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FACTORS INFLUENCING (AFFECTING) ON SOLUBILITY OF DRUGS IN SOLVENT

Factors that influence drug solubility include temperature, nature of the solvent, pressure, pH, particle size, crystal structure, molecular structure, solute-solvent interactions, melting point and boiling point, addition of substituents, and solubilizing agents. Solubility generally increases with temperature, a polar solvent, pressure, small particle size, and amorphous form. The molecular structure, interactions, and functional groups impact solubility as well. Solubilizing agents can increase the solubility of poorly soluble drugs.

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FACTORS INFLUENCING (AFFECTING) ON SOLUBILITY OF DRUGS IN SOLVENT WHICH FACTORS AFFECT ON SOLUBOLITY? SOLUBILITY PHYSICAL PHARMACEUTICS-I
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)
SOLUBILITY OF SUGAR
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
TYPES OF SOLUTION
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
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.
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.
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.
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.
4. Pressure
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.
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.
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.
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
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.
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.
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.
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.
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
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.
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.
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
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.
10. Particle size (surface area)  Particle size (surface area) of drug particles  ↓Particle size → ↑ surface area→ ↑Solubility
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
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.
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
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.
12. Solubilizing agents on solubility  Surfactants,  SLS  Span, tween  Alcohol,  Isopropyl alcohol,  Glycerin,  Propylene glycol,  Polyethylene glycol 400