W4.2_Dissolution

Question 1

Describe the two consecutive stages of dissolution.

Answer 1

• Interfacial reaction that results in liberation of solute molecules from solid phase to liquid phase
• Solute molecules migrate through boundary layer surrounding the crystal to bulk of solution

Question 2

Describe the molecular aspect of solubility. What is the process of dissolution in solid dosage forms?

Answer 2

• Bonds break between solid and liquid molecules
• Cavity created in solution to allow insertion of solute molecules into solvent -> solution
• Tablets/capsules -disintegration-> granules/aggregates -disaggregation-> fine particles
• Any form can dissolute into drug in solution -> drug in blood/other fluids and tissues

Question 3

Explain the Noyes-Whitney equation.

Answer 3

dm/dt=DA(c(s)-c)/h
dm/dt: rate of dissolution (change of mass over time)
D: diffusion coefficient
A: surface area of particle
h: thickness of diffusion layer (between c(s) & c)
c(s): saturation concentration in diffusion layer (interface)
c: concentration in GI fluid

Question 4

Explain how changes of different parameters in Noyes-Whitney equation can impact dissolution.

Answer 4

• Decrease size of particles/increase porosity of particles -> increase A -> favourable for hydrophilic particles but unfavourable for hydrophobic particles as it leads to agglomeration (surface tension, require surfactants instead)
• ex. maize starch: a disintegrant that absorbs water (∵ hygroscopic polymer) -> swell -> more lines of fractures -> particles push apart -> breaking up of tablet release active ingredients
• c(s): depends on interaction between molecules in solid and with intermolecular forces in solvent
  ex. weak acid solubility increases with pH, weak base solubility decreases with pH
• c: best if low
• D: changes with environment, viscosity of medium (more viscous with food and in villi)
• h: influenced by degree of agitation in GIT (higher motility reduces h), high solubility reduces h

Question 5

What are the other drug factors that can impact dissolution (4)?

Answer 5

• Salt form of drugs: much more readily dissociates than free acid/base
• Counterion of salt: Cl- in HCl salts ensures pH is lower than normal but may suffer from salting out (common ion effect) (different salts may affect chemical stability, hygroscopicity, crystallinity, manufacturability)
• Surfactants: used as solubilising agents/wetting agents for poorly soluble drugs
• Solid form of API: amorphous solids are better to solubilise and release than crystals

Question 6

Explain the intrinsic dissolution rate (IDR) equation, its aim, and variables.

Answer 6

• IDR=kc(s) -> independent of boundary layer, in mg/mm^2/s
• Aim: determine rate of substance released from dosage form and dissolve in particular medium -> as quality control (QC)/predict performance in GIT
• Variables: type of dissolution apparatus, volume/composition of dissolution medium, hydrodynamics, number of units tested

Question 7

Refering to the diagrams, describe the different IDR measuring apparatus, their rotation speed, and the types of tablets that can be used in each apparatus.

Answer 7

• Basket apparatus
• Rotation 50-120 rpm
• Conventional tablets, chewable tablets
• Paddle apparatus
• Rotation 35-50 rpm
• Oral dispersible tablets, chewable tablets, suspensions
• Flow through cell apparatus
• N/A
• Poorly soluble API, powder, granules, microparticles, implants

Question 8

Explain the requirements of QC testing under sink conditions. State the dissolution limits of QC in immediate release and G/R products.

Answer 8

• Medium where drug is soluble
• Medium should not contribute to decomposition of drug
• Must withstand pH changes (dilute acid solution, aqueous buffer of high pH, phosphate buffer)
• Surfactants can be added to favour dissolution
• Immediate release products: ≥75% released in 45 minutes
• G/R products: ≤10% release in acidic conditions within 2 hours, ≥75% in 45 minutes at pH 6.8