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
[Link] 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
