Preservation of Pharmaceutical Products Using Antimicrobial Agents: Pharmaceutical products are defined as any substance or mixture of substances for use in humans for the diagnosis, treatment, or prevention of a disease, or 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 preserve to minimize or inhibit spoilage during the storage and multi-dose applications by the risk of microbial contamination. Prescription drugs are the main pharmaceutical industry products like flumadine, acyclovir, 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 are like a needle, syringe, hand gloves, some OTC drugs like aspirin, paracetamol is also considered as pharmaceutical products. These products are contaminated by the use of various microorganisms such as E. coli, Clostridium botulinum, Clostridium perfringens, Pseudomonas aeruginosa, Salmonella caveman, etc. Antimicrobial preservatives are considered exceptions to such categorization, being added to help to 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 characters 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 Flowchart 1.
- Cationic detergents: Examples: Benzalkonium chloride, alkyl trimethyl ammonium chloride.
- Alcohols: Examples: Chlorbutanol, bronopol, phenyl, and phenoxyethanol.
- Phenolic compounds: Examples: chlorinated and isopropyl derivatives of meta cresol.
- Organic acids: Examples: Salicylic acid, benzoic acid, acetic acid, lactic acid, hydroxyl benzoic acid.
Factor affecting the efficacy and availability of preservatives:
- Chemical structure of preservatives.
- The 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 the pharmaceutical products under aseptic conditions or else there is a chance for microbial growth. Operating persons are also an important factor for 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-user 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 of lengthening of product’s shelf life and protecting the dry film from algae, mold, and mildew.
3. Waterproof protection: The 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 packing under proper care for minimizing microbial activity. For ‘dry’ dosage forms with a very low water activity (Aw) protect against microbial attack. The moisture vapor properties of packaging materials require careful examination.
5. Water vapor proof protection with desiccant: This method is also used for dry products that absorbed moisture from the environment and are spoiled due to the 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 which 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 micro-organisms which causes degradation of pharmaceutical preparation, active in small inclusion level. For example Benzoates, Sodium benzoate, Sorbates.
3. Chelating agents: They are the agents which form the complex with pharmaceutical ingredient and prevent the degradation of pharmaceutical formulation. For example Disodium ethylenediaminetetraacetic acid (EDTA), Polyphosphates, 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 preservatives; 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 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 preservatives:
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 after 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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