Drug Solubilisation Flashcards
What is meant by high solubility?
Compound must be able to dissolve in 250ml water or less.
Why is solubilisation of drugs in aqueous formulation necessary?
- improves efficacy
- improves bioavailability
- improves processability e.g. allows for a flexible dose
- reduces side effects e.g. less toxicity, less pain at site of injection
Describe the process of solubilisation step by step.
Overcome the lattice energy of crystalline solid, one molecule is removed from the lattice (high energy)
A cavity is created in solvent (low energy)
Insertion of solute molecule into solvent, form solute-solvent interaction
What are the 3 factors affecting aqueous stability of a solid drug?
- drug-solvent interaction
- weak electrolytes
- solubility and dissolution rate
How can the solubilisation of a solid drug in aqueous environment be improved?
- Reduce the intermolecular forces in solid state - lower the crystalline lattice energy.
- Increase the strength of the drug-solvent interaction - if drug more easily interacting with solvent, delta G=0.
- Increase the surface area of the drug to allow dissolution.
List the 9 strategies used to improve drug solubilisation.
- optimisation of the crystal form
- buffer and salt formation
- co-solvents
- surfactants
- molecular complexation
- particle size reduction
- solid dispersion
- lipid-based formulation
- nanoparticle drug delivery
Name the different polymorphic forms of the crystal lattice of solid.
Amorphous
Polymorph
Hydrate/solvate - contains wanter/solvent
Co-crystal - contains a neutral coformer
Salt - contains counterion
What is a co-crystal?
Consists of two or more molecular species held together by noncovalent bond and non-ionic forces.
- add a coformer.
Name a few coformers (bind to crystals to form a co-crystal).
- coformers enhance the dissolution rate.
Maleic acid
Succinic acid
Saccharin
4-aminobenzoic acid
What is a salt in terms of polymorphic forms of crystal lattices?
Salt = crystals bound with counterions with ionic bonding involved.
List 6 counterions used to form a salt.
Amino-methyl-propanediol Ammonium Tromethamine Amino-propanediol Tert-butylamine Adamantanamine
Why is buffer/salt form in oral formulation for solubilisation useful?
Suitable for GI conditions.
Greater solubility in comparison to free acid or base form.
Increase ionization to increase dissolution rate and solubility.
Increase Cs for passive diffusion.
What are co-solvents/
Co-solvents are substances added to a primary solvent (water) to increase the solubility of a poorly-water soluble drug.
Give 3 examples of co-solvents?
Ethanol
Glycerol
Propylene glycol
What are the two roles of surfactants?
- reduce the interfacial tension
- increase drug solubilisation in water
What is CMC?
Critical Micelle Concentration.
- the concentration of surfactants above which, micelles form and all additional surfactants added to the system will form micelles.
Describe the toxicity of surfactants.
Surfactants are generally toxic.
Ionic surfactants are more toxic than non-ionic.
Name three surfactants.
Poloxamer
Tween
Labrasol
What is molecular complexation?
Key way in enhance water solubility of fat-soluble drugs by adding cyclodextrin.
Why is cyclodextrin not accepted in oral or parenteral fomulations?
High amounts can cause diarrhoea.
How does larger surface area affect drug solubilisation?
Allows for a faster dissolution rate
Higher concentration at the point of absorption
What is the preparation method for particle size reduction?
Nanoisation and micronisation
Method involves changing the surface area of the particles of the drug.
Top-down approach via nano-milling (cheap), stabilised with anti-crystallisation excipients.
Why might nanoisation/micronisation be considered?
Towards patients’ needs:
Long acting, 30-90 days per single injection
Less disruption on daily life
Better patient’s compliance
Subcutaneous and intramuscular
Enhanced dissolution rate at point of delivery
Sink condition due to rapid body fluid replacement
HIV, AIDS, Cancer, Parasitic, etc.
What is solid dispersion?
Drug molecule dispersed within a solid matrix, either small molecule or polymer.
