dissolution

• Molecular solubilisation process

  1. Energy must be supplied to break the intermolecular bonds

  2. Solvent molecules surrounding the drug crystal provide an environment for dissociation to occur

  3. Solvent molecules need to make space for the incoming drug molecules, creating gaps or holes in the solvent structure

  4. Drug molecules, now free from the solid lattice, diffuse into the solvent

  5. Solvent molecules surround the drug molecules, encapsulating them and preventing them from re-aggregating into a solid

  6. Drug molecules interact with the solvent molecules - these include h-bonds, dipole-dipole interactions etc
• Reason for molecular solubilisation

  To remove a drug molecule from a crystal/solid particle
• dissolution process of solid dosage forms...

  A) disintegration

  B) disaggregation

  C) dissolution

  D) solution

  
• the dissolution process has been formalised by which equation?

  Noyes-Whitney equation

  A) dm/dt

  B) A

  C) h

  
• terms for the Noyes-Whitney equation

  A) dissolution

  B) diffusion

  C) A

  D) thickness

  E) GI

  F) saturation

  
• how can an increase in surface area modify the dissolution rate?

  Increase surface area increases dissolution rate.
• what are the two ways the surface area of particles can be increased?

  decrease the size of the particles

  increase the porosity of the particles
• decreasing the size of the particle to increase the surface area is favourable for what type of particles?

  • Favourable for hydrophilic particles e.g. griseofulvin
  • Not favourable for hydrophobic particles as leads to agglomeration (reduces contact to water/surface tension) → Requires the use of surfactants (wetting agents)
  • example aspirin requires the use of polysorbate 80 (not very ionic and not a lot of side effects)
  • This increases dm/dt (rate of dissolution)
• how do you modify the rate of dissolution via the solubility in the diffusion layer (cs)?

  • increase the solubility in the diffusion layer, cs
  • Solubility depends on the interactions between molecules in the solid (crystal/amorphous) and with intermolecular interactions in the solvent
  • 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
• for an increase in the rate of dissolution, what should the value of the concentration in the GI fluid be?

  best if low
• the diffusion coefficient changes with what?

  changes with the environment - the viscosity of the medium.

  If more viscous, D decreases and dm/dt decreases
• villi has a very viscous environment due to what?

  proteoglycans
• how does the thickness of the diffusion layer (h) influence the rate of dissolution?

  • h increases, dm/dt decreases
  • Influenced by the degree of agitation in the GI tract, higher motility may decrease h thus increasing dm/dt.
  • Sparingly soluble (poorly soluble) drugs, h decreases thus dm/dt increases
• what are the drug factors that affect dm/dt?

  • salt of a drug - dissociates more readily
  • however, counter ions of the salt can affect the hydration of the crystal, form and solubility
  • Crystals vs amorphous solids - amorphous solids = more readily dissolved but less stable
• for poorly soluble drugs, what can be used as solubilising agents and wetting agents?

  surfactants
• Measuring the dissolution rate is important in early stages of formulation and for quality control purposes
• In what conditions can the Noyes-Whitney equation be simplified?

  when cs is at least 10x c (so c can be ignored) →  these are called ‘sink’ conditions:

  
• what is the intrinsic dissolution rate?

  is the rate of mass transfer per area of dissolving surface (usually expressed mg/mm^2/s)

  
• what is the aim of dissolution testing?

  to determine the rate at which a substance is released from the dosage form and dissolves in a particular medium
• what are the standard methods for dissolution testing for quality control?

  • Usually done in sink conditions and temperature at 37.5ºC
  • 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 the 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.
• for dissolution testing protocols and conditions vary depending on whether aimed at quality control (QC) or predicted performance in GIT.
• techniques for dissolution testing to predict performance in GIT...

  A) poorly

  B) basket

  C) suspensions

  D) conventional

  
• dissolution and absorption can be controlled by changing parameters such as what?

  pH, surface area, wetting agents, salts etc…
• IDR is used for what?

  used both to predict and ensure the quality of a formulated API