Preservation of Pharmaceutical Products Using Antimicrobial Agents

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.


Types of preservatives

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.

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