Solubility and Partition Phenomena

Contents General Principles Solvent-Solute Interactions Solubility of Gases in Liquids Solubility of Liquids in Liquids Solubility of Solids in Liquids Partition Phenomena

Ⅰ. General Principles Definitions Solubility Expressions Factors Affecting Solubility

Definitions Solution : a liquid in which a solid substance has been dissolved. Solute : a solid substance that is dissolved in a liquid. Solvent : a liquid that can dissolve other substances. Solubility : the concentration of solute in a saturated solution at equilibrium at a given temperature given as per weight or volume of solvent g (solute) / 100g (solvent) 1g (solute) / volume (ml) of solvent

Unsaturated or Subsaturated Solution the solute is in equilibrium with the solid phase Unsaturated or Subsaturated Solution one containing the dissolved solute in a concentration that necessary for complete saturation at a definite temperature Supersaturated Solution one that contains more of the dissolved solute than it would normally contain at a definite temperature

Miscible the solute when it is a liquid and will form a solution with a solvent over any concentration range The Phase Rule F = C – P + 2

Solubility Expressions 대한약전 제 8개정 USP Chart of Descriptive terms Term Parts solvent to 1 part solute Very soluble Less than 1 Freely soluble 1-10 (3-10%) Soluble 10-30 Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly soluble 1000-10,000 Practically insoluble, insoluble More than 10,000 용어 썩 잘 녹는다 잘 녹는다 녹는다 조금 녹는다 녹이 어렵다 매우 녹기 어렵다 거의 녹지 않는다

Factors Affecting Solubility Temperature Pressure C2 = σp pH Chemical Structures - Dipole moment - Dielectric properties - Hydrogen bonding

Ⅱ. Solvent – Solute Interactions Polar Solvents Nonpolar Solvents Semipolar Solvents “Like Dissolves Like”

Polar Solvents Influential Factors Mechanism Water Dipole moment (dissolve ionic solutes and other polar substances) Influential Factors Dipole moment Hydrogen bonds Acidic and basic character of constituents Structural features Mechanism High dielectric constant Amphiprotic Dipole interaction force Water

Non-polar Solvents Influential Factors Hydrocarbons (dissolve nonpolar solutes) Influential Factors Induced dipole interactions Weak van der Waals-London type forces Hydrocarbons

Semi-polar Solvents (Intermediate solvents) Influential Factors Induce a certain degree of polarity in non-polar solvent molecules Ketones and alcohols

Ⅲ. Solubility of Gases in Liquids Effect of Pressure Effect of Temperature Salting Out Effect of Chemical Reaction Solubility Calculations

Effect of Pressure C2 = σp Henry’s Law C2 = concentration of the dissolve gas (g/l) p = partial pressure (mm of the undissolve gas) σ = inverse of the Henry’s law constant, K in a dilute solution at constant temperature, the concentration of dissolved gas is proportional to the partial pressure of the gas above the solution at equilibrium

Effect of Temperature As the temperature increases, the solubility of most gases decreases, owing to the greater tendency of the gas to expand

Salting Out Gases are often liberated from solutions in which they are dissolved by the introduction of an electrolytes and sometimes by a nonelectrolyte NaCl gases sucrose carbonated solution

Effect of Chemical Reaction Gases (HCl, NH3, CO2) + Solvent → Chemical reaction → Increase solubility

Solubility Calculations Inverse Henry’s law constant,  C2 =  P Bunsen absorption coefficient,   : 일정 온도, gas의 partial pressure 1 기압하에 solvent 1L 에 녹 는 gas의 volume (L) Satuated condition : 0℃, 760mmHg Vgas. STP Vsoln. =  P

Ⅳ Solubility of Liquids in Liquids Ideal and Real Solutions Complete Miscibility vs Partial Miscibility Influence of Foreign Substances Influence of Solvents on Solubility

Ideal and Real Solutions Ideal Solutions Raoult’s Law: Nonideal Solutions a. Negative deviation b. Positive deviation

Raoult’s Law Negative deviation A B Associated with hydrogen bonding between polar comp A B Increased solubility Chloroform & acetone

Raoult’s Law Positive deviation A A B A Cannot mingle with each other Partial solubility Decreased solubility

Miscibility Complete Miscibility Partial Miscibility Solvents are said to be completely miscible when they are mix in all proportions Partial Miscibility When certain amounts of two liquids are mixed, two liquid layers are formed, each containing some of the other liquid in the dissolved state

Miscibility

Influence of Foreign Substances Binary addition Ternary If the added material is soluble in only one of the two components / if the solubilities in the two liquids are markedly different mutual solubility of the liquid pair is decreased When the third substance is soluble in both of the liquids roughly the same extent the mutual solubility of the liquid pair is increased Blending : the increase in mutual solubility of two partially miscible solvents by another agent Micellar Solubilization : solubility in water of a non-polar liquid is increased by a micelle-forming surface-active agent

Ⅴ Solubility of Solids in Liquids Ideal Solutions Nonideal Solutions Solvation and Association in Solutions of Polar Compounds Solubility and the Heat of Solution Solubility of Strong Electrolytes Solubility of Slightly Soluble Electrolytes Solubility of Weak Acids and Weak Bases in Water as Influenced by pH The Influence of Solvents on the Solubility of Drugs

Ideal Solutions Depends on temperature, melting point of the solid, and molar heat of fusion T = absolute temp. of the solution T0 = melting point of the solid solute X2i = ideal solubility of the solute expressed in mole fraction ∆Hf = Heat of solutions → Heat of fusion Heat of solution = Heat of fusion Not affected by the nature of the solvent No longer applies when T > T0 and at temperatures considerably below the melting point

Nonideal Solutions T = absolute temp. of the solution T0 = melting point of the solid solute ∆Hf = Heat of solutions → Heat of fusion γ2 = the mole fraction scale is known as the rational activity coefficient log γ2 : intermolecular forces of attraction in removing a molecule from the solute phase and depositing it in the solvent

Liberation of a molecule from W22 solute Liberation of a molecule from the solute (b) W11 solvent Creation of a hole in the solvent (c) -2W12 solute molecule solution solvent Total work : (W22 + W11 -2W12)

Solubility Parameter ΔHv = the heat of vaporization Vl = the molar volume of the liquid at the desired temperature

Solvation and Association in Solutions of Polar Compounds - 2w12 > w11 + w22 - = negative - negative deviation from Raoult’s law Association - interaction occurs between like molecules of one of the components in a solution - = positive - positive deviation from Raoult’s law

Solubility and the Heat of Solution ∆Hsoln : heat of solution

Solubility of Strong Electrolytes Exothermic process (heat is evolved) the solubility decreases with an elevation of the temperature Endothermic process (absorbs heat) a rise in temperature increases the solubility of a solid

Solubility of Slightly Soluble Electrolytes Solubility product, : the real solution solubility of poorly soluble strong electrolytes in water is calculated by using the solubility product constant obtained from thermodynamics Common ion : adding a common ion is to reduce the solubility of a slightly soluble electrolyte

Solubility of Weak Acids and Weak Bases in Water as Influenced by pH

The Influence of Solvents on the Solubility of Drugs Strong Electrolytes : strong acids and bases and all salts are soluble in water Weak Electrolytes : weak acids and bases with high molecular weight are not soluble in water Nonelectrolytes : high-molecular-weight organic drugs that do not dissociate or associate in water are generally soluble in organic solvents and have little or no solubility in water Cosolvency : a solute is more soluble in a mixture of solvents than in one solvent alone

Cosolvency The solubility of phenobarbital in a mixture of water, alcohol, and glycerin at 25℃

Ⅵ. Partition Phenomena General Partitioning Concepts For Strong Electrolytes as Solutes For Nonelectrolyte Solutes For Weak Electrolytes as Solutes Application of Distribution Concepts Drug Action / Absorption Site of Drug Partitioning Considering pH Effects Alone

General Paritioning Concepts The partition law : a solute will distribute itself between two immiscible solvents so that the ratio of its conc. in each solvent is equal to the ratio of its solubility in each one Co = molar conc. in organic layer Cw = molar conc. in aqueous layer Kd = partition coefficient or distribution constant

For Strong / Nonelectrolytes as Solutes Strong Electrolyte Strong electrolytes are completely dissociated in aqueous solution → cations & anions in aqueous layer → water soluble Without ion pairing, do not partition into the organic layer Nonelectrolyte

For Weak Electrolytes as Solutes The partition law : depends on pH pH different from pKa (pH < pKa for weak acid ; pH > pKa for weak base) For a weak organic acid, For a weak organic base,

Application of Distribution Concepts Preservation of Emulsions The total preservative added = C, where C = C0 + Cw

Drug Action / Absorption ; by passive diffusion ; due only to a concentration gradient across the barrier Drug Absorption ; water solubility of the drug, the lipid/water partition coefficient of the drug molecule, MW, chemical structure ; drugs must be in solution in aqueous intestinal fluids

Site of Drug Partitioning Considering pH Effects Alone Absorption from the stomach (pH 1-3) Absorption from the intestines (pH 4-6) Urinary Excretion (pH 5-7) Excretion of drugs in sweat (pH 5-7) Excretion of drugs in human milk (pH 6.6) Rectal administration (pH 7.8)