefficient and water solubility are increased by using SMEDDS Drug absorption is increased and bioavailability is increased too.

*

* European Journal of Pharmaceutics and Biopharmaceutics 76 (2010) 475 - 485

PH PARTITION HYPOTHESIS

Drug absorption is a function of pH for weak electrolytes because pH changes ionization

Only the uncharged molecular form of the organic weak electrolytes is absorbed→ The unionized drug is provided for aque-ous extracellular medium and out of the cell

PH PARTITION HYPOTHESIS

Using Henderson-Hasselbalch equation

I = ionized drug (dissociated weak acid) U = unionized drug (associated weak acid)

PH PARTITION HYPOTHESIS

Calculating the % ionization of papaverine at pH = 3.9

Papaverine is a weak base, pKa = 5.9

PH PARTITION HYPOTHESIS

If pH = pKa ± 2, a small change in pH will result in a large change in ion-ization

SITE OF DRUG PARTITIONING

In the human body, the ratios calculated would be for only an instant as the drug en-ters into tissue and is metabolized and elim-inated

Absorption from the stomach (pH 1 to 3) The weaker the acid (pKa > 7), the greater the

percent unionized in the stomach

SITE OF DRUG PARTITIONING

Absorption from the intestines (pH 4 to 6) The weaker the base (pKa < 6), the grater th percent ion-

ization in the intestine

Urinary excretion (pH 5 to 7) Barbiturate poisoning may be treated by increasing the

pH of plasma and urine, which clears barbiturate ion from the body

Excretion of drugs in sweat (pH 5-7) Excretion of drugs in human milk (pH 6.6) Rectal administration (pH 7.8)