Dissolution Flashcards
Overview
! A drug should be dissolved before it is absorbed
! Dissolution refers to the process by which a drug molecule (or ion, i.e. salts) moves from the solid phase to the liquid phase
! Widely used for a range of dosage forms:
! Tablets, capsules, suppositories, ointments, creams, patches, etc.
! Different experimental designs for assessment of dissolution.
! If a drug has low solubility in the body dissolution may be the rate-limiting step to absorption and, thereafter, therapeutic effect
! Consider in the wider context of solubility
Solutions
! Solutions are homogeneous mixtures of two or more pure substances.
! In a solution, the solute is dispersed uniformly throughout the solvent.
Units – concentration
equations slide 13/14
How Does A Solution Form?
! E.g. NaCl dissolving in water
! NaCl is the solute, water is the solvent
! Disruption of the hydrogen bonds between water molecules - thermodynamics
! Dissociation of NaCl into Na+ and Cl-
! Formation of ion-dipole interactions:
! Na+…δ-OH2 and Cl-…δ+H2O
! …which means that the ions are solvated by water
! …as water is the solvent, the ions are hydrated
Structure and solubility
! If the intermolecular forces between solute and solvent are stronger it is more likely that the solute will dissolve in the solvent.
! A range of intermolecular forces may occur: hydrogen bonds, dipole-dipole interactions; van der Waals bonds; ion-dipole interactions (for ionic species).
-For example, the degree of hydrogen bonding influences solubility for the given examples (right) of glucose and cyclohexane
vitamins
! Vitamins A, D, K and E are soluble in non-polar solvents (e.g. oils)
! Vitamins B and C are water-soluble
How Does A Solution Form?
! Solvent molecules are attracted to surface ions.
! Each ion is surrounded by solvent molecules.
! Energy change results in solvation / hydration ! E.g. an ionic solid dissolving in water
Degree of saturation
! Saturated solution:
! Solvent holds as much solute as possible
at a particular temperature
! Undissolved solid remains in the vessel, i.e. as a sediment
! Dissolved solute is in dynamic equilibrium with the solid solute particles
! Unsaturated (sub-saturated) solution
! Contains less than the max possible amount of solute (at a specific temperature)
! There will be no excess solid present in the vessel
Supersaturation
! Solvent holds more solvent than is normally possible at a specific temperature
! Super saturated solutions are unstable and often result in crystallisation, the opposite of solvation
Mechanism of dissolution
! An interfacial reaction:
! Results in the liberation of a solute molecule from the solid phase
! The solution in contact with the solid will become saturated
! Solute molecules migrate through the boundary layers surrounding the solid to the bulk solution
! In this situation the concentration is C
! The boundary layer is predominately static and surrounds the wetted surface of the solid
! Mass transfer occurs slowly through the boundary layer to the bulk solution
! Reaction must be energetically favourable
Dissolution – boundary layer
! A thin layer of solution in contact with the solid (i.e. the dosage form)
! Boundary layers are static, or slow moving, liquid layers
! Saturated concentration, Cs, which may be described as Csat, next to the surface of the solid
! Dissolved molecules diffuse through the boundary layer into the bulk solution, where their concentration is represented by C.
! The concentration gradient is therefore (CS–C)/h
Mechanisms of diffusion
- dissolution depends on the slowest or rate limiting step of the process, governed by ficks first law:
dC/dt = ktriangleC
where triangleC is the conc difference at the solid surface (Cs - C)
Noyes & Whitney Equation
describes the rate of dissolution of a solid in a liquid:
dM/dt = DS/h (Cs - C)
dC/dt = DS/Vh (Cs - C)
If C is significantly smaller than CS, the system is said to be at “sink condition”, allowing the equation to be simplified:-
dM/dt = DS/h Cs = kSCs
k=D/h is referred to as the dissolution rate constant
Noyes & Whitney Equation
! Diffusion coefficient:
D = kT/ 6 pie na = RT/ 6 pie uaNa
k=R/Na
! Consider how:
! Temperature affects the diffusion coefficient ! Viscosity affects the diffusion coefficient
! …therefore, the dissolution rate is affected by temperature and viscosity
“Sink conditions”
! Usually when the bulk concentration is significantly lower than the concentration in the boundary layer
! Normally, C needs to be five times lower than CS.
! “Sink conditions” occurs in a volume of dissolution medium that is at least 5 to 10 times the saturation volume (BP 2005)
! This means that the rate of dissolution will not be affected by drug already in the media, provided sink conditions are maintained
An “alternative” definition, used frequently for studies of percutaneous absorption, is that sink conditions are maintained if the concentration of the analyte in the donor phase remains at less than 10% of its saturated solution throughout the experiment
! What does the term / phenomena “sink conditions” represent?
! …think what happens to the drug when it enters the body…
! …think of a diffusion gradient; for example, the mixing of a dye with water
