W4 L3 - Dissolution

Question 1

Dissolution definition

Answer 1

the transfer of molecules from the solid state to the liquid state

Question 2

Process of dissolution

Answer 2

1. drug removed from solid particle
2. creation of cavity in the solvent
3. insertion of drug molecule in the solvent
4. creation of interactions (bonds) between solvent and solute

tablets/ capsules disintegrate into granules or aggregates which disaggregate into fine particles

Question 3

effect of increasing SA on dissolution

Answer 3

faster dissolution

Question 4

Noyes-Whitney equation (rate of dissolution)

Answer 4

dm/dt = DA(Cs - C)/h
where:
dm/dt: rate of dissolution (or change of mass over time)
D: diffusion coefficient
A: Surface area of particle
h: thickness of diffusion layer
cs: saturation concentration in the diffusion layer
c: concentration in the GI fluid

Question 5

how to modify the rate?

Answer 5

• changing SA of particles, Increase the porosity of the particles to increase SA
• Favourable for hydrophilic particles e.g. griseofulvin
• Not favourable for hydrophobic particles as leads to agglomeration (reduce contact to water / surface tension)
• Requires the use of surfactants (wetting agents)
• Increase the solubility in the diffusion layer, cs. pH in the diffusion layer is different from pH in the bulk, but:
  Weak acid solubility increases with pH
  Weak base solubility decreases with pH
• Concentration, c, (in the bulk/solution/juice): best if low
  Diffusion coefficient, D changes with environment, viscosity of medium: food slows the movement of molecules (more viscous, tortuous), vili has a very viscous environment due to proteoglycans.
  If more viscous, D decreases, thus dm/dt decreases.

Thickness of the diffusion layer, h, (h increases, dm/dt decreases). Influenced by degree of agitation in GI tract, higher motility may decrease h thus increase dm/dt. Sparingly soluble drugs, h decreases thus dm/dt increases.

Question 6

drug factors affecting dm/dt

Answer 6

Salt of a drug increases dissolution.
However, consider counterion of salt

For poorly soluble drugs, surfactants can be used as solubilising agents and wetting agents.

Solid form of the API will also play a role: crystals vs amorphous (not crystalline) solids

Question 7

Intrinsic dissolution rate

Answer 7

• The Noyes-Whitney equation can be simplified when cs is about 10x c: these are called “sink” conditions.
• Intrinsic dissolution rate (IDR) is the rate of mass transfer per area of dissolving surface (usually expressed mg/mm2/s)
  IDR = dm/dt x 1/A = D/h x Cs = KCs
  IDR = KCs

Question 8

dissolution testing

Answer 8

• The aim: to determine the rate at which a substance is released from the dosage form and dissolve in a particular medium
• Protocols and conditions vary depending whether aimed at QC (quality control?) or predict performance in GIT.
• basket apparatus - conventional tablets, chewable tablets
• paddle apparatus - orally disintegrating tablets, chewable tablets, suspensions
• flow though cell apparatus - poorly soluble API, powder, granules, microparticles, implants

Question 9

Intrinsic dissolution rate: Quality Control

Answer 9

Standard methods describe in Pharmacopoeias
- Usually done in sink conditions and temperature at 37.5 C
- Medium should not contribute to the decomposition of the drug, e.g. hydrolysis,
- Use dilute acid solution (0.1M HCl), phosphate buffer (pH 5 to 9)
- Test role of surfactants
- Immediate release formulation should not be less than 75% released in 45 min,
- Gastro resistant: limited dissolution in acidic conditions, fast in small intestine, i.e. no more than 10% in 2 hours in 0.1M HCl, no less than 75% within 45 min at pH 6.8.