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Different Preservatives And Concentration Dosage For Pharmaceutical Liquid Preparation

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As companies move to clearer labelling, LFA is observing less and less use of chemicals in its customers’ products. Nevertheless when wet granulation is employed, for example, it is sometimes impossible not to have to include a preservative in the product formulation.

In the pharmaceutical industry, many of the ingredients used in formulations have the ability to promote microbial growth. Such formulations are therefore susceptible to unwanted contamination. To prevent this from occurring, antimicrobial agents or preservatives need to be added to the formulation. In concept such preservatives protect the product against microbial proliferation but should not compromise product performance. In practice, this means that any preservative or antimicrobial agent must:

  • exert a wide spectrum of antimicrobial activity against all possible micro-organisms at low inclusion levels
  • maintain activity throughout product manufacture, shelf life and usage
  • be non-toxic and compatible with other constituents of the preparation
  • not compromise the quality or performance of product, pack or delivery system.
  • not adversely affect patient safety or tolerance of the product.

Criteria for choosing antimicrobial preservatives include:

  • Preservative dose
  • Effects on the active ingredient
  • Antimicrobial functionality

The evaluation of preservatives has traditionally involved time-consuming tests –pharmacopoeial antimicrobial effectiveness tests (AET) or preservative efficacy tests (PET). Such tests involve challenging a product with a defined number of colony forming units (cfu) of a variety of test microorganisms (bacteria, yeasts and fungi), enumeration at time zero and then monitoring the kill / survival rate at defined time intervals up to 28-days. Test organisms that are recommended by all of the pharmacopoeias include,

  • Gram positive coccus, Staphylococcus aureus.
  • Gram negative rod, Pseudomonas aeruginosa.
  • Fungi / mould, Aspergillus niger.
  • Yeast, Candida albicans.

In addition, USP and Ph. Eur. recommend the use of E. coli. The list may be supplemented by additional organisms that may be associated with a particular process, facility or material, e.g. Burkholderia cepaceia an opportunistic pathogen often isolated in manufacturing environments, Bacillis subtilis a spore-forming bacteria, etc. Tests typically require satisfactory reduction of colony forming units (CFUs) for each challenge organism with no subsequent increase from the initial count after 14- and 28-days.

The acceptance tests form part of the preservative optimization. They need to be performed at the end of the product shelf-life to confirm adequate preservation over the total duration of the products’s use. Some regulatory authorities also require confirmation that the product is adequately preserved during its in-use period, when it is being routinely opened, dispensed and closed, and the potential for microbial contamination is at its highest.

High sensitive analytical techniques are being investigated as possible replacements for the cumbersome and time-consuming pharmacopoeial tests. These include methods such as ATP bioluminescence, electrical impedance spectroscopy, spectro-fluorimetry and chemiluminescence. Such approaches offer the potential for automation of testing and high throughput screening of formulations during development.

Common microbial preservatives:

  • Phenol and Benzyl alcohol – effective for peptide and protein products
  • Phenoxyethanol – vaccine preservation

A combination of propylparaben and methylparaben or benzyl alcohol is usually present in small volume parenteral formulations. It is required especially for multi-dose or semi-solid parenteral formulations.

For a preservative to be effective, it must decrease the percentage of the microbes and prevent any re-growth and these effects must be both microbiostatic and microbiocidal in nature. A microbicidal agent kills microorganisms such as bacteria, while a microbiostatic agent only prohibits the growth of such microorganisms. In the presence of microbiostatics, the microorganisms eventually die due to lack of reproduction. Microbicidals are irreversible and lethal, while microbiostatics are reversible.

Synergizing of Preservatives

Some preservatives are ineffective with some microbe strains and should be combined with others to be effective. Benzalkonium chloride is an example of a preservative that is ineffective against some strains of Pseudomonas aeruginosa. This particular bacterium is commonly spread in hospitals and other health care facilities, making it a nosocomial pathogen. It is also becoming increasingly resistant to treatment with antibiotics, as of 2015. Pseudomonas aeruginosa is a frequent culprit in causing infections of the lungs, bones and joints, skin, blood and urinary tract. It is particularly dangerous in people with compromised immune systems. Two antipseudomonal drug combination therapy (eg, a beta-lactam antibiotic with an aminoglycoside) is usually recommended for the initial empiric treatment of a pseudomonal infection, especially for patients with neutropenia, bacteremia, sepsis, severe upper respiratory infections (URIs), or abscess formation. Antibiotics when combined, however, with benzyl alcohol, EDTA, and 2-phenylethanol can help enhance anti-pseudomas activity. Synergy is also observed when organo mercurial, cetrimide, chlorhexidine and 3-cresol are combined.

Preservative concentrations recommended for parental preparation

Sr. No. Name Recommended Concentration
1. Benzyl Alcohol 0.5 to 10%
2. Benzalkonium Chloride 0.01%
3. Butyl Paraben 0.015%
4. Chlorobutanol 0.25 to 0.5%
5. Meta Cresol 01 to 0.25%
6. Chlorocresol 0.1 to 0.18%
7. Methyl Paraben 0.01 to 0.5%
8. Phenyl Ethyl Alcohol 0.25 to 0.002%
9. Propyl Paraben 0.005 to 0.002%
10. Phenol 0.065 to 0.02%

Preservative Concentration for Liquid Oral Preparation

Sr. No. Name Recommended Concentration
1. Benzonic Acid 0.1 to 0.2%
2. Sorbic Acid 0.1 to 0.2%
3. Methyl Paraben 0.25%
4. Propyl Paraben 0.5 to 0.25%
5. Sodium Benzonate 0.1 to 0.2%
6. Bronidol 0.001 to 0.05%
7. Propylene Glycol 0.25%

If you would like any more information on this topic we are happy to try and help. While this topic is not a specialised area for us we do have a basic understanding and are more than happy to try and point you in the right direction for further assistance. At LFA we pride ourselves on helping our customers set up and run effectively their production facilities for a wide range of products. We have worked with clients in the food, pharmaceutical, nutraceutical, holistic, chemical and industrial sectors to produce a wide range of tablets using our tablet presses. If you need any help getting set up please do get in contact and we will be happy to help.

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