The preservatives are added in pharmaceutical preparation to prevent contamination, deterioration, and spoilage by bacteria and fungi (Microorganism).
No single preservative exists that satisfies all of these requirements for all formulations. Frequently, a combination of two or more preservatives are needed to achieve the desired antimicrobial effect.
(*as per new Syllabus of D.pharmacy)
Note:
- Single-use formulations/containers-No need to add preservative. (since drug is used immediately so there is not sufficient time for the bacteria to colonize.
- A multi-dose drug product must contain a preservative to prevent bacterial growth (on storage, it is possible for a significant number of bacteria to grow. For this reason, a multi-dose drug product must contain a preservative to prevent bacterial growth)
- p-Hydroxybenzoic acid esters and salts of benzoic acid, are the most widely used for oral preparations. These are adequately soluble in aqueous systems and possess both antifungal and antibacterial properties.
Ideal Properties of Preservatives
1. It should not be irritant.
2. It should not be toxic.
3. It should be physically and chemically stable.
4. Preservative should be compatible with other ingredients used in formulation.
5. It should be act as good antimicrobial agent and should exert wide spectrum of activity.
6. It should act as preservative in small concentration i.e. it must be potent.
7. It should maintain activity throughout product manufacturing, shelf life and usage
Classification of Preservatives
I. On the basis of Mechanism of action
i) Antimicrobial agents
These agents act against microorganisms by affecting the various cellular portions of microbial cell and thereby inhibiting their growth. Cell wall, cytoplasmic membrane and cytoplasm are such portions of microbial cell wall that are mostly targeted by the preservatives.
The antimicrobial agents that have been used as preservatives can be classified into four major groupings: acidic, neutral, mercurial, and quaternary ammonium compounds.
| Type of Antimicrobial agent | Example with Concentration |
|---|---|
| Acidic Mostly used for Oral Preparation | Phenol: 0.2–0.5 Chlorocresol: 0.05–0.1 o-phenyl phenol: 0.005–0.01 Alkyl esters of parahydroxy-benzoic acid: 0.001–0.2 Benzoic acid and its salts: 0.1–0.3 Boric acid and its salts: 0.5–1.0 Sorbic acid and its salts |
| Neutral | Chlorbutanol: 0.5 Benzyl alcohol: 1.0 o-phenylethyl alcohol: 0.2–1.0 |
| Mercurial | Thimerosal 0.001–0.1 Phenylmercuric acetate and nitrate 0.002–0.005 |
| Quaternary ammonium compounds | Benzalkonium chloride 0.004–0.02 Cetylpyridinium chloride 0.01–0.02 |
Note:
Acidic Antimicrobial agent:
- Phenols: little used in oral pharmaceuticals, owing to their characteristic odor and instability when exposed to oxygen.
- p-hydroxybenzoic acid esters and the salts of benzoic and sorbic acid
- have both antifungal and antibacterial properties
- have aqueous solubility
- Mostly used for oral preparation
- A combination of two or more esters of parahydroxybenzoic acid are used to achieve the desired antimicrobial effect. Methyl and propyl parahydroxybenzoic acid are often used together in a ratio of 10 to 1, respectively.
The remaining three classes of preservatives (i.e. neutral, mercurial, and quaternary ammonium compounds) have been widely used in ophthalmic, nasal, and parenteral preparation).
ii) Antioxidant
They are self reducing agents that oxidize themselves and prevent oxidation of the components that are sensitive to oxygen.
There are three main types of antioxidants:
True Antioxidants (water insoluble)
They act by a chain-termination mechanism by reacting with free radicals, e.g. BHA, BHT
Reducing Agents (water soluble)
They have a lower redox potential than the drug and get preferentially oxidized, e.g. ascorbic acid. Thus, they can be consumed during the shelf-life of the product.
Antioxidant Synergists (chelating agents)
These enhance the effect of antioxidants, e.g. EDTA (ethylenediamine tetraacetic acid), tetraacetic acid derivatives and salts, dihydroxyethyl glycine, citric acid, and tartaric acid.
| Antioxidant | Example |
|---|---|
| Antioxidants commonly used for aqueous systems/water soluble | Sodium sulfite Sodium metabisulfite Sodium bisulfite Sodium thiosulfate Sodium formaldehyde sulfoxylate Sulfur dioxide Ascorbic acid Isoascorbic acid Thioglycerol Thioglycolic acid Cysteine hydrochloride Acetylcysteine |
| Antioxidants commonly used for oil systems/Water insoluble | Butylated hydroxy toluene (BHT) Butylated hydroxy anisole (BHA) Ascorbyl palmitate Hydroquinone Propyl gallate α-tocopherol Nordihydroguaiaretic acid Lecithin |
iii) Chelating Agents
The effectiveness of antioxidants can be enhanced through the use of synergists such as chelating agents. Chelating agents tend to form complexes with the trace amounts of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments. Examples of some chelating agents are ethylenediamine tetraacetic acid derivatives and salts, dihydroxyethyl glycine, citric acid, and tartaric acid.
I. On the basis of Mechanism of action
i. Antioxidants
The agent which prevent oxidation of Active pharmaceutical ingredient which undergo degradation due to oxidation as they are sensitive to oxygen.
Example:
- Vitamin E
- Vitamin C
- Butylatedhydroxyanisole ( BHA)
- Butylatedhydroxytoluene (BHT)
ii. Antimicrobial agents
The agent which active against gram positive & gram negative micro-organism which causes degradation of pharmaceutical preparation.
Example:
- •Benzoic acid,
- •Sodium benzoate,
- •Sod. paraben,
- •Ethyl paraben,
- •Propyl paraben, Alcohols,
- •Phenols
iii. Chelating agents
The agents which form the complex with pharmaceutical ingredient and prevent the degradation of pharmaceutical formulation.
Example
- •EDTA,
- •Polyphosphates,
- •Citric acid
II. On the basis on source
i) Natural Preservatives
- These drugs are obtained by natural sources that is plant, mineral sources, animal etc.
- Eg. Neem Oil; Salt (sodium chloride); Lemon; Honey
ii) Artificial Preservatives
- These preservative are man made by chemical synthesis active against by various micro-organisms in small concentration.
- Eg. Benzoates, Sodium benzoate Sorbates, propionets, nitrites
Important point for GPAT, Pharmacist, DI exams
- 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. benzyl alcohol also act as local anesthetic.
- Thiomersal: Used as preservative in some cosmetics, topical pharmaceuticals, and biological drug products, which includes vaccines
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% |
There are three term that are used to describe microbial organisms associated with pharmaceutical and cosmetic products:
- Harmful
- Objectionable
- Opportunistic
Harmful
- The term “harmful” to refer to microbial organisms or their toxins that are responsible for human disease or infection.
- Examples of organisms that must not be present in a product are
- Salmonella species
- Escherichia coli
- P. aeruginosa
- Staphylococcus aureus
Objectionable
- An “objectionable” organism can cause disease, or its presence may interrupt the function of the drug or lead to the deterioration of the product.
- Objectionable organisms should not be present in a pharmaceutical or cosmetic product:
- Example: P. putida, P. multivorans, P.maltophilia, Proteus mirabilis, Serratia marcescens, Klebsiella sp., Acinetobacter anitratus (Bacterium anitratum), and Candida sp.
Opportunistic
Organisms are defined as “opportunistic” pathogens if they produce disease or infection under special environmental situations, as in the newborn or the debilitated person.
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