Oral RoA Flashcards
What is the diffusion control process?
As soon as drug is solubilised, it is removed, so a quick drop in concenration in the diffusion layer.
In what circumstances is diffusion control process seen?
When absorption is limited by diffusion rate
How is ionisation often overpredicted in weak acids and bases?
The pH of the unstirred diffusion layer (ie immediate surroundings of the dissolving molecule) is often different
weak base - would assume it ionises well at gastric pH, but surround pH may be higher so less ionised and less soluble
reverse seen for weak acids in the intestine
Characteristics of BCS Class II?
poor solubility, high permeability
Characteristics of BCS Clas III?
high solubility, poor permeability
Methods to get from BCS II to I?
improve solubility
- particle size reduction
- soluble salts
- solid dispersions
- self emulsifying systems
- surfactants
- nanoparticles
- change pH of diffusion layer
How to change pH of the diffusion layer?
making an alkaline salt of a weak acid will help improve its solubility - higher pH surrounding the WA so dissolves better
Methods to get from Class III to I?
improve permeability
- permeation enhancer
- absorption enhancing excipients
- efflux inhibitors
- lipid filled caps
Methods to get from Clas IV to I?
prodrugs, salts, co-solvents, surfactants, nanoparticles, liposomes, lyophilisation
What are cyclodextrins?
complexes formed by supersaturation of a cyclodextrin solution with the drug, using mild agitation for an extended period
(can also add a mass of drug to CD and solvent to produce a slurry to knead)
What help to improve the solubilising effects of cyclodextrins?
hydrophilic polymers
Why are there not many cyclodextrins?
toxicity and stability issues
What are amorphous solid dispersions?
a more soluble but less stable form of the drug, formulated with polymers
How are amorphous solid dispersions made?
- spray dry using solvents or supercritical fluids
- hot melt extrusion (soften polymer, add API and mix. rapidly cool to get strands of polymeric glass containing drug, then mill to powder)
Examples of polar excipients and their uses?
- polyethylene glycol (co-solvent in liquid forms to prevent precipitation, dispersion enhancing/wetting agent in solid forms)
- gelatin (positive and negative charges, granulating and improves wettability
- sugar glasses e.g. inulin (mix w drug solution then freeze dry to form sugar glass, dissolution profile simular to that of the sugar, also improves stability)
- lipids as polar excipients, or self emusifying systems
Benefits of particle engineering?
decreased size, increased surface area of particles
How can particle engineering be carried out?
recrystallisation, conventional comminution (though can impact degradation)
Benefits of nanoparticles?
- v. high surface area, better dissolution and absorption
- greater bioavailability
- less food variability (lower fed to fasted ratio)
- improved dose/AUC proportionality
How are nanoparticles formed?
traditional methods can’t usually achieve sizes needed
- micro-milling (a lot of stress on particles)
- piston gap methods through hydrodynamic cavitation)
What are supercritical fluids?
can assume properties of both a liquid and a gas (dissolve through solids but still dissolve materials)
highly compressible so changes in temp and pressure greatly impact density, mass transport and solvating power
used to create nanoparticles by control of pressure and temp in solvents such as carbon dioxide
What are self-emulsifying systems?
soft or hard liquid filled caps
- non-ionic surfactants allow more solubilisation and avoid precipitation
What excipients are used in self-emulsifying systems?
Tweens and Labrafil (high HLB to ensure immediate droplet formation o/w)
Co-solvents and surfactants to increase drug dissolved in lipid base
How can presence of fat/lipids improve absorption of lipophilic drugs?
increase solubilisation
- fat in the duodenum stimulates secretion of biliary lipids, generates micelles etc.
- solubilising and absorption effect from triglycerides and surfactants in intestine wall
- uptake into lymphatics, which also avoids first pass metabolism
How are self-emulsifying lipid formulations made?
incorporation of drug into oil-surfactant mix until clear solution, then filling into caps
