5.
1 Definitions
Solution A system in which molecules of a solute are dissolved in a solvent vehicle
The concentration of solute in a saturated solution at a certain
Solubility Temperature and pressure
A solution contains a solute at the limit of its solubility at any given
Saturated Solution temperature and pressure
A solution containing the dissolved solute in a concentration below that
Sub-saturated Solution necessary for complete saturation
Supersaturated Solution A Solution containing the dissolved solute above its normal solubility limit
The maximum equilibrium solubility of a drug in a given medium is of
practical pharmaceutical interest because it dictates the rate of solution
(dissolution) of the drug (the rate at which the drug dissolves from the
solid state).
The higher the solubility, the more rapid is the rate of solution when no
chemical reaction is involved.
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5.1.1 Expressions of solubility
• In quantitative way, the solubility can be expressed in “ppm”
• other expressions expressed in chapter 3, section 1.
Dissolution Process
1. A solute molecule is ‘removed’ from its crystal.
ð Breaking the cohesive forces between solute molecules in its structure
2. A cavity for the molecule is created in the solvent.
3. The solute molecule is inserted into this cavity.
ð Forming the adhesive forces between solute and solvent molecule
Key parameters
Surface area 5 ] Solubility 6
Size 5 ] Solubility 6
Boiling point or melting point 5 ] Solubility 6
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5.2 Factors influencing solubility
1. Surface area of solute
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5.2 Factors influencing solubility
2. Structural features of solute
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5.2 Factors influencing solubility
2. Structural features of solute
Ø Substituents
• Influence on the molecular cohesion and its
interaction with water molecules.
• Polar groups (-OH) are capable of hydrogen bonding
with water molecules impart high solubility.
• Nonpolar groups (- CH3, - Cl) are hydrophobic and
impart low solubility.
• Ionisation of the substituents increases solubility:
- COOH and – NH2 ; - COO- and – NH3+.
• For inorganic electrolytes: the solubility is
influenced by their crystal properties and
the interaction
of their ion with water (hydration).
** The polarity is guide to the solvent
interactions
so it enables to expect approximate solubility
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5.2 Factors influencing solubility
2. Structural features of solute
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5.2 Factors influencing solubility
3. Hydration and solvation
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5.2 Factors influencing solubility
4. Additives
Additives may either increase or decrease the solubility of
a solute in a given solvent.
• The solubility of solutes may be evaluated using the
solubility product (Ksp).
- Salts that increase solubility are said to salt in
- Salts that decrease solubility salt out the solute.
The effect that they have will depend on several factors:
– the effect the additive has on the structure of water
– the interaction of the additive with the solute
– the interaction of the additive with the solvent.
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5.2 Factors influencing solubility
5. pH of solution
S represents the total saturation solubility of drug
S0 represents the undissociated species of drug
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5.2 Factors influencing solubility
5. pH of solution
[Basic Drugs]
Contrary to acidic drugs,
Basic drugs are more soluble in acidic
[Amphoteric Drugs]
solutions
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5.2 Factors influencing solubility
5. pH of solution
Solubility of (a) indometacin, (b) chlorpromazine and (c) oxytetracycline
as a function of pH, plotted as logarithm of the solubility.
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Acidic drug Undissociated form means “S0”
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As the solubility decreases with increasing pH, the
compound is a base.
The drug has a pKa value of 9.0 and is thus
likely to be an amine.
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EXAMPLE 5.5
Calculate the pH at which the following drugs will precipitate from solution given the
information supplied.
(a) (b)
Thus at pH values between
3.05 and 7.56
the solution containing 1.4 mg
cm-3 will precipitate.
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Solubility in mixed solvents
• Mixed solvent is used when
– drugs have limited solubility
– the stability of drugs is low
• Phenobarbital in mixed solvent
– Solubility : 0.12 % w/v in water
– Solubility is slightly higher in glycerol
and much higher in ethanol
– Solubility is much higher in ethanol-water
and ethanol-glycerol mixed solvents
– Drug dissolves in ‘pockets’ of the cosolvent
A : glycerol in water
• An expected Problem B : ethanol in water
– Reduction in ionisation may occur C : ethanol in glycerol
[ This will favour decreased solubility
[ The greater affinity of the undissociated species to cosolvent can overcome this effect
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Solubility problems in formulation
• Mixtures of acidic and basic compound
Sulfamethoxazole, pKa = 6.03 Trimethoprim, pKa = 7.05
– For optimal solubility of each drugs, basic and acidic solutions required respectively
– High degree of incompatibility
– Mutual precipitation occurs on mixing
How can we optimize mutual dissolution?
– Infusion formulation : an aqueous solution includes 40% propylene glycol
– pH between 9.5 - 11.0
– Precipitation can be occurred by Dilution, pH change, ionic composition, and any
drug additives.
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• Choice of drug salt to optimize solubility
– The solubility in water may be markedly dependent on the salt
form
– Formation of water-soluble entities from poorly soluble drugs
– By the use of hydrophilic counterions
– Limit factors : Common ion effect and pH
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Partitioning
v Partitioning of drugs between immiscible solvents
• Examples of partitioning
o Drugs partitioning between aqueous phases and lipid biophases
o Preservative molecules in emulsions partitioning between aqueous
and oil phase
o Antibiotics partitioning into microorganisms
o Drugs and preservative molecules partitioning into the plastic of
containers or giving sets
• Partition coefficient or distribution coefficient (P) : P = C0 / Cw
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Partitioning
v Partitioning of drugs between immiscible solvents
• Papp is apparent partition coefficient calculated by assay of solute in
both phases
• For amphoteric drugs, the pH dependence of partition coefficient is
complex and Papp is maximal at the isoelectric point
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Partitioning
In single solvent
q Nature of drug : structure, hydrophobic/hydrophilic properties,
substituent, ionization (pKa value)
q pH of medium
F pKa of drug is the indicator to predict its solubility in certain pH medium
F pH of medium is adjusted to get the optimal solubility of drug
In mixed solvents
q Selection of co-solvents
In immiscible solvents
q Partition coefficient of drug in two immiscible solvents
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