Solubility and Distribution Phenomena

Solubility

Maximum amount of a substance that will dissolve in a given amount of solvent at a specified temperature

Quantitative terms

as the concentration of solute in a saturated solution at a certain temperature

Qualitative solubility

is defined as the spontaneous interaction of two or more substances to form homogenous molecular dispersion.

Thermodynamic Solubility of Drugs

The maximum amount of the most stable crystalline form that remains in solution in a given volume of the solvent at a given temperature and pressure under equilibrium conditions

SOLUTION

Defined as a chemically and physically homogenous mixture of two or more substances

Solute – dissolving substance

▪ Solvent – dissolving medium

Components of Solution:

Saturated Solution

Is one in which solute in solution us in equilibrium with the solid phase (balanced)

Unsaturated or Subsaturated Solution

Is one containing the dissolved solute in a conc below the 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 present

▪ Physicochemical properties of the solute and solvent

▪ Temperature

▪ Pressure

▪ pH of the solution

The solubility of a compound depends on 4

factors:

1. Break up of solute-solute intermolecular bond.

2. Break up of solvent intermolecular bond.

3. Formation of cavity in solvent phase large enough to accommodate solute molecule.

4. Transfer of solute into the cavity of solvent phase.

5. Formation of solute-solvent intermolecular bond.

Mechanistic perspective of solubilization process for organic solute in water involve the following steps:

1. Solvent with solvent

2. Solute with solvent

3. Solvent with solute

EQUILIBRIUM–BALANCE OF ENERGY OF 3 INTERACTIONS AGAINST EACH OTHER

Enthalpy

is released it absorbed during the dissolving process (constant pressure)

Enthalpy

It is the measurement of total heat content in energy, particularly in a thermodynamic system under constant pressure

▪ Positive Enthalpy – endothermic reaction (happened within)

▪ Negative Enthalpy – exothermic reaction (happens outside)

Types of Enthalpy:

BIOPHARMACEUTICS CLASSIFICATION SYSTEM

(BCS)

Is the scientific framework for classifying drug substances according to their minimum aqueous solubility (in the pH range of 1-7.5) (dose; fraction absorbed) and their intestinal permeability

BIOPHARMACEUTICS CLASSIFICATION SYSTEM

(BCS)

The purpose of this is to characterize drugs for which products of those drugs may be eligible for a biowaiver of in vivo bioequivalence studies (mainly for classification)

High solubility

High permeability

CLASS 1

Low solubility

High permeability

CLASS 2

High solubility

Low permeability

CLASS 3

Low solubility

Low permeability

CLASS 4

Propranolol, Metoprolol, Verapamil

Class 1 drugs

Ketoprofen, Naproxen, Carbamazepine

Class 2: drugs

Ranitidine, Cimetidine, Atenolol, Vancomycin

Class 3: drugs

Furosemide, HCTZ (Hydrochlorothiazide)

Class 4: drugs

BIOPHARMACEUTICS CLASSIFICATION SYSTEM

(BCS)

This serves as a fundamental guideline for determining the conditions under which in-vitro (using instruments)/in-vivo (living tissues) correlations are expected

In-vitro/in-vivo correlation (IVIVC)

is normally expected for highly permeable drugs or drugs under dissolution rate-limiting conditions

• Polarity of solute and solvent

• Ability of the solute to form Hydrogen bonds

→ Accordingly, water mixes in all proportions in alcohol and dissolves sugar and other polyhydroxy compounds due to the ability of the solute to form H bonds is a far more significant factor than is the is polarity reflected in a high dipole moment

• Ratio of polar and non-polar group of the

molecule

The Solubility of a Drug in Polar Solvents Depends on these 3 Factors:

SEMIPOLAR SOLVENTS

Acts as intermediate solvents – bring about miscibility of polar and nonpolar liquids

Acetone

increase solubility of ether in water

Alcohol

mineral oil/castor oil and water

Propylene glycol

increase solubility of water and peppermint oil and water and benzyl benzoate

benzyl benzoate

commonly used as a preservative

water + alcohol

Hydroalcoholic

volatile oil + water

Aromatic water

volatile oil + alcohol

Spirits and elixir

ether and alcohol

Collodion

Lotion, sprays and, medicated oil

combination of fixed oils

Miscibility

Refers to the mutual solubilities of the components in liquid-liquid system

Complete Miscibility

Partial Miscibility

Miscibility Two Categories:

Fatty acids

containing more than 10 Carbon atoms forms soluble soaps with the alkaline metals and insoluble soaps with other metal ions (soluble in solvents with low dielectric constant)

Oleic acid

is insoluble in water but soluble in alcohol and ether

Benzoic acid

soluble in sodium hydroxide solution, alcohol and fixed oils.

Salicylic acid

is soluble in alkalines and in alcohol (its hydroxyl group cannot contribute to the solubility because it is involved in an intramolecular hydrogen bond)

Phenol

weakly acidic and only slightly soluble in water but is quite soluble in diluted sodium hydroxide solution

AA>>A-B

solvent molecules will be attracted to each other’s and the solute will be excluded

BB>>AA

solvent will NOT be able to break the binding forces between solute molecules

AB>>AA or BB three forces are equal

Solute will form a solution

Non-polar Solvents

Are unable to reduce the attraction of the ions due to their low dielectric constant, and are therefore unable to form Hydrogen bonds with non-electrolytes

Non-polar Solvents

Can dissolve NP solutes through weak Van der Waals forces (e.g., oils and fats in carbon tetrachloride, benzene, or mineral oil)

Semi-polar Solvents

Can induce a certain degree of polarity in non-polar solvent molecules (e.g., ketones) –act as intermediate solvents to bring about miscibility of polar and non-polar liquids

Gas in Liquids

Liquids in Liquids

• Complete Miscibility

• Partial Miscibility

Solids in Liquids

TYPES OF SOLUTION

(of Pharmaceutical Importance)

EXTRACTION

The process of selectively removing a compound of interest from a mixture using a solvent

Particle Size Surface Area of Drug

Molecular Size

Boiling Point and Melting Point

Influence of Substituents

Temperature

FACTORS INFLUENCING SOLUBILITY