Solubility and Distribution Phenomena

Ana Marie L. Rubenicia, RPH

Solubility Phenomena Importance of understanding the theory and applications of solubility phenomena:

1. Permits the pharmacist to choose the best solvent medium for a drug or drug combinations.

2. Helps to overcome difficulties in the preparation of pharmaceutical solutions.

3. Serve as a standard or test of purity.4. Yields information about the structure

and intermolecular forces of drugs.

Solubility PhenomenaSOLUTION - A homogenous system in which the solute is molecularly dispersed, or dissolved in a solvent.types of solutions, solubility expressions, solvent solute intrxn)

Components of solutionSolvent – present in greatest quantity Polar Nonpolar Semipolar Solute – can be gases, liquids, or solidsa. Non-electrolytes – do not form ions when dissolved in water; do not conduct electric currentExamples: Estradiol, glycerin, urea and sucroseb. Electrolytes

Do form ions in solution, thus conduct electric current> Strong electrolytes – completely ionized in water (Ex.: Sodium chloride, HCl)> Weak electrolytes – partially ionized in water (Ex.: Aspirin, Atropine)

Solubility PhenomenaPOLAR SOLVENTS Dissolve ionic solutes and other polar substance

The solubility of various solutes in water may be due to:

Dipole moment Hydrogen bonds (dissolves phenols, alcohols, aldehydes, ketones, amines and other O and N containing compounds

Difference in acidic and basic character of the constituents

Structural features such as the ratio of the polar to the nonpolar groups of the molecule

Solubility PhenomenaPOLAR SOLVENTSSolubility of substances is affected by structural features

Solubility PhenomenaPOLAR SOLVENTSMechanism of Solvent Action High dielectric constant (water-80, chloroform-5,benzene-2)

Break covalent bonds of potentially strong electrolytes by acid-base reactions

HCl + H2O→H3O+ + Cl-

Capable of solvating molecules and ions through dipole interaction force, particularly H-bond formation.(internal pressures).

Solubility Phenomena

Solubility Phenomena

NON-POLAR SOLVENTS Hydrocarbons Unable to reduce attraction between ions of strong and weak electrolytes due to low dielectric constant

Aprotic solvents (neither accept nor donate protons), so cannot break covalent bonds and ionize weak electrolytes

Can dissolve nonpolar solutes with similar internal pressures through induced-dipole interactions

Ionic and polar solutes are not soluble or are only slightly soluble

Examples: CCl4, benzene and mineral oil - dissolve oils and fats Alkaloidal bases and fatty acids – soluble in nonpolar solvents

Nonpolar solvents

Solubility PhenomenaSEMIPOLAR SOLVENTS May act as intermediate solvents to bring out the miscibility of polar and nonpolar liquids

Examples;› Acetone – increases the solubility of ether in water

› Alcohol – increases miscibility of water-castor oil mixture

› Propylene glycol – increases miscibility of water and peppermint oil; water and benzyl benzoate

Solubility PhenomenaSOLUBILITY  Is defined as the concentration of solute in a saturated solution at certain temperature (quantitative )

Is defined as the spontaneous interaction of two or more substances to form homogenous molecular dispersion (qualitative)

Solubility PhenomenaDescriptive Term Parts of solvent

required to dissolve 1 part of solute

VERY SOLUBLE Less than 1 partFREELY SOLUBLE 1 – 10 partsSOLUBLE 10 – 30 partsSPARINGLY SOLUBLE 30 – 100 partsSLIGHTLY SOLUBLE 100 – 1,000 partsVERY SLIGHTLY SOLUBLE 1,000 – 10,000 partsPRACTICALLY INSOLUBLE OR INSOLUBLE

More than 10,000 parts

Solubility PhenomenaSolutions and Solubility Saturated solution – is one in which the solute is in equilibrium with the solid phase (solute)

Unsaturated or subsaturated solution› Is one containing the dissolve solute in a concentration below that necessary for complete saturation at a definite temperature.

Supersaturated solution› Is one that contains more of the dissolved solute that it would normally contain at a definite temperature, were the undissolved solute is present

Solubility PhenomenaSOLUBILITY OF LIQUIDS IN LIQUIDSLiquid-liquid pharmaceutical solutions include;

Spirits and elixirs Collodions Aromatic waters Hydroalcoholic solutions Lotions, sprays and medicated oils

Solubility PhenomenaCATEGORIES OF LIQUID-LIQUID SYSTEM Complete miscibility

› Liquids that mix in all proportions› Examples: Water-alcohol; glycerin-alcohol; alcohol-acetone; benzene-CCl4

Partial miscibility› When liquids are mixed, two layers are formed, each containing some of the

› other liquid in dissolved state› Examples: water-ether; water-phenol

Solubility PhenomenaPartial MiscibiltyThe mutual solubilities of partially miscible liquids are influenced by temperature(Critical Solution Temperature).

Upper Consolute Temperature – the mutual solubilities of the two conjugate phases increase with temperature until the composition becomes identical. A homogenous or a single phase is formed Ex phenol and water(66.8 deg C).

Lower Consolute Temperature – the solubilities of two liquid phase increase as the temperature is lowered Ex . Triethylamine and water

No Critical Solution Temperature – has neither an upper nor a lower consulate temperature, shows partial miscibility over the entire temperature range at which the mixture exists. Ex ethyl ether and water.

Both Upper and Lower Consolute – nicotine and water (208 and 60.8 deg C).

Solubility PhenomenaInfluence of Foreign Substance Naphthalene added to water and phenol mixture

KCl to water and phenol mixture

Succinic acid to water phenol mixture

Blending- an increase in mutual solubility of 2 partially miscible solvents by another agent.

Micellar solubilization – when the solubility in water of a nonpolar liquid is increased by micelle-forming surfaceactive-agent.

Three- Component SystemsExamples-water, carbon tetrachloride,and acetic acid

-water , phenol and acetone

-water, castor oil and alcohol

-water peppermint oil and PEG

-methyl salicylate, isopropanolol and water

Solubility PhenomenaSolubility of Solids in Liquids The most important type of pharmaceutical solutions.

Most drugs belong to a class of weak acids and bases that are made to react with strong acids and bases that within a definite pH range increases water solubility of the drugs.

Solubility PhenomenaSolubility of Solids in Liquids The most important type of pharmaceutical solutions.

Most drugs belong to a class of weak acids and bases that are made to react with strong acids and bases that within a definite pH range increases water solubility of the drugs.

Solubility Phenomena Carboxylic acids with more than 5 carbons are relatively insoluble in water but form soluble salts with NaOH, carbonates, and bicarbonates.

Oleic acid is insoluble in water but is soluble in alcohol and ether.

Sodium citrate is used to dissolve water-insoluble ASA due to formation of soluble acetylacetate ion and acetic acid.

Benzoic acid is soluble in NaOH sol’n, alcohol and fixed oils. Salicylic acid is soluble in alkalies and alcohols.

Organic compounds containing a basic nitrogen atom such as alkaloids, sympathomimetic amines, antihistamines, local anesthetics are not very soluble in water.

Solubility Phenomena1. The molar solubility of morphine in water

is 0.0005M, tha pKb is 6.13, and the molecular weight of sodium morphine sufate is 758.82. What is the lowest pH allowable for complete solubility in a 5% solution?

2. The molar solubility of sulfathiazole in water is 0.002, the pKa is 7.12, and the molecular weight of sodium sulfathiazole is 304. What is the lowest pH allowable for complete solubility in a 5% solution of the salt?

Sample Problem3. The molar solubility of morphine in water is

0.0005M, tha neg log disassociation constant is 6.13, and the molecular weight of sodium morphine sufate is 758.82. What is the lowest pH allowable for complete solubility in a 5% solution?

4. Below at what pH will free phenobarbital begin to precipitate from a solution containing 1.3 g of phenobarbital sodium / 100 mL at 25 deg. The molar solubility of phenobarbital is 0.0050 and its its neg log disassociation consatant is 7.41. MW of phenobarbital sodium is 254 g/mole.

Sample Problem

5. Above what pH will free cocaine begin to precipitate from a solution initially containing 0.0294 mole of cocaine HCl per liter. The negative log of disassociation constant of cocaine is 5.59 and its molar solubility is .00560?

Solubility Phenomena NON-IDEAL SOLUTION The heat of solution has a positive (energy absorbed) or negative (energy liberated) value

A negative heat of solution favors solubility while a positive heat works against dissolution

SOLUBILITY OF STRONG ELECTROLYTES The process of dissolution is generally accompanied by;

1. ABSORPTION OF HEAT (Endothermic)› The solution becomes cold› Increase in temperature, increases solubility› Dissolution of Na2SO4.H2O

Solubility Phenomena . EVOLUTION OF HEAT Exothermic, so the solution is hot Solubility decreases with an elevation of the temperature

Dissolution of anhydrous Na2SO4 Sodium chloride does not evolve or absorb heat when it

dissolves in water, thus its solubility is not altered much by a change of temperature, and the heat of solution is zero.

Effect of Temperature on Solubility Decrease in solubility with temperature (exothermic)

Increase in solubility with temperature (endothermic

Solubility Phenomena Solubility of Slightly Soluble Electrolytes

SOLUBILITY PRODUCT , Ksp

› Describes the solubility of slightly soluble electrolytes to form a saturated solution

› Ksp = A+aB-b

Example: The Ksp of Calcium carbonate is 9 x 10-9 at 25C where the dissociation equation at saturation is

CaCO3 Ca+2 + CO3-2

A solution contains 1 gm of sodium Phenobarbital in 100 ml at 25oC. Below what pH will precipitation occur given that solubility is 4.78X10-3 M and pka is 7.48 and mol. Weight is 254 gm/mol.