Drug additives are the various substances added to drugs in preparing suitable formulations for clinical use and/or for modifying the effects of drug administration.
Reasons for use of drug additives
The major reasons for such drug additives are:
- To maintain drug solubility
- To maintain drug stability
- To prevent contamination
- To modify drug pharmacokinetics or pharmacodynamics
Many drugs are prepared in vehicles in which they are soluble. Water is the most commonly used, but non-aqueous vehicles such as propylene glycol and benzyl alcohol are appropriate for some drugs.
For parenterally administered lipophilic drugs it is usually an advantage if the formulation of the drug can render it water-soluble. Some of the strategies to allow this are:
- formulation as an emulsion (eg propofol-soybean oil emulsion)
- control of the pH of the solution to ensure a water-soluble drug form is present (eg thiopentone, midazolam, lignocaine)
- formulation with surfactants (eg Cremophor EL)
- formulation of drug-cyclodextrin complexes
- preparation of a pro-drug with desirable properties (which is bioactivated following injection)
Drug stability is important and some strategies used to assist this are:
- presentation as a powder to be mixed with water just prior to use (eg thiopentone, vecuronium)
- control of environmental conditions of storage (temperature, light exposure)
- control of the properties of the solution (eg pH, osmolality)
- additives which inhibit certain reactions (eg anti-oxidants )
Microbial contamination of the drug can lead to decomposition of the drug, or more seriously to severe infective and septic complications. The group of drug additives known as preservatives are agents added to drug formulations to prevent or at least inhibit the growth of micro-organisms. Commonly used agents in this class are benzalkonium chloride, benzethonium chloride, chlorobutol, the parabens, sodium benzoate and benzoic acid.
Methyl, propyl and butyl parabens prevent the growth of fungi and yeasts rather then bacteria.
Most preservatives are weak acids with pKa's of 4 to 5, so they are more effective in an acidic environment where larger amounts of the un-ionised form is present, as this is the form that penetrates bacteria cell membrane more easily. Acidifying agents may be added to achieve an optimum pH for anti-microbial activity.
Agents to modify drug pharmacology
Some additives are present for their effect are the drug is administered. For example addition of vasoconstrictor agents such as adrenaline to local anaesthetic solutions. Some drugs given by subcutaneous or intramuscular injections have binding agents which slow the absorption of the drug from the site of injection (eg protamine-zinc-insulin).
Another example is the sublingual preparation (Suboxone) which contains a mixture of buprenorphine and naloxone in a ratio of 4:1. The inclusion of the naloxone is very effective at preventing intravenous misuse of the dose.
Particular drug additives
- Propylene glycol
- Cremophor EL
- Benzalkonium chloride
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- MacPherson. Pharmaceutics for the Anaesthetist Anaesthesia 2001(October) 965 (Access via the ANZCA Library page as password required)
Abstract: Pharmaceutics is that branch of science concerned with the manufacture and formulation of pharmaceutical products, and is a subject almost exclusively in the domain of pharmacists and those concerned with pharmaceutical manufacture. However, there are some aspects of pharmaceutics that are of particular importance to the anaesthetist, such as the pharmacology of the various preservatives, antimicrobials and other additives found in anaesthetic products, and an understanding of basic processes such as emulsification and lyophylisation. This review aims to survey those areas.
- Walsh R. Drug Preservatives and Solvents. In: Prys-Roberts C, Hug CC, eds. Pharmacokinetics of Anaesthesia. London: Blackwell Scientific, 1984: 321–45.
- This is the only other major anaesthetic-related resource in this area.