What does the extent of dissolution depend on?
Under given experimental conditions it depends on the solubility of the solute in the solvent
What is dissolution?
The process of transferring molecules or ions of solute into solution
What is the mechanism of dissolution?
Dissolution starts with the wetting of the solid surface
This forms an aqueous diffusion layer
The solute then starts to dissolve as solvent molecules penetrate the aqueous diffusion layer
Then the solute migrates into the bulk of the solution. This continues as long as the system is operating under sink conditions
What are the components of the Noyes Whitney equation?
Dissolution rate: this is the amount of drug dissolved over a given period of time (mg/h/cm^2)
D: this is the diffusion coefficient (cm^2/s)
A: surface area of particle (cm^2)
Cs: solubility of the solid (mg/mL)
C: concentration in bulk of the solution at time t (mg/mL)
h: thickness of the stagnant layer (cm)
What is removed from the Noyes Whitney equation under sink conditions and why?
C is removed because under sink conditions the receptor compartment is continuously removing the solution and replacing with fresh solvent to mimic the stomach emptying conditions of the body
So C becomes very small so can be removed in this equation
What is aspirin?
What is aspirin hydrolysed to?
What influences the surface area of the undissolved solid?
Size of the particle
Porosity of solid particle. More porous = more soluble
What influences the solubility of solid in dissolution medium?
Nature of dissolution medium
Molecular structure of solute
Crystalline form of solute
What influences the concentration of solute in solution at time t?
Volume of dissolution medium
Processes that remove dissolved solute from dissolution medium
What factors affect the diffusion coefficient?
Dissolution rate constant
Viscosity of the dissolution medium
Size of the diffusing molecule
What influences the thickness of the stagnant layer?
What elements of the NW equation are proportional to dissolution?
Concentration of drug in solution
What happens if the dissolution of a substance is endothermic?
Then heat is required to dissolve
Increasing temperature would increase diffusion coefficient and increase dissolution
ΔH would be positive
How do you calculate the amount of aspirin released?
- Calculate the concentration of salicylic acetate from absorbance using A=εbc
- This is equivalent to the amount aspirin released
- Calculate the dilution factor. We diluted 1mL to 10mL so the DF = 10
- Multiply the concentration by the dilution factor
- Convert the units of concentration from molL-1 to gL-1 by using n=m/M
- Convert this to mg/mL (no change needed)
In the lab, what is the volume of the sample?
This is the amount of sample withdrawn from the dissolution apparatus at each time point
How do you calculate the mass in the sample withdrawn?
Volume x concentration (in mg/ml)
What is the total volume of the dissolution medium?
The volume of the vessel
What can the volume of the vessel tell us?
We can work out the amount of aspirin using this volume.
It tell us the total amount of aspirin present in the vessel at that time point
How do you calculate the total amount of aspirin released?
This is the sum of aspirin released at each time point
What factors should be considered when formulating orally administrated drugs in powdered form?
The aqueous solubility Melting point Crystalline form of the drug Surface area and particle size Drug excipient interactions like complexation, adsorption Chemical stability
What factors should be considered when choosing the cosolvent?
Choice is limited due to toxicity and irritancy especially for oral or parenatal drug delivery
A suitable range for aspirin would have a DC between 25-80
How can the solubility of poor drugs in water be improved?
By the addition of a surface active agent like surfactant
What must be controlled when adding a SAA to improve solubility?
The amount of surfactant
Insufficient amounts may not completely solubilise the drug, this can cause precipitation
Large excess is also undesireable doe to cost, toxicity, (although non-ionic surfactants have a lower toxicity profile), strong drug adsorption within the micelle
How can cyclodextrins play a part in solubilisation?
They can also increase solubility of a drug by binding to it.
The polar functional groups on the outside of the cyclodextrin aids solubilisation of aspirin (which will have binded on the inside)
How can particle size aid solubility?
As particle size decreases, the aqueous solubility will increase
Molecular dispersion of drugs can exhibit improved bioavailability owing to the increased solubility of the dispersed drug
How does salt formation aid solubility?
The sodium salt of an acidic drug is charged so dissolution is increased. This can then diffuse to give fine precipitates of the free acid form of the drug (no longer charged) when in gastric fluid (pH 1-3.5) which aids absorption
Would you expect aspirin to be absorbed mainly in the stomach or the small intestine? Why?
The unionised form is greater in the stomach, this is because aspirin is an acidic drug and in acidic environments like the stomach, its unionised form predominates.
The unionised form can pass through the cell membrane easily.
However, the surface area of the intestine is much larger than that of the stomach so more aspirin is absorbed here.
Also note that aspirin is poorly soluble in acid because the unionised form predeominates and so is less soluble in aqueous fluid. This limit in solubility delays absorption of high doses