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
Factors affecting dissolution (1)
! Surface area of particles:
! In general, larger surface area, higher dissolution rate:
! Particle size: smaller size = larger surface area
! Porosity: more porous = larger surface area
! Dispersability: does the powder disperse easily, or form lumps?
! Solubility (CS)
! Particle size: solubility increases when the particle size is
reduced
! Temperature: solubility normally increases if the temperature is increased – there are some cases where the opposite is the case
Factors affecting dissolution (2)
Solvent choice
! Co-solvents may alter the solubility of drugs
! Consider this in the context of experiments / BP tests
! pH of the media may change the ionisation state of weak acids and bases, influencing solubility
! The Common Ion Effect: The solubility of one salt is reduced by the presence of another having a common ion
! Structure of the drug molecule
! Weak acid, weak base, hydrophobic or hydrophilic?
! Polymorphism
Factors affecting dissolution (3)
! Thickness of the boundary layer (h)
! Speed of stirring
! Also, consider the relevance of this for a biological system
! Viscosity of the dissolution media
! Shape of the container in which the experiment is carried out
! Comparison of results
! Again, consider the in vivo relevance
Biological factors & dissolution (1)
! Viscosity of fluid in the GI tract may be increased by food
! This may reduce dissolution due to the effect of viscosity on the diffusion rate
! Dissolution increases due to the presence and activity of surfactants and bile salts in the gastric fluid
! Changeswettabilityofthedrug
! Therefore effective surface area is important
! Drugsolubility
! Gastric motility can reduce the size of the diffusion layer; reducing h will result in an increase in the dissolution rate
Biological factors & dissolution (2)
! Gastric pH is acidic
! Dissolution of weakly basic drugs will increase in the
stomach
! pH in the small intestine is higher than the stomach, so more acidic drugs will have a faster dissolution rate there.
The antifungal drug ketoconazole is a weak base. Cimetidine reduces gastric secretion. Why is the bioavailability of ketoconazole reduced if cimetidine is administered two hours before?
Liquid-liquid solubility
! Polar liquids tend to dissolve in polar solvents (“like dissolves like”)
! due to hydrogen bonding and dipole-dipole interactions
! Non-polar liquids are normally insoluble in polar liquids
! i.e. hexane (C6H14) does not dissolve in water; increasing the non polar nature of a chemical will decrease its aqueous solubility
Pressure
- the solubility of liquids and solids changes little which increases in pressure
- increasing the pressure in a system will significantly increase the solubility of dissolved gases
- higher pressure results in greater contact between the gas and the solvent
Pressure - Henrys law
The amount of a gas dissolved in a solution is directly proportional to the pressure of the gas above the solution:
W = kP
- where W is the mass (mol fraction) of gas dissolved in the solvent
- k is the henrys law constant for a gas in a solvent
- P is the partial pressure of the gas above the liquid
In vitro – in vivo correlations
! Mathematical relationships which attempt to relate the in vitro dissolution data with the in vivo rate and extent of absorption
! Permeability – the rate at which a molecule can penetrate a biological membrane (i.e. skin, mucosal surfaces, etc.)
dissolution profile determines
the rate of drug release under steady-state condition
In vitro – in vivo correlations diagram
solubility going up
permeability going across
6 factors affecting dissolution
- surface area of particles
- solubility (Cs)
- solvent choice
- structure of drug molecule
- polymorphism
- thickness of boundary layer (h)
Transdermal examples
Drug in adhesive patch - draw and label
- Drug impermeable metallic plastic laminate
- Drug-containing adhesive
- DRUG DIFFUSION FROM MATRIX
Transdermal examples
Adhesive diffusion-controlled patch - draw and label
- Drug-impermeable metallic plastic laminate
- Adhesive layer
- Drug reservoir layer
- Rate-controlling adhesive layer
- DRUG DIFFUSION FROM MATRIX
Classic examples include the Deponit® device (Pharma Schwarz) and Frandol Tape® (Nitto Electric Co.) for the delivery of nicotine.
Transdermal examples
Membrane-moderated transdermal patch system
- Drug-impermeable metallic plastic laminate
- Adhesive layer
- Drug reservoir
- Rate-controlling polymeric membrane
- DRUG DIFFUSION FROM MATRIX
Commercial examples of these devices include Transderm-Nitro® and Transderm-Scop® systems (Alza/Ciba-Geigy), Catapres-TTS® (Alza/Boehringer Ingelheim) and Estraderm® (Alza/Ciba-Geigy), employed for the treatment of angina pectoris, motion sickness, blood pressure disorders and oestrogen replacement, respectively.
Membrane-moderated transdermal patch system equation
dQ / dt =
Km/r . Ka/m . Da . CR / Km/r. Dm. ha + Ka/m. Da. hm
Membrane-moderated transdermal patch system equation - km/r and ka/m represent ?
where Km/r and Ka/m represent respectively the partition coefficients of the drug from the reservoir to the membrane and from the membrane to the adhesive
Membrane-moderated transdermal patch system equation - Dm and Da ?
Dm and Da the diffusion coefficients in the rate-limiting and adhesive layers respectively
Membrane-moderated transdermal patch system equation - hm and ha? also what must be taken into account?
hm and ha are the thickness of the rate-controlling and adhesive layers.
The porosity of microporous membranes must also be taken into account where necessary.
