Oral RoA

Question 1

What is the diffusion control process?

Answer 1

As soon as drug is solubilised, it is removed, so a quick drop in concenration in the diffusion layer.

Question 2

In what circumstances is diffusion control process seen?

Answer 2

When absorption is limited by diffusion rate

Question 3

How is ionisation often overpredicted in weak acids and bases?

Answer 3

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

Question 4

Characteristics of BCS Class II?

Answer 4

poor solubility, high permeability

Question 5

Characteristics of BCS Clas III?

Answer 5

high solubility, poor permeability

Question 6

Methods to get from BCS II to I?

Answer 6

improve solubility

• particle size reduction
• soluble salts
• solid dispersions
• self emulsifying systems
• surfactants
• nanoparticles
• change pH of diffusion layer

Question 7

How to change pH of the diffusion layer?

Answer 7

making an alkaline salt of a weak acid will help improve its solubility - higher pH surrounding the WA so dissolves better

Question 8

Methods to get from Class III to I?

Answer 8

improve permeability

• permeation enhancer
• absorption enhancing excipients
• efflux inhibitors
• lipid filled caps

Question 9

Methods to get from Clas IV to I?

Answer 9

prodrugs, salts, co-solvents, surfactants, nanoparticles, liposomes, lyophilisation

Question 10

What are cyclodextrins?

Answer 10

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)

Question 11

What help to improve the solubilising effects of cyclodextrins?

Answer 11

hydrophilic polymers

Question 12

Why are there not many cyclodextrins?

Answer 12

toxicity and stability issues

Question 13

What are amorphous solid dispersions?

Answer 13

a more soluble but less stable form of the drug, formulated with polymers

Question 14

How are amorphous solid dispersions made?

Answer 14

• 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)

Question 15

Examples of polar excipients and their uses?

Answer 15

1. polyethylene glycol (co-solvent in liquid forms to prevent precipitation, dispersion enhancing/wetting agent in solid forms)
2. gelatin (positive and negative charges, granulating and improves wettability
3. 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)
4. lipids as polar excipients, or self emusifying systems

Question 16

Benefits of particle engineering?

Answer 16

decreased size, increased surface area of particles

Question 17

How can particle engineering be carried out?

Answer 17

recrystallisation, conventional comminution (though can impact degradation)

Question 18

Benefits of nanoparticles?

Answer 18

• v. high surface area, better dissolution and absorption
• greater bioavailability
• less food variability (lower fed to fasted ratio)
• improved dose/AUC proportionality

Question 19

How are nanoparticles formed?

Answer 19

traditional methods can’t usually achieve sizes needed

• micro-milling (a lot of stress on particles)
• piston gap methods through hydrodynamic cavitation)

Question 20

What are supercritical fluids?

Answer 20

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

Question 21

What are self-emulsifying systems?

Answer 21

soft or hard liquid filled caps

- non-ionic surfactants allow more solubilisation and avoid precipitation

Question 22

What excipients are used in self-emulsifying systems?

Answer 22

Tweens and Labrafil (high HLB to ensure immediate droplet formation o/w)
Co-solvents and surfactants to increase drug dissolved in lipid base

Question 23

How can presence of fat/lipids improve absorption of lipophilic drugs?

Answer 23

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

Question 24

How are self-emulsifying lipid formulations made?

Answer 24

incorporation of drug into oil-surfactant mix until clear solution, then filling into caps