Drug Solubility Flashcards
Why drug solubility is important?
To develop stable and efficacious pharmaceutical solutions
- Oral solutions, eye drops, injections
To determine the necessary conditions for the manufacturing of dosage forms
Impact of dissolution, absorption and bioavailability
To develop suitable strategies for the delivery of poorly soluble drugs
Crystallization process
Saturated Solution
one in which an equilibrium is established between dissolved and undissolved solute at a definite temperature OR a solution that contains the maximum amount of solute at a definite temperature
Unsaturated Solution
subsaturated solution is one containing the dissolved solute in a concentration below that is necessary for complete saturation at a definite temperature
Solubility: Driving Forces
Polarity of solvent plays a major role in determining solubility
- Polar molecules = molecules in which charge is not distributed symmetrically among the atoms making up the molecule
Sugar dissolves in water but not in oil
Wax dissolves in oil but not in water
Polar
High dipole moment and high dielectric constant
Examples:
- Water
- Alcohols
Non-Polar
Low / no dipole moment and low dielectric constant
Examples:
- Hydrocarbons
- Oils
- Lipids
Semi-polar
Intermediate solvents, can increase miscibility of polar and non-polar solvents with each other
Examples:
- Ketones
- Polyethylene glycol
Dielectric Constant
Measure of polarity
Hydrogen Bonds
Unusually strong dipole-dipole (1-10 kcal/mole) interactions
Hydrogen atoms is bonded to a highly electronegative atom such as oxygen or nitrogen
Greater the number of hydrogen bonds that can be formed by a molecule/ion with water, the higher the solubility
Inter-molecular hydrogen bonding between water and other molecules is the basis for water solubility
Intra-Molecular Hydrogen Bonding
If a molecule can form intra-molecular hydrogen bonds, its solubility in water decreases
Examples:
- o-nitrophenol
- p-nitrophenol
- Salicylic acid
- p-hydroxybenzoic acid
pH solubility profile of ionizable drugs
Acid:
- low pH = low solubility
- high pH = high solubility
Base
- low pH = high solubility
- high pH = low solubility
A drug can be available in different salts
Salt Types
- Na+
- K+
- Diethylamine
- N-(2-hydroxyethyl)pyrrolidine (HEP)
Different salts of the same drug will have different aqueous solubility
Lipophilicity
The body contains an aqueous and lipid environment
Drugs need to have the ability to dissolve and be efficacious in both types of environments
Lipophilicity is a key factor in determining in vivo drug behavior:
- Permeation through membranes
- Transport
- Binding
- Accumulation
- Recognition
- Affinity
- Specificity
Partition Coefficient
- Balance between lipophilicity and hydrophobicity of a compound in its unionized, non-electrolyte form is characterized by a parameter
Lipophilicity - the Log P value
As for pH, it is more convenient to express P as its log. It has been determined for thousands of substances
In general, a compound with log P < 0 (or P < 1) = too hydrophilic, and a log P > 3.5 (or P > ~3000) is too lipophilic to become a drug
Drugs need to have log P in the range 0 - 3.5
It has been noted through examination of thousands of experimental log P values that chemicals with a +ve log P over +0.5 are considered water insoluble while those with values less than +0.5 are considered water soluble
If a compound shows real therapeutic potential, it can be modified
Biopharmaceutics Classification System (BCS)
Class I
- High solubility
- High permeability
- Example:
- Metoprolol
Class II
- Low solubility
- High permeability
- Example:
- Celecoxib
Class III
- High solubility
- Low permeability
- Example:
- Acyclovir
Class IV
- Low solubility
- Low permeability
- Example:
- Paclitaxel
