UNIT –I: SOLUBILITY OF DRUGS

Presented By

MUKESH TIWARI

MAHATMA GANDHI INSTITUTE OF PHARMACY,

LUCKNOW
 SOLUTIONS
Solution is a homogeneous mixture in which one substance is said to be
dissolved in other.
Solvent- Component in large proportion
Solute- Component in small proportion
• Also known as Molecular dispersion / True solutions
Classification:
1. Dilute and Concentrated Solutions
2. Solution in liquid state/ gaseous state/ solid state
Ex. Gas in gas- Air
Gas in liquid- Aerated water
Gas in solid- Hydrogen in palladium
Liquid in liquid- Benzene in toluene
Liquid in solid- Mercury in Zinc Amalgam
Solid in liquid- Salt in water
Solid in solid- Alloy
 Gas in Liquids: Follow Henary’s law

 Liquid in Liquids: Explained by Raoult’s Law

1. Miscible Liquids
2. Partially Miscible Liquids
3. Immiscible Liquids

 Solid in Liquids: Dilute & Concentrated Solution

1. Unsaturated Solutions
2. Saturated Solutions
3. Supersaturated Solutions
 IMPORTANCE & ROLE

• Therapeutic effectiveness of a drug depends upon the bioavailability

and ultimately upon the solubility of drug molecules.

• Formulation Development

• Effect on stability

• Solubility is one of the important parameter to achieve desired

concentration of drug in systemic circulation for pharmacological
response to be shown.

• Currently only 8% of new drug candidates have both high solubility

and permeability.
SOLUBILITY Parts of
solvent
DEFINITION: Definition required for
one part of
solute

 Solubility of a solute is Very soluble <1

the maximum quantity Freely soluble 1 - 10
of solute that can
dissolve in a certain Soluble 10 - 30

quantity of a solvent or Sparingly soluble 30 - 100

solution at a constant
temperature and Slightly soluble 100 - 1000
specified pressure.
Very slightly soluble 1000 - 10,000

Insoluble > 10,000

 PROCESS OF SOLUBILIZATION

Step 1: Holes opens in the solvent

Step2: Molecules of the solid breaks away from the bulk

Step 3:The freed solid molecule is intergrated into the hole in the solvent
 MOLECULAR ASSOCIATION AND
SOLVATION
• In solvation solute(ion/ molecule) strongly interacts
with the solvent and form organic solvate, where as if
solvent of crystallization is water drug hydrate is
formed.
• Molecular association and solvation promote solubility.
• Like-dissolves-like

• SOLVENTS:
1. Polar solvents (H- Bonding)
2. Nonpolar solvents(Vander Waal forces)
3. Semipolar Solvents (ketone & alcohols)
 MOLECULAR ASSOCIATION AND
SOLVATION
ROLE OF ENERGY:
• Exothermic and endothermic recations.
• In salts for which the hydration energy is higher than
the lattice energy, solvation occurs with release of
energy in form of heat.

FACTORS:
1. Temperature
2. Surface area of solute
3.Concentration of solvent
4. Agitation(Mechanical force)
 MECHANISM OF INTERACTIONS –
INTERMOLECULAR FORCES
2 Types of Forces: Cohesive & Adhesive Forces
 FACTOR INFLUENCING
INTERMOLECULAR FORCES
 Distance Between Molecules:
• Attractive and repulsive forces between atoms of same type
depend upon intermolecular distance.
• Equilibrium distance 0.3 to 0.4 nm.
 FACTORS INFLUENCING….

 Chemical Nature of Molecules:

Like-dissolves-like
Based on chemical nature defferent type of forces are involved.
1. Vander waal forces
2. Ionic interactions
3. H- Bonding
4. Hydrophobic interactions

 Spatial Arrangement (Disposition):

3 types of disposition due to interaction forces:
1. Molecular orientation
2. Induction
3. Dispersion
 METHODS OF EXPRESSING
CONCENTRATION
• The amount of solute present in a definite volume of
solution is known as concentration.

MUST KNOWN TERMS:

 Weight per Cent
Weight % of Solute A = Weight of A X 100
Total weight of solution
 Volume per Cent
Volume % of Solute A = Weight of A X 100
Total weight of solution

 Equivalent Weight = Molecular weight

Equivalent valence(n)
 Normality
N= Gram–equivalent weight
Number of liters of the solution
 Molarity
M= Number of moles of solute
Number of liters of the solution
Where,
Number of moles = weight of substance/ Molecular wt.

 Molality
m= Number of moles of solute
Number of Kg of the solvent
Where,
Number of moles = weight of substance/ Molecular wt.
 Mole Fraction: Mole fraction of a component is defined as
the ratio of number of moles of the component to total number of
moles(all components) present in the solution.
Mole fraction of solute:
X2 = Number of moles of solute present in solution
Total number of moles of solute and solvent
Mole fraction of solvent:
X1 = Number of moles of solvent present in solution
Total number of moles of solute and solvent

 Mole per Cent: Mole fraction expressed as % mole fraction

Mole fraction percent of solute, X2 = n2 X 100
n1 + n 2
Where n1 & n2 are moles of solute and solvent respectively.
 FACTORS INFLUENCING SOLUBILITY
OF DRUGS
 SOLUTE RELATED FACTORS:

• Structural Features of drugs

• Nature of solute- Size , Shape & Surface Area
• Physico-chemical properties:
– Melting Point
– Heat of Fusion
– Molar Volume
– pKa
• Physical forms: Salt, Crystalline state &
Polymorphism
 FACTORS…CONT...

 SOLVENT RELATED: Nature of solvent

• Polarity
• pH of medium
• Volume of solvent

 ENVIRONMENTAL FACTORS:
• Tempreaturre
• Pressure

 FORMULATION FACTORS:Other ingredients

Structural Features Of Drug:
Depends upon structure and functional groups.
Solubility depends upon ratio of polar and non polar groups.
Increase in functional groups increases the aqueous solubility.
Alkaloids are more soluble in acidic solutions.
Branching of carbon chain reduce non- polar effect of carbon chain.
Polarity of compounds depend upon the substituent.
Sulfonamides and tetracyclines form zwitter ions and have lowest
solubility at isoelectric point.

Influence Of Particle Size, Shape & Surface Area

Increase in surface area increases contact with the medium and
promote dissolution.
Symmetric molecules are less soluble than asymmetric ones.
Influence Of Physico-chemical Proprties Of Drug:
High melting point is indicative of low solubility.
Dissociation constant helps in prediction of solubility of ionic
compound.
Other factors like molar heat of fusion, entropy of fusion are also
important.
 Physical forms of drug:
Amorphous forms show greater aq. solubility than crystalline form.
In crystals, metastable form show greater aq. solubility than stable
form.
Anhydrous from have greater aq. solubility than hydrate form.
Organic solvate from have greater aq. solubility than unsolvated form.
Salt form have greater aq. solubility than parent drug.
Influence of Solvent:
Solubility of drug depends upon polarity of solvent.(dipole moment)
H- Bonding also affect the solubility.
Like dissolve like
Non-aqueous vehicles are used for poorly water soluble drugs.
Mixture of solvents show better solubilization than single solvent.
Use of co-solvent (ethanol, PEG)
Ex. Acetone is used to dissolve benzene in water where as PEG is
used in multivitamin preparations as co-solvent.
Co-solvency is useful in formulations of syrups, elixers, injection,
lotions & creams.
Supplementary solvents(DMSO, DMF, DMA).
Some times large volume required for solubilization.
Influence of pH of Medium:
Most of drugs are weak electrolytes.
Drugs are more soluble in water when they are in ionised forms and
unionised drugs are poorly water-soluble.
Ex. Alkaloidal salts are more soluble in acidic pH and precipitate at
higher pH.

Relation between pH of solution, solubility and pKa :

For Acidic Drugs: pH = pka + log (S-So/So)
For Basic Drugs: pH = pka + log (So/S-So)
where pKa is dissociation constant of drug, So is solubility of
unionized form(mol/L) and S is overall solubility of drug(mol/L)
Influence Of Temprature:
For endothermic reactions increase in temperature increases
solubility. Ex- potassium nitrate in water.
For exothermic reactions increase in temperature decreases solubility
(∆H is –ve.). Ex- Calcium acetate in water.
Little effect on solubilization. Ex- NaCl in water.

Influence Of Other Ingredients:

Common Ion Effect: Decreases solubility.
Effect Of Other Electrolytes: Solubility of a sparingly soluble
electrolyte can be increased by addition of second electrolyte.

Influence Of Surfactants:
Surface active agents promote micellar solubilization of poorly water
soluble drugs. Ex- Tween, Span, SLS
 THEORIES OF SOLUTIONS

Solubility depends upon solute – solvent interactions.

2 types of solutions on the basis of their interactions:

a) Ideal Solutions

b) Regular (Non-ideal) solutions

….................. To be continued in next class……………….

THANK YOU