Drug Solubilisation

Question 1

What is meant by high solubility?

Answer 1

Compound must be able to dissolve in 250ml water or less.

Question 2

Why is solubilisation of drugs in aqueous formulation necessary?

Answer 2

• 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

Question 3

Describe the process of solubilisation step by step.

Answer 3

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

Question 4

What are the 3 factors affecting aqueous stability of a solid drug?

Answer 4

1. drug-solvent interaction
2. weak electrolytes
3. solubility and dissolution rate

Question 5

How can the solubilisation of a solid drug in aqueous environment be improved?

Answer 5

1. Reduce the intermolecular forces in solid state - lower the crystalline lattice energy.
2. Increase the strength of the drug-solvent interaction - if drug more easily interacting with solvent, delta G=0.
3. Increase the surface area of the drug to allow dissolution.

Question 6

List the 9 strategies used to improve drug solubilisation.

Answer 6

1. optimisation of the crystal form
2. buffer and salt formation
3. co-solvents
4. surfactants
5. molecular complexation
6. particle size reduction
7. solid dispersion
8. lipid-based formulation
9. nanoparticle drug delivery

Question 7

Name the different polymorphic forms of the crystal lattice of solid.

Answer 7

Amorphous
Polymorph
Hydrate/solvate - contains wanter/solvent
Co-crystal - contains a neutral coformer
Salt - contains counterion

Question 8

What is a co-crystal?

Answer 8

Consists of two or more molecular species held together by noncovalent bond and non-ionic forces.
- add a coformer.

Question 9

Name a few coformers (bind to crystals to form a co-crystal).
- coformers enhance the dissolution rate.

Answer 9

Maleic acid
Succinic acid
Saccharin
4-aminobenzoic acid

Question 10

What is a salt in terms of polymorphic forms of crystal lattices?

Answer 10

Salt = crystals bound with counterions with ionic bonding involved.

Question 11

List 6 counterions used to form a salt.

Answer 11

Amino-methyl-propanediol
Ammonium
Tromethamine
Amino-propanediol
Tert-butylamine
Adamantanamine

Question 12

Why is buffer/salt form in oral formulation for solubilisation useful?

Answer 12

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.

Question 13

What are co-solvents/

Answer 13

Co-solvents are substances added to a primary solvent (water) to increase the solubility of a poorly-water soluble drug.

Question 14

Give 3 examples of co-solvents?

Answer 14

Ethanol
Glycerol
Propylene glycol

Question 15

What are the two roles of surfactants?

Answer 15

• reduce the interfacial tension

- increase drug solubilisation in water

Question 16

What is CMC?

Answer 16

Critical Micelle Concentration.
- the concentration of surfactants above which, micelles form and all additional surfactants added to the system will form micelles.

Question 17

Describe the toxicity of surfactants.

Answer 17

Surfactants are generally toxic.

Ionic surfactants are more toxic than non-ionic.

Question 18

Name three surfactants.

Answer 18

Poloxamer
Tween
Labrasol

Question 19

What is molecular complexation?

Answer 19

Key way in enhance water solubility of fat-soluble drugs by adding cyclodextrin.

Question 20

Why is cyclodextrin not accepted in oral or parenteral fomulations?

Answer 20

High amounts can cause diarrhoea.

Question 21

How does larger surface area affect drug solubilisation?

Answer 21

Allows for a faster dissolution rate

Higher concentration at the point of absorption

Question 22

What is the preparation method for particle size reduction?

Nanoisation and micronisation

Answer 22

Method involves changing the surface area of the particles of the drug.
Top-down approach via nano-milling (cheap), stabilised with anti-crystallisation excipients.

Question 23

Why might nanoisation/micronisation be considered?

Answer 23

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.

Question 24

What is solid dispersion?

Answer 24

Drug molecule dispersed within a solid matrix, either small molecule or polymer.

Question 25

What are the benefits of solid dispersion?

Answer 25

Drug lattice energy = 0.
Dilution effect.
Enhanced surface area – nanosized drug particles.
Enhanced hygroscopicity – by other matrix, sugar, sugar alcohol, amino acids, hydrophilic polymer.

Question 26

What are the advantages of using lipid-based formulations?

Answer 26

• Lipids in food can enhance the absorption of poorly water soluble drugs
• Protection of drug from degradations (acid/ bacteria)
• Bile salts/phospholipids secretions in GI act as surfactants
• Natural absorption site - small/large intestine
• Recycling of lipids in lymphatic system improve the absorption of drugs
• Bypass first pass metabolism