Drug preservation

Under drug conservation is understood in the pharmaceutical industry to protect a drug from microbial spoilage. Contamination with microorganisms can lead to the appearance of mold , fermentation and the formation of odors. Microorganisms are also a direct source of infection and can endanger humans through toxic metabolic products. Contamination with microorganisms can arise during the manufacture, storage and use of pharmaceuticals, whereby the main sources of contamination are people, the environment, work equipment , active ingredients and pharmaceutical excipients and the primary packaging . Some pharmaceuticals therefore need preservation if they have favorable living conditions for microorganisms in order to maintain their perfect microbiological condition over their entire shelf life up to the expiry date . This particularly applies to systems containing water, such as emulsions , juices, creams and suspensions . However, preservation must not replace compliance with good pharmaceutical manufacturing practice . Regardless of this, preservation can be important for the shelf life after opening, since germs can easily be introduced into a drug by opening a drug package and removing the drug .

Medicines for use on the eye and for parenteral administration are made sterile by means of sterilization processes or aseptic production, and are made durable by subsequent sterile sealing; chemical preservation of the drugs is then usually not necessary, provided they are used up during use. When packing in containers for multiple dispensing, however, preservation is mandatory by most pharmacopoeias .

Check for adequate preservation (preservative exposure test)

In order to ensure the effectiveness of the preservation of a drug, pharmacopoeias prescribe a “test for sufficient preservation” (preservative exposure test). It is checked whether the selected preservative concentration is suitable for suppressing microbial contamination such as that caused by the possible multiplication of microorganisms during storage or by the introduction of germs during use. The effectiveness of the preservation must be guaranteed over the entire shelf life (i.e. up to the expiry date ) of a medicinal product.

To carry out the test, the corresponding medicinal preparation, usually in its normal storage container, is mixed with the type and quantity of test germs prescribed and stored at 20 to 25 ° C under protection from light. The germ counts are determined at fixed time intervals for up to 28 days . Graded according to the type of application of the drug ( parenteral and ophthalmological , topical , perorally ), different strict assessment criteria apply in order to judge the current preservative concentration as sufficient based on the extent of the reduction in the number of bacteria.

Classification of preservatives

The number of substances used to preserve pharmaceuticals is manageable. Due to their chemical structure, they can be divided into the following categories:

• Phenol and its derivatives
  • Example: cresol , parabens ( methyl 4-hydroxybenzoate etc.), chlorocresol
  • Belong to the oldest antimicrobial substances used.
  • Its action is due to its general cytotoxic effect.
• Aliphatic and aromatic alcohols
  • Example: ethanol , propylene glycol , chlorobutanol , benzyl alcohol
  • Their effect is also due to the general toxicity .
  • Ethanol and propylene glycol have a preservative effect from a concentration of around 20%.
• Organic mercury compounds
  • Example: thimerosal
  • Effective from a concentration of 0.001 to 0.002%.
• Quaternary ammonium compounds
  • Example: benzalkonium chloride , cetylpyridinium chloride
  • Are cation-active surfactants .
  • Work by depositing themselves in plasma membranes due to their surface activity and changing their permeability to a toxic extent.
• Carboxylic acids
  • Example: sorbic acid , benzoic acid
  • Effect is due in particular to their intervention in the primary metabolic processes .
  • The advantage is the lack of smell and taste.
• Others
  • Chlorhexidine

Overview

Antimicrobial	Concentration [%]	optimal ph range	Effectiveness against
			gram positive bacteria	gram negative bacteria	Yeasts	Mushrooms
phenol	0.3	2–4– (8)	well effective	well effective	weakly effective	weakly effective
Cresol	0.3	2–4– (8)	well effective	well effective	well effective	well effective
p -Chlor- m -cresol	0.2	2–4– (8)	well effective	well effective	well effective	well effective
Phenylethyl alcohol	1	2–4– (7)	well effective	well effective	weakly effective	weakly effective
Chlorobutanol	0.5	2-4	well effective	well effective	weakly effective	weakly effective
Benzyl alcohol	1	2–4– (7)	well effective	weakly effective	weakly effective	weakly effective
PHB methyl ester	0.18	2–4– (9)	well effective	well effective	ineffective	ineffective
PHB propyl ester	0.02	2–4– (9)	well effective	well effective	weakly effective	ineffective
Sorbic acid	0.2	2–3– (5)	well effective	well effective	well effective	well effective
Benzoic acid	0.1	2–3– (5)	well effective	well effective	well effective	well effective
Phenyl mercury nitrate	0.001	7-10	well effective	well effective	well effective	well effective
Thimerosal	0.002	2–7– (9)	well effective	well effective	well effective	well effective
Benzalkonium chloride	0.01	(3) -5-8- (10)	well effective	well effective	well effective	well effective

according to Wallhäusser , Pharm. Ind. 36 , 716 (1974).

swell

• Rudolf Voigt and Alfred Fahr - Pharmaceutical Technology
• Kurt H. Bauer, Karl-Heinz Frömming, Claus Führer, Bernhardt C. Lippold - Textbook of pharmaceutical technology

Individual evidence

1. ↑ European Pharmacopoeia in the currently valid version, Section 5.1.3.
2. ↑ US Pharmacopeia. General Chapters. <51> Antimicrobial Effectiveness Testing.
3. ↑ Hans Mollet, Arnold Grubenmann: Formulation technology emulsions, suspensions, solid forms . Wiley-VCH, Weinheim 1999, ISBN 978-3-527-62571-0 , p. 380.

literature

• Dietlinde Goltz: The preservation of drugs and dosage forms from a historical perspective. In: Pharmaceutische Zeitschrift 117, 1972, pp. 428-435.