A REVIEW ON: PRESERVATIVES USED IN PHARMACEUTICALS AND IMPACTS ON HEALTH

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ABOUT AUTHORS
Sabir M. Shaikh*1, Rajendra C. Doijad1, Amol S. Shete1, Poournima S. Sankpal2
1 Department of Pharmaceutics, Shree Santkrupa College of Pharmacy, Ghogaon, Karad, Maharashtra, India.
2 Department of Pharmaceutical chemistry, Shree Santkrupa College of Pharmacy, Ghogaon, Karad, Maharashtra, India.
*sabirmshaikh17@gmail.com

ABSTRACT
For several decades pharmacist have been aware of the need to protect their products against microbial contamination but it is only during the last one or perhaps two decades the serious thought of has been applied to the science of preservation. Preservatives are commonly used as additives in pharmaceutical products, food and cosmetics. Some of the liquid preparation are susceptible to microbial contamination because of the nature of ingredients present in it. Such preparation are protected by preservatives which avoids degradation and alteration of the product.A preservative is a natural or synthetic chemical added to various products which helps to prevent microbial decomposition. Present article deals with the study of ideal properties, classification, mechanism of action, Pharmaceutical applications and its impact on health of various preservatives used in pharmaceuticals.

REFERENCE ID: PHARMATUTOR-ART-2410

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 4, Issue 5

Received On: 08/12/2015; Accepted On: 04/01/2016; Published On: 01/05/2016

How to cite this article: Shaikh SM, Doijad RC, Shete AS, Sankpal PS; A Review on: Preservatives used in Pharmaceuticals and impacts on Health; PharmaTutor; 2016; 4(5); 25-34

INTRODUCTION
A preservative is a natural or synthetic chemical that is added to products such as foods, pharmaceuticals, paints, biological samples, wood, etc. to prevent decomposition by microbial growth or by undesirable chemical changes. Preservatives are substances that are commonly added to various foods and pharmaceutical products in order to prolong their shelf life. The addition of preservatives to such products, especially to those that have higher water content, is essential for avoiding alteration and degradation by microorganisms during storage. Preservatives are put in foods to inhibit growth of bacteria, yeasts, or molds that can cause disease. Chemical preservation cannot totally keep products from spoiling, but they slow the spoiling process caused by microorganisms. Frozen and canned foods often do not contain any preservatives. Processed Foods are foods that are put through a process to kill harmful bacteria that may form in the food. These processes are supposed to be helpful to the products, but they can also add harmful substances.

When a natural food is processed it may be crushed, heated and have chemicals added to it that may kill all the nutritional value of the food. Then often additives are added to the product to put back some vitamins and nutrients that were lost when the food product was processed. Preservative are added to keep foods fresh and to keep them from spoiling.[1] The first preservatives to be used were vinegar, salt and sugar. Now many of the preservatives are man-made chemicals.Many of the synthetic food and cosmetic additives are considered to be safe, but some of them were found to be carcinogenic and toxic and it is better to limit their use. In general all synthetic chemical additives and preservatives may be avoided, as many of them have not been properly tested. It happens fairly often that a synthetic chemical additive that has been judged to be safe and has been used for year is later found to be toxic and in some cases causes children and adult to die.

All of the chemical food coloring can be potentially harmful, so it is better to avoid all food coloring made from synthetic chemicals. It is important to understand that the efficacy of antimicrobial preservatives relies, by definition, on their ability to kill live cells; in other words, their toxicity is an unavoidable component of their reason of being. A number of natural extracts, plants and essential oils contain substances that have the power to effectively kill bacteria, yeast and fungi; however, in many cases these substances are or can be toxic for humans, too. A typical example is citrus or grapefruit seed extracts: although these have natural antimicrobial properties, some of their constituents are thought to be responsible for life-threatening hormonal imbalances. Also, citrus seed extracts are not approved for cosmetic use in Europe and in Japan, and are therefore not an option in those countries. In the last few months, a new type of natural preservative has appeared on the market. Similar in look, feel and scent to an essential oil blend, and made by combining active fractions of essential oils, this new preservative system seems to have the potential to address the needs of those skin care manufacturers who want their products to be completely natural - yet, being such a new product, some time might be required before its efficacy and possible contraindications are proven once for all.[2]

Current review focuses on the commonly used preservatives, their chemistry, mechanism of action, factors to be considered while selecting preservatives, their potential toxicities and impact on the health caused by their repeated use.

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.[3]

CLASSIFICATION OF PRESERVATIVES
Preservatives are classified on variety of the basis and some of these are as follows

A. CLASSIFICATION BASED ON MECHANISM OF ACTION

1. Antioxidants:
The agent which prevent oxidation of Active pharmaceutical ingradient which otherwise undergo degradation due to oxidation as they are sensitive to oxygen.
Eg.Vitamin E
Vitamin C
Butylatedhydroxyanisole ( BHA).
Butylatedhydroxytoluene (BHT).

2. Antimicrobial agents:
The agent which active against gram positive & gram negative micro-organism which causes degradation of pharmaceutical preparation. Which are active in small inclusion level.
Eg. Benzoates
Sodium benzoate
Sorbates

3. Chelating agents:
The agents which form the complex with pharmaceutical ingredient and prevent the degradation of pharmaceutical formulation.
Eg. Disodium ethylenediaminetetraacetic acid (EDTA)
Polyphosphates
Citric acid

B. CLASSIFICATION BASED ON SOURCE

1. Natural Preservatives:-
These drugs are obtained by natural sources that is plant, mineral sources, animal etc.
Eg. Neem Oil
Salt (sodium chloride)
Lemon
Honey

2. 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.[4]

MECHANISM OF ACTION:  PRESERVATIVES HOW THEY ACT?
Natural substances such as salt, sugar, vinegar, and diatomaceous earthare also used as traditional preservatives. Certain processes such as freezing, pickling, smokingand saltingcan also be used to preserve food. Another group of preservatives targets enzymes in fruits and vegetables that continue to metabolize after they are cut. For instance, citricand ascorbic acidsfrom lemonor other citrusjuice can inhibit the action of the enzyme phenolase which turns surfaces of cut apples and potatoes brown. Caution must be taken, however, since FDA standards do not currently require fruit and vegetable product labels to accurately reflect the type of preservative used in the products.[5]

Antimicrobial agent:-The agent which active against gram positive & gram negative micro-organism which causes degradation of pharmaceutical preparation. Which are active in small inclusion level. Which acting by cell wall inhibition, protein synthesis inhibition, DNA &RNA synthesis inhibition.
Example- Benzoates, Sodiumbenzoate, Sorbates, Propionates, Nitrites

Antioxidants: The agent which prevent oxidation of pharmaceutical formulation. Antioxidant agents are acting self reducing agent and prevent oxidation of oxygen sensitive ingredients.
Example:-Sulfites , Vitamin E, Vitamin C, Butylatedhydroxyanisole ( BHA). ,Butylatedhydroxytoluene (BHT).

Chelating agent: Which forming a complex with pharmaceutical ingredients and prevent the degradiation of formulation.
Examples:- Disodium ethylenediamine tetraacetic acid (EDTA), Polyphosphates, Citric acid.

PRESERVATIVES:

Ethyl Alcohol
-Synonyms: Ethanolum (96 per centum); ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol.

-Chemical Name: Ethanol

-Empirical Formula and Molecular Weight: C2H6O 46.07

Structural Formula

-Functional Category: Antimicrobial preservative; disinfectant; skin penetrant; solvent.

-Applications in Pharmaceutical Formulation or Technology: Ethanol and aqueous ethanol solutions of various concentrations are widely used in pharmaceutical formulations and cosmetics. Although ethanol is primarily used as a solvent, it is also employed as a disinfectant, and in solutions as an antimicrobial preservative. Topical ethanol solutions are used in the development of transdermal drug delivery systems as penetration enhancers. Ethanol has also been used in the development of transdermal preparations as a co-surfactant.

-Description
In the BP 2009, the term ‘ethanol’ used without other qualification refers to ethanol containing 599.5% v/v of C2H6O.The term ‘alcohol’, without other qualification, refers to ethanol 95.1–96.9%v/v. Where other strengths are intended, the term ‘alcohol’ or ‘ethanol’ is used, followed by the statement of the strength. In the PhEur 6.0, anhydrous ethanol contains not less than99.5% v/v of C2H6O at 208C. The term ethanol (96%) is used to describe the material containing water and 95.1–96.9% v/v of C2H6O at 208C.In the USP 32, the term ‘dehydrated alcohol’ refers to ethanol 599.5% v/v. The term ‘alcohol’ without other qualification refers to ethanol 94.9–96.0% v/v. In the JP XV, ethanol (alcohol) contains 95.1–96.9% v/v (by specific gravity) of C2H6O at 158C.In the Handbook of Pharmaceutical Excipients, the term ‘alcohol’ is used for either ethanol 95% v/v or ethanol 96% v/v. Alcohol is a clear, colorless, mobile, and volatile liquid with as light, characteristic odor and burning taste

-Typical Properties: Antimicrobial activity Ethanol is bactericidal in aqueous mixtures at concentrations between 60% and 95% v/v; the optimum concentration is generally considered to be 70% v/v. Antimicrobial activity is enhanced in the presence of eidetic acid or edentate salts. Ethanol is inactivated in the presence of nonionic surfactants and is ineffective against bacterial spores. Boiling point 78.158C Flammability Readily flammable, burning with a blue, smokeless flame. Flash point 148C (closed cup). Solubility Miscible with chloroform, ether, glycerin, and water (with rise of temperature and contraction of volume). Specific gravity 0.8119–0.8139 at 208CNote the above typical properties are for alcohol (ethanol 95% or96% v/v).

-Incompatibilities: In acidic conditions, ethanol solutions may react vigorously with oxidizing materials. Mixtures with alkali may darken in color owing to a reaction with residual amounts of aldehyde.[6]

Alpha Tocopherol
-Synonyms
: Copherol F1300; 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; RRR-a-tocopherolum; synthetic alpha tocopherol; all-rac-a-tocopherol; dl-a-tocopherol;5,7,8-trimethyltocol.

-Chemical Name: (2RS,40RS,80RS)-2,5,7,8-Tetramethyl-2-(40,80,120-trimethyltridecyl)-6-chromanol

-Empirical Formula and Molecular Weight: C29H50O2 & 430.72

-Structure

-Structural Formula

Alpha tocopherol: R1 = R2 = R3 = CH3

Beta tocopherol: R1 = R3 = CH3; R2 = H

Delta tocopherol: R1 = CH3; R2 = R3 = H

Gamma tocopherol: R1 = R2 = CH3; R3 = H

-Functional Category: Antioxidant; therapeutic agent.

-Applications in Pharmaceutical Formulation or Technology: Alpha tocopherol is primarily recognized as a source of vitamin E, and the commercially available materials and specifications reflect this purpose. While alpha tocopherol also exhibits antioxidant properties, the beta, delta, and gamma tocopherols are considered to be more effective as antioxidants. Alpha-tocopherol is a highly lipophilic compound, and is anexcellent solvent for many poorly soluble drugs of wide spread regulatory acceptability, tocopherols are of value in oil- or fat-based pharmaceutical products and are normally used in the concentration range 0.001–0.05% v/v. There is frequently an optimum concentration; thus the autoxidation of linoleic acid and methyllinolenate is reduced at low concentrations of alpha tocopherol, andis accelerated by higher concentrations. Antioxidant effectiveness can be increased by the addition of oil-soluble synergists such as lecithin and ascorbylpalmitate. Alpha tocopherol may be used as an efficient plasticizer. It hasbeen used in the development of deformable liposomes as topical formulations.

-Description: Alpha tocopherol is a natural product. The PhEur 6.0 describes alpha-tocopherol as a clear, colorless or yellowish-brown, viscous, oily liquid.

-Typical Properties: Boiling point 2358C, Density 0.947–0.951 g/cm3, Flash point 2408C, Ignition point 3408C
Refractive index n D 20 = 1.503–1.507 Solubility Practically insoluble in water; freely soluble in acetone, ethanol, ether, and vegetable oils.
11 Stability and Storage Conditions Tocopherols are oxidized slowly by atmospheric oxygen and rapidly by ferric and silver salts. Oxidation products include tocopheroxide, tocopheryl quinone, and tocopheryl hydroquinone.

-Safety: Tocopherols (vitamin E) occur in many food substances that are consumed as part of the normal diet. The daily nutritionalrequirement has not been clearly defined but is estimated to be3.0–20.0 mg. Absorption from the gastrointestinal tract is dependent upon normal pancreatic function and the presence of bile. Tocopherols are widely distributed throughout the body, with some ingested tocopherol metabolized in the liver; excretion of metabolitesis via the urine or bile. Individuals with vitamin E deficiency are usually treated by oral administration of tocopherols, although intramuscular and intravenous administration may sometimes be used.[7]

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