Preformulation - Injectable and Oral Liquid Products

Question 1

PROPERTIES OF SOLUTIONS and SOLIDS

Answer 1

Solutions

1. Acid-base Equilibria
2. Solubility
3. Partitioning
4. Chromatography
5. Chemical stability and Degradation
6. Spectroscopic and other molecular properties
7. Permeability

Solids

1. Crystal Structure and bulk energetics
2. Surface energetics and Surface area
3. Spectroscopic properties
4. Micromeritics - solid powder properties

Question 2

Solution properties - Acid-base Equilibria

Answer 2

Acid base reactions control solution by changing the polarity of the drug in solution
- Ionised form increase polarity
- Unionised form decrease polarity
Properties affected on ionisation:
- solubility in water
- dissolution rate
- partitioning (prefer aq phase when ionised)
- chemical degradation
- permeability across biomembrane

Question 3

Solution properties - Polarity as a function of pH

Answer 3

• function of state of ionisation
  Speciation Curve:
• describes variation in protonation-deprotonation as a function of pH
• plot intersects at 50:50 proton/deprotonation (pH=pka)
• gradual change 98% over 4pH units
• 80% over 2 pH units
  %Deprotonation= 100/ (1+10^pka-pH)

Question 4

Solubility as a function of pH

Answer 4

Total solubility depends on intrinsic solubility and solubility increase related to extent of polarity change from ionisation
Solubility-pH profile uses:
S=So(1+Ka/(H30+))
Drug solubility complicated by nature of solid state
- low internal energy low solubility
- high melting point low solubility
- polarity is not the main determinant
- solubility increases with lower melting point due to less intermolecular interactions in the solid state

Question 5

Causes of low aq solubility

Answer 5

Solid:
- low crystal lattice energy i.e. high m.p. therefore harder to disrupt solid state to form a solution
Solution:
- High crystal lattice energy
- Low m.p
- Low polarity therefore increased hydrophobicity can give low aq solubility

Question 6

Methods to increase solubility for formulations

For Solution

Answer 6

END RESULT: AQUEOUS LIKE OR AQUEOUS-MISCIBLE VEHICLE
Modify hydrophobicity
1. Make drug more polar
2. Make solvent less polar
3. Use complexing agents
4. Use amphiphiles (micelles) to form sub-micron dispersions
5. Use dispersed water-immiscible organics in the aqueous vehicle with amphiphiles (SEDDS)

Question 7

Methods to increase solubility for formulations

For Solid

Answer 7

INCREASE SOLID STATE ENERGY
1. Change salt form
2. Use complexing agent
3. Change polymorphic form
4. Change hydrate form
5. Use amorphous form alone
6. Use amorphous form with stabilisers
All disrupt highly stable solid state

Question 8

Lower free energy of drug in solution to improve solubility

Answer 8

1. ionisation reactions to increase polarity and drug-water interactions
2. Co-solvents can closely match the polarity of the vehicle to the polarity of drug
3. Micellar, liposomal or emulsion systems to increase interaction with low polarity molecule by presenting to a lower polarity environment which internalises the drug so that the exterior (high polarity) can interact with aqueous continuous phase
4. Use complexing agents to increase interactions of drug and solvent by acting as a ‘bridge’

Question 9

Classification of solubilising vehicles

Answer 9

Phospholipids should be class 2 amphiphiles except lysophopholipids which should be surfactants
Monoglycerides are not water insoluble, should be surfactants

Question 10

a-cyclodextrin

Answer 10

good for hydrocarbon side chains