Pharmaceutical products are defined as any substance or mixture of substances for human use for the diagnosis, treatment, or prevention of a disease, abnormal physical statements, or altering or modifying any organic function. When these pharmaceutical products deteriorate due to contaminant microbes, is known as microbial spoilage. Hence, products are required to be preserved to minimize or inhibit spoilage during storage and multi-dose applications to the risk of microbial contamination. Prescription drugs are the main pharmaceutical industry products like flumadine, acyclovir, and amantadine (essential medicines) whereas biological products are composed of different types of products such as vaccines, antibodies, blood, therapeutic proteins, tissues, etc. Some medical devices like needles, syringes, hand gloves, and some OTC drugs like aspirin, and paracetamol are also considered as pharmaceutical products. These products are contaminated by the use of various microorganisms such as E. coli, Clostridium botulinum, Clostridium perfingens, Pseudomonas aeruginosa, Salmonella cavaban, etc. Antimicrobial preservatives are considered exceptions to such categorization, being added to help improve antimicrobial stability and hence required for antimicrobial activity. Therefore, preservatives play a vital role in the storage of pharmaceutical products using antimicrobial agents. Some ideal characteristics of preservatives are:
• They should be free from toxic or irritant effects at the
specified concentration.
• They should be effective in preventing the growth of
microorganisms.
• They should be soluble in water so that they should
achieve the required concentration for the activity.
• They should be heat stable and prolong storage capability.
• They should be chemically compatible with all other
formulations.
• They should be not adversely affected by the container or
closure of the products.
• They should be cheap.
There are various types of preservatives used in the
preservation of pharmaceutical products that are listed in the Flowchart.
Flowchart: Types of preservatives
1. Cationic detergents: Examples: Benzalkolium chloride,
alkyl trimethyl ammonium chloride.
2. Alcohols: Examples: Chlorbutanol, bronopol, phenyl, and
phenoxy ethanol.
3. Phenolic compounds: Examples: chlorinated and isopropyl
derivatives of meta cresol.
4. Organic acids: Examples: Salicylic acid, benzoic acid,
acetic acid, lactic acid, hydroxyl benzoic acid.
Factor affecting the efficacy and availability of
preservatives:
• Temperature.
• Chemical structure of preservatives.
• Capacity of preservatives.
• Inoculum size.
• Effect of pH.
• Effect of containers and packaging.
• Changes of concentration.
Methods of Preservation:
1. Physical protection: It is used for proper
packaging of pharmaceutical products under aseptic conditions or else there is
a chance for microbial growth. Operating persons are also an important factor in
the proper processing of the products under an aseptic environment.
2. Preservative coating: Aqueous raw materials used
in the formulation of paints and coatings create the perfect environment for
the growth of bacteria, fungi, and yeast. They can destroy valuable
pharmaceutical formulations. Controlling these microorganisms helps increase
efficiency, helps deliver a better end-use product, and helps employees and
consumers avoid contact with spoilage microorganisms. Biocides are necessary
for protecting the integrity and functionality of water-based paints and
coatings from destruction by microbial contamination as a result lengthening of
product’s shelf life and protecting dry film from algae, mold, and mildew.
3. Water proof protection: Packaging of pharmaceutical
products should be under waterproof protection because water favors the growth
of microorganisms.
4. Water vapor-proof protection: This method is
applicable for certain pharmaceutical products when they are packed under
proper care to minimize microbial activity. For ‘dry’ dosage forms with very
low water activity (Aw) provides protection against microbial attack. The
moisture vapor properties of packaging materials require careful examination.
5. Water vapour-proof protection with desiccant: This
method is also used for dry products that absorb moisture from the environment
and are spoiled due to growth of microorganisms. Packing should be proper with
this method to minimize the microbial growth and spoilage of the products.
Classification of Preservatives based on Mechanism of
Action:
1. Antioxidants: The agents that prevent oxidation of
active pharmaceutical ingredients which otherwise undergo degradation due to
oxidation as they are sensitive to oxygen. For example: Vitamin E, Vitamin C,
Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT).
2. Antimicrobial agents: They are the agents that are
active against gram-positive and gram-negative microorganisms which cause
degradation of pharmaceutical preparation, active at a small inclusion level.
For example: Benzoates, Sodium benzoate, and Sorbates.
3. Chelating agents: They are the agents that form
the complex with pharmaceutical ingredients and prevent the degradation of
pharmaceutical formulation. For example: Disodium ethylenediaminetetraacetic
acid (EDTA), Polyphosphates, and Citric acid.
Modes of Action of Preservatives:
Preservatives provide limited protection against viral
contamination. Bactericides and fungicides may evince their effects on a
variety of microbial cellular targets, for example; the cell wall, the
cytoplasmic membrane, or the cytoplasm. It is sometimes difficult to assign a
precise target for a specific class of preservative; the target does change
with preservative concentration. Hence, they should have:
• A wide spectrum of antimicrobial activity at low inclusion
levels.
• Maintain activity throughout product manufacture, shelf
life, and usage.
• No compromise on the quality or performance of the product,
pack, or delivery system.
• Adverse influence on patient safety or tolerance of the
product.
With these concepts, the preservative system protects the
product against microbial proliferation.
Mode of action of antimicrobial agents as preservative:
Antimicrobial agents act by cell wall inhibition, protein
synthesis inhibition, DNA and RNA synthesis inhibition. For example: Benzoates,
Sodium benzoate, Sorbates, Propionates, Nitrites.
Emulsions contain water which will support microbial growth.
Microbes produce an unpleasant odor, color changes, and gases and may affect
the emulsifying agents. Other ingredients of emulsions support the growth
medium for microbes. Examples: Arachis oil supports Aspergillus species and
liquid paraffin supports Penicillium species.
Antimicrobial preservatives are added to non-sterile dosage
forms to protect from microbiological growth or from microorganisms that are
introduced inadvertently during or subsequent to the manufacturing process. In
the case of sterile articles packed in multiple-dose containers, antimicrobial
preservatives are added to inhibit the growth of microorganisms that may be
introduced from repeatedly withdrawing individual doses. Examples of
antimicrobial preservatives include alcohol, formaldehyde, and iodine.
An antimicrobial ‘preservative’ is included in a formulation
to minimize the risk of spoilage and to kill low levels of contaminants
introduced during storage or repeated use of a multidose container. The strong
antimicrobial agents are often non-selective in action but interact
significantly with formulation ingredients as well as with patients and
microorganisms.