Pharmaceutics

[Anaesthesia 2001(56):p965-979]

Main principles

Main goals:

• To prevent contamination
• To maintain potency
  * By reducing breadown
  * By stablising the product
  * By adjusting pH and tonicity

Solvents

Dielectric constant

• Measure of polarity
• Measurement:
  * A sample is place between two plates attached to a voltage source
  * Capacitance between the two plates is measured and compared to that with vacuum between the two plates
• When dielectric constant
  * >50 = Polar
  * 1 - 20 = No-polar
  * In between = semi-polar
• Dielectric constant:
  * N-methylformamide = 190
  * Water = 78
  * Glycerine = 46
  * Methanol = 33
  * Propylene glycol = 32
  * Castor oil = 4.6
  * Olive oil = 3.1

Aqueous solvents

Water

• Polar solvent
• Dielectric constant = 78

Advantages

• Non-irritant
• Pharmacologically inert

Disadvantages

• Drugs liable to break down by hydrolysis
• Easily contaminated by microorganisms

Non-aqueous solvents

Advantage

• Non-polar or hydrophobic drugs are relatively insoluble in aqueous solvents
• Reduces rate of decomposition by hydrolysis

Glycol

• Glycols (as a class) are dihydric alcohol derived from natural gas
• Miscible with water in all concentrations
• Used in foods and industrial products
  * e.g. antifreeze, brake fluid

Ethylene glycol

• Too toxic for human use
• Metabolised by ethanol dehydrogenase
• End metabolite = oxalic acid (toxic)

Propylene glycol

• Dielectric constant = 32

Used for

• Solubilising agent
• Mild preservative action

Metabolism

Metablised into

• Lactic acid
• Pyruvic acid

Examples

Used in:

• Phenytoin
• Digoxin
• Diazepam (but now reformulated)
• Etomidate

Side effects

• Hypotension
• Arrhythmias
• Thrombophlebitis

Benzyl alcohol

Action

• Low concentration up to 2%
  --> Preservative and antimicrobial action
  * e.g. phenobarbitone, d-tubocurarine
  * e.g. certain formulations of midazolam and diazepam
• High concentration (>5%)
  --> Non-aqueous solvent
• Also some local anaesthetic properties

Metabolism

• Benzyl alcohol is metabolised into benzoic acid
  --> Conjugation with glycine to form hippuric acid

Side effects (dose-dependent)

• Hypotension
  * by peripheral vasodilation and direct myocardial depression
• Contact dermatitis
  * Higher incidence in patients with aspirin allergy

Emulsion

Definition of emulsions

• A two-phase system
• A pair of immiscible liquids, one dispersed as small droplet within the other
• Very high surface area
  --> High interfacial energy system
  --> Unstable thermodynamically (sensitive to storage condition, additives, temperature)
• Can be:
  * Oil-in-water (also known as internal or discontinuous phase)
  * Water-in-oil (also known as external or continuous phase)
• Water is prone to contamination
  --> Needs a water-soluble preservative
• Oil is prone to rancidity
  --> Needs a lipophilic anti-oxidant (e.g. tocopherol)
• Example:
  * Propofol

Emulsifying agents

• Stabilise the system by maintaining droplets in dispersed phase
• Example:
  * Surfactant
  * Hydrocolloid
• Examples of mechanisms:
  * Forming physical or chemical barriers around the droplet
  * Impart electric charges around droplets so they repel each other
  * Reducing interfacial tension between the two phases

Propofol (example)

• Emulsion
• Soya bean oil = oil phase
• Egg lecithin = emulsifying agent
• Pain on injection may be due to lipid solvent causing activation of plasma kallikrein system
  --> Production of bradykinin
  * Evidence conflicting