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fdocuments.in_solubility-physical-pharmacy
fdocuments.in_solubility-physical-pharmacy
fdocuments.in_solubility-physical-pharmacy
Aseel Samaro
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Objectives of the Chapter
2. Define solubility, saturated & unsaturated solutions and polar & non
polar solvents.
Solvent : is the component in which the solute is dissolved (more abundant part of
the solution).
Solubility:
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
+
Solubility process
ΔH sol = ΔH 1 + ΔH 2 + ΔH 3
+
Enthalpy
solution
Solubility expressions
solvent
Weight
Volume
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.
High solubility
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
Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in
water .
The -OH group on alcohol is polar and mixes with the polar water
through the formation of hydrogen bonds.
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
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.
+
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.
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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Non polar solvents can dissolve non polar solutes through weak van der
Waals forces
Castor oil
+
Semi polar solvents
Gases in liquids
Liquids in liquids
Solids in liquids
+ Solubility of gases in liquids
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
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.
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
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
The larger the molecule or the higher its molecular weight the less
soluble the substance.
If the solution process releases energy then the solubility will decrease
with increasing temperature.
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
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
carboxyl group (RCO2H)
relatively insoluble in water,
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.
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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.
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
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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.
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[ BH ][OH ] [ BH ]
Kb log K b log[OH ] log( )
[ B]
[ B]
[ BH ] [ BH ]
log[OH ] log K b log( ) pOH pK b log( )
[ B] [ B]
The pH is the pH above which the drug begins to precipitate from solution as the free base
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
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.
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Ionization and pH
For basic drugs, everything is the same except that the ratio reverses:
Log(unionized/ionized) = pH – pKa, or
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
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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
[ B]
WEAK
pH pK a log( )
BASES: [ BH ]
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,
pKa is 3.5.
pH – pKa = 6 – 8 = - 2
(pH) – (pKa) -2 -1 0 1 2
Weak base 1 10 50 90 99
% nonionized
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Please remember – ionized means
nonabsorbable !
In the table for weak base, -2 matches with 1%. But this 1% is
nonionized form. What is asked is – ionized.
CO
Kd = ---------
CW
[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:
Drug absorption/distribution/action
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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
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Application
Preservative action
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
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In general