FACTORS INFLUENCING (AFFECTING) ON SOLUBILITY OF DRUGS IN SOLVENT SOLUBILITY

1. FACTORS INFLUENCING (AFFECTING) ON
SOLUBILITY OF DRUGS IN SOLVENT
WHICH FACTORS AFFECT ON SOLUBOLITY?
SOLUBILITY PHYSICAL PHARMACEUTICS-I

2. SOLUBILITY
 Solubility is a capacity of any substance to
solubalize or to dissolve in a suitable solvent at
given temperature.
 It is a property referring to the ability for a given
substance, solute, to dissolve in solvent
 It is measured in terms of maximum amount of
solute dissolved in a solvent at equilibrium
 The resulting solution is called a saturated
solution at given temperature.
 SOLUTION = Salt (solute) + water (solvent)

3. SOLUBILITY OF SUGAR

4. SOLUTE AND SOLVENT
 Solute: is the dissolved agent .
 (less abundant part of the
solution)
 Solvent : is the component in
which the solute is dissolved
(more abundant part of solution)
 They form homogenous mixture
 That called solution

5. TYPES OF SOLUTION

6. FACTORS INFLUENCING SOLUBILITY
 1. Temperature
 2. Nature of solvent
 (like dissolves like)
 3. Pressure
 4. pH
 5. Particle size
 6. Crystal structure
 7. Molecular structure
 8. Solute- solvent
interactions
 9. Melting point and
boiling point.
 10. Particle size
 11. Addition of substituent
 12. Solubilizing agents

7. 1. Temperature
 Temperature will affect solubility.
 If the solution process absorbs
energy then the solubility will be
increased as the temperature is
increased.
 If the solution process releases
energy then the solubility will
decrease with increasing
temperature.

8. 2. Temperature
 Generally, an increase in the
temperature of the solution
increases the solubility of a solid
solute.
 A few solid solutes are less soluble
in warm solutions.
 For all gases, solubility decreases
as the temperature of the solution
increases.

9. 3. Nature of solvent ( like dissolves like)
 POLAR DISSOLVE POLAR “LIKE DISSOLVES LIKE”
 Water (HOH), Methanol (CH3OH), Ethanol (CH3CH2OH),
Acetic acid (CH3CO2H).
 NON-POLAR DISSOLVE NON-POLAR “LIKE DISSOLVES LIKE”
 Non polar solvents can dissolve non polar solutes through
weak van der Waals forces
 Example: solutions of oils & fats in carbon tetrachloride or
benzene, Polyethylene glycol 400, Castor oil.

10. 4. Pressure
 Typically, a gas will increase in solubility with an
increase in pressure.
 The higher the pressure above a liquid, the more gas
that can be dissolved in that liquid, to a limit of
course.
 The solubility of gases depends on the pressure: an
increase in pressure increases solubility, whereas a
decrease in pressure decreases solubility.

11. 4. Pressure

12. 5. pH
 pH is one of the primary influences on the solubility of
most drugs that contain ionizable groups
 Large number of drugs are weak acids or weak base.
 Solubility depends on the degree of ionization.
 Degree of ionization depends on the pH
 About 85% of marketed drugs contain functional groups
that are ionised to some extent at physiological pH (pH
1.5 – 8) and shows solubility.

13. 5. pH
 For ionic compounds containing
basic anions, solubility
increases as the pH of the
solution is decreased.
 For ionic compounds containing
anions of negligible basicity
(such as the conjugate bases of
strong acids), solubility is
unaffected by changes in pH.

14. 6. Crystal structure
 Polymorphic Crystals, Solvates, Amorphous forms
 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
 Amorphous salt dissolve faster compare to crystalline
salt.

15. 7. Molecular structure
 Molecular size will affect the solubility.
 The larger the molecule or the higher its molecular weight
the less soluble the substance.
 Larger molecules are more difficult to surround with
solvent molecules in order to solvate the substance.
 In the case of organic compounds the amount of carbon
branching will increase the solubility since more branching
will reduce the size (or volume) of the molecule and make it
easier to solvate the molecules with solvent

16. 7. Molecular structure
 Carboxylic acids
containing more than
five carbons are
relatively insoluble in
water, they react with
dilute sodium
hydroxide, carbonates
and bicarbonates to
form soluble salts.

17. 7. Molecular structure
 As the number of
carbons in a
carboxylic acid
series becomes
greater, the boiling
point increases and
the solubility in
water decreases.

18. 8. Solute- solvent interactions
 In pre - or early formulation, selection of the most suitable
solvent is based on the principle of “like dissolves like”
 That is, a solute dissolves best in a solvent with similar
chemical properties. Or two substances with similar
intermolecular forces are likely to be soluble in each others
 Polar solutes dissolve in polar solvents.
 E.g salts & sugar dissolve in water .
 Non polar solutes dissolve in non polar solvents.
 E.g. Naphtalene dissolves in benzene.

19. 8. Solute- solvent interactions
 In pre - or early formulation, selection of the most suitable
solvent is based on the principle of “like dissolves like”
 That is, a solute dissolves best in a solvent with similar
chemical properties. Or two substances with similar
intermolecular forces are likely to be soluble in each others
 Polar solutes dissolve in polar solvents.
 E.g salts & sugar dissolve in water .
 Non polar solutes dissolve in non polar solvents.
 E.g. Naphtalene dissolves in benzene.

20. Solvent-Solute Interactions
 If the solvent is A
 the solute is B
 The forces of attraction are represented by
 A-A = Solvent-solvent interaction
 B-B = Solute-solute interaction
 A-B = solvent- solute interaction

21. Solvent - Solute Interactions
 If A-A >> A-B
 The solvent molecules will be attracted
to each other & the solute will be
excluded (leave out/separated)
 Example:
 Benzene & water, where benzene
molecules are unable to penetrate the
closely bound water aggregates.
 Thus, they do not miscible in each other.

22. Solvent - Solute Interactions
 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.

23. Solvent - Solute Interactions
 If A-B >> A-A or A-B >> B-B or
 The three forces are equal
 A-B = A-A = B-B
 The solute will form a solution.
 Example:
 1. NaCl in water.
 2. Sugar in water
 3. Alcohol in water

24. 9. MELTING POINT AND BOILING POINT
 The boiling point of liquids & the melting point of solids:
 Both reflect the strengths of interactions between the molecules
in the pure liquid or the solid state.
 In general, aqueous solubility decreases with increasing boiling
point and melting point.

25. 10. Particle size (surface area)
 Particle size (surface area) of drug particles
 ↓Particle size → ↑ surface area→ ↑Solubility

26. 11. Effect of Addition of substituent
 The influence of substituents on the
solubility of molecules in water can
be due to their effect on the
properties of the solid or liquid (for
example, on its molecular cohesion,
or to the effect of the substituent on
its interaction with water molecules.
 Substituents can be classified as
either hydrophobic or hydrophilic,
depending on their polarity

27. 11. Effect of Addition of substituent
 Polar groups such as –OH capable of hydrogen bonding
with water molecules impart high solubility
 Non-polar groups such as –CH3 and –Cl are
hydrophobic and impart low solubility.
 Ionization of the substituent increases solubility,
 e.g. –COOH and –NH2 are slightly hydrophilic whereas
–COO– and –NH3 are very hydrophilic.

28. 11. Effect of Addition of substituent
 The position of the substituent on the molecule can
influence its effect on solubility, for example the aqueous
solubilities of o-, m- and p-dihydroxy benzenes

29. 12. Solubilizing agents on solubility
 Solubilization is the increase in solubility of a poorly water–
soluble substance with surface-active agents.
 The mechanism involves entrapment (adsorbed or
dissolved) of molecules in micelles and the tendency of
surfactants to form colloidal aggregations at critical micelle
concentration levels.

30. 12. Solubilizing agents on solubility
 Surfactants,
 SLS
 Span, tween
 Alcohol,
 Isopropyl alcohol,
 Glycerin,
 Propylene glycol,
 Polyethylene glycol 400