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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)
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