PRESERVATIVES

DR PARNEET KAUR DEOL

ASSOCIATE PROFESSOR

G.H.G. KHALSA COLLEGE OF PHARMACY GURUSAR SADHAR

 Cosmetics and toiletries are not necessarily intended to be sterile

• However, aqueous products in multiple use containers must be adequately preserved so

that they are self-sterilizing.
• In addition, appropriate packaging is necessary to help prevent contamination from
the environment and during use by consumers.
• Prevent spoilage
• Prolong shelf-life
ADD PRESERVATIVE TO PRODUCT • Protect consumer from
infection

Preservation must never be used to correct defects because of inadequate compliance with good manufacturing practices
(GMPs)
 DOES FDA REGULATE THE USE OF PRESERVATIVES IN
COSMETICS?

• FDA has no rules that apply specifically to preservatives in cosmetics. The law treats preservatives in
cosmetics the same as other cosmetic ingredients.
• Under the Federal Food, Drug and Cosmetic Act, cosmetic products and ingredients, other than colour
additives, do not need FDA approval before they go on the market.
• However, it is against the law to market a cosmetic if it is adulterated or misbranded.
• FDA can take action against a cosmetic on the market that does not comply with the laws. However, to take
action against a cosmetic for safety reasons, reliable scientific information, showing that the product is
harmful when consumers use it according to directions, label or in the customary way, should be available.
SOURCES OF CONTAMINATION

Raw material

Personnals Environment

Packaging
Equipment
materials
 FACTORS REGULATING
MICROBIAL GROWTH IN PRODUCT

WATER CONTENT NUTRIENTS

Emulsions with a continuous water phase are

Carbohydrates, proteins, and phospholipids will
more susceptible to bacterial attack than those
increase the need for adequate preservation.
with a continuous oil phase
Sorbitol, glycerol, and even surface-active agents
Some bacteria and fungi can survive for extended (particularly the nonionics) when present at low
periods of time in hydrocarbons free of any concentrations can be metabolized by
separate aqueous phase. microorganisms
 FACTORS REGULATING
MICROBIAL GROWTH IN PRODUCT
pH Value OSMOTIC PRESSURE/
WATER ACTIVITY

Concentrations of 40-50% glycerin and sorbitol

Best growth around neutral pH (5-8) are inhibitory to nearly all bacteria and fungi of
interest in cosmetic products.

Growth tolerance limits for pH differwidely for

various microorganisms

Gram-negative bacteria including Pseudomonas

species can exist over as wide a pH (3-11).
 FACTORS REGULATING
MICROBIAL GROWTH IN PRODUCT
SURFACTE TENSION &
OXYGEN TENSION TEMPERATURE

Gram negative grow in presence of surfactants, Gram

Bacteria grow well at 30-37 °C
positive do not grow below 0.05 N/m surface tension

Cationic surfactant toxic to many, Anionic to few, Yeasts and molds grow best at 20-25 °C
Nonionic to none.
 PROPERTIES OF AN IDEAL PRESERVATIVE

• Effective at low concentration against a wide range of microorganism.

• Chemically stable under normal condition of use over a wide pH and temperature range.
• Soluble at required concentration.
• Compatible with wide range of drugs and excipients.
• Free from objectionable odour, taste, colour or stinging.
• Non–toxic and non-sensitizing both externally and internally at the required concentration.
• Reasonable cost.
• Unreactive (do not adsorb, penetrate or interact) with containers or closures.
 PRESERVATIVES IN COSMETICS

• Parabens
• Isothiazolinones
• 2-phenoxyethanol
• Formaldehyde releasers
• Quaternary Ammonium Compounds (QAC)
• Nitrogen Compounds
 PARABENS
(P-HYDROXY BENZOIC ACID ESTERS)

• Synthetic “broad-based” preservatives (anti-bacterial and anti-

fungal) effective against bacteria, yeast, moulds and fungi, viz.
✓Butylparaben
✓Ethylparaben
✓Methylparaben
✓Propylparaben
✓p-Hydroxybenzoate
 METHYL PARABEN

• Formula- C8H8O3
• Used at a concentration of 0.05-0.25%
• Lower part of the range effective only when used with another preservative like propyl
paraben, benzyl alcohol or propylene glycol.
• Has water solubility identical to it’s effective concentration.
• Being a hydrophobic powder, difficult to dissolve in aqueous solution.
• Has activity over wide pH range- 4 to 8.
• Effectiveness enhanced by 2-5% propylene glycol.
 PROPYL PARABEN

• Formula: C10H12O3
• Used at a concentration of 0.02-0.04%
• Most effective when used with another preservative like methyl paraben (in aqueous phase).
• Hydrophobic powder.
• Rarely used alone because it is impossible to get enough concentration of it dissolved for
sufficient preservative action.
• Combination with methyl paraben has a synergistic effect.
 2-PHENOXYETHANOL
• It is oily, with faint rose like scent.
• Used as a preservative in wide variety of cosmetics like- lipstick, foundation, blushers, eye
make up and skin care products.
• Effective against fungi, bacteria and yeast; enhances shelf life and safety of products.

Isothiazolinones
• Types- methyl chloro isothiazolinones and methyl isothiazolinones.
• Used upto 15% in rinse off products like shampoos and 8% in other cosmetics.
• Has antibacterial and anti fungal effect.
• Can cause chemical burns and is a skin irritant at high concentration.
• Used where contact time with skin is short and in forms which makes it more acceptable to sensitive
users.
 FORMALDEHYDE RELEASERS
• Chemical compound that slowly releases formaldehyde as it decomposes in a product.
• Used as antimicrobial/antifungal preservative in cosmetics and hair care products.
• Like formaldehyde, formaldehyde-releasers are also known allergens and sensitizers.
Commonly used formaldehyde-releasers:
• DMDM hydantoin
• Imidazolidinyl urea
• Diazolidinyl urea
• Quaternium-15
• Bronopol
• 5-Bromo-5-nitro-1,3-dioxane
• Sodium hydroxymethyl glycinate

•
• Formaldehyde and formaldehyde-releasers are widely used in the
following products :
➢ Hair products (shampoos and conditioners)
➢ Moisturizers (cream and lotions)
➢ Nail products (nail hardeners, nail polish)
➢ Shaving products
➢ Oral care products (tooth paste, mouth wash)
➢ Deodorants
 QUATERNARY AMMONIUM COMPOUNDS (QAC)

• Represent cationic surfactants used as antiseptics and disinfectants.

• The antimicrobial activity of the QACs is a function of the length of the N-alkyl chain, which
confers lipophilicity. Thus, for a QAC to have high microbicidal activity, at least one of the R
groups must have a chain length in the C8 to C16 range.

• The optimum activity against Gram-positive bacteria and yeast is obtained with chain lengths of
12 to 14 alkyls, while optimum activity against Gram-negative bacteria is obtained with chain
lengths of 14–16 alkyls. Compounds with N-alkyl chain lengths 18 are virtually inactive.
 NITROGEN COMPOUNDS

• Gram-positive bacteria are more sensitive than Gram-negative ones to their action.

• Substituted amides of C8 to C12 are most active.

• For N-amide upto C18, addition of one epoxy group appears to contribute more to antimicrobial activity than
unsaturation or halogenation. However, the addition of a second epoxy group does not improve this activity.

• The lower alkyl amide of C12 is more active than those of a longer chain, and the addition of a second amide group
at position 9 or 10 of the amide alkyl seems to increase antimicrobial activity.
 MERITS OF PRESERVATIVES

• Protect cosmetics from microbial attack thus preventing them from smelling bad or
turning into unpleasant colours.
• Contaminated products can bring about skin rashes, eye irritation or infections in open
wounds or cuts, thus preservatives help prevent them.
• Stabilize the product.
• Increase shelf life of the product.
• Enhance the activity and efficacy of the product.
 DEMERITS OF PRESERVATIVES

• Parabens are potential endocrine disruptors due to their ability to mimic estrogen. They have been shown to increase cell
proliferation in human breast cancer MCF-7 cells and development of malignant melanoma (skin cancer) through their
estrogenic and genotoxic activities.
• Applying personal care product containing parabens—especially methylparaben—can lead to UV-induced damage of skin cells
and disruption of cell proliferation (cell growth rate).

• Propyl and butyl parabens reduce sperm production and lead to reduced testosterone levels.
• Laboratory evidence suggests that maternal exposure to isobutylparaben during gestation can lead to anxiety and behavioral
changes in offspring.
• Formaldehyde exposure is associated with nasopharyngeal and sinonasal cancers in humans.

• Formaldehyde-releasers can cause allergic contact dermatitis in sensitive persons.

• 2-phenoxyethanol can be toxic and harmful for infants. Accidental ingestion can produce depression of CNS and lead to
diarrhoea and vomiting.
• Isothiazolinones are mild skin irritating agents and may be linked to nerve damage.
FACTORS AFFECTING RATE OF
ANTIMICROBIAL ACTION

Factors connected with organism

 MORPHOLOGICAL STATE

• The spores are more resistant than the vegetative forms.

• Higher resistance may also be found in bacteria with slime layers or

capsules because these may prevent penetration of the bactericide
into the cell.

• The water-repellent layer of the mycobacteria behaves similarly.

 CULTURAL STATE

• Ability to resist chemical action is usually low when an organism is in an active

metabolic state e.g. when the cells are actively dividing in the log phase of growth.

• This sensitivity may be due to the fact that even a minor interference with the replication
of nucleic acids and with protein synthesis have a profound effect on the continuation of
high metabolic activity.
 PREVIOUS HISTORY

• Nature of the culture medium influences the type of metabolite produced by the
growing organism.

• Glycerol-containing media promote synthesis of lipids in certain organisms and this

results in increased resistance to antimicrobials.
Factors connected with the reaction
medium/ formulation
 Nature of the medium

• Most bactericides are more active in aqueous solution than in

organic or oily solvent.
Inoculum Size
• If all of the organisms in the initial inoculum are alive, reaction
rates may be accurately predicted. This will not apply if the
inoculum contains an appreciable number of dead cells.

• For example, if the bactericide is only slightly soluble, its

solution could become seriously depleted due to take up of the
chemical by the dead cells.
 Concentration of the bactericide
• The effect of this is usually expressed by the equation- K=Cnt Where;
K is the rate constant; C is the concentration of the bactericide; n is the concentration exponent for
the particular system; t is the time required to produce a given result.
• In very dilute solutions it bears a direct relationship to concentration but in more concentrated
solutions departure from this is marked.
• The simple equation presupposes that the chemical is inimical to the organism at all concentration
levels.
• In many cases there will be a minimal concentration below which no reaction will take place, because
insufficient chemical reaches the enzyme receptors, and a maximal concentration above which, the
reaction rate does not increase, probably because the receptor sites have become saturated with the
chemical or because steric interference prevents further adsorption.
• The equation is useful in deciding the type of bactericide to use in a particular situation.
Factors connected with the organism
and the reaction medium/ formulation
 pH

• The effects of the pH on the reaction mixture is complex and difficult to predict.
• Changes in pH can markedly affect the nature of the bactericide and it’s receptor sites in the
bacterial cell.
• Sometimes, as with the triphenylmethane dyes, there is a profound change in the ionisation
of the bactericide, resulting in dramatic changes in it’s activity.
• In one experiment the minimum inhibitory concentration (MIC) of crystal violet for
Staphylococcus aureus in peptone water medium at pH 7 was 1 x l0-7 molar, but when the
pH was raised to 8 the MIC became 4 x l0-9 molar.
• Alterations in the pH of protein content of a medium may affect it’s buffering capacity
because the buffering effects of different proteins at various pH are not same, due to
differences in their iso-electric points.
 OXIDATION-REDUCTION POTENTIAL

• Important where bactericides act by oxidation or reduction.

• Many antibacterial agents (e.g. the hypochlorite) oxidise bacterial proteins and the
presence of reducing substances, in the form of protein or other organic matter, leads to
considerable loss of activity and, sometimes, failure of the disinfection process.
 REACTION BETWEEN BACTERICIDES AND
CONSTITUENTS OF THE REACTION MEDIUM/
FORMULATION
A. Chemical
• A molecular species in the bactericide may combine with one in the formulation, modifying
the kinetics of the reaction.
• An example is the inactivation of bactericides containing Hg++ ions by thiol-containing
compounds such as proteins.
B. Physico-chemical

If the reaction mixture is biphasic several major changes may occur-

• Adsorption - When finely divided particles or droplets are present, molecules of the
bactericide may be adsorbed and become unavailable for action on the bacteria unless a large
excess is present in the solution. This problem arises in the preservation of suspensions/
emulsions.

• Partition - When two liquid phases are present as in an emulsion. If the bactericide is much
more soluble in oil than in water, it’s effects will be reduced in the final formulation. This is
true of the highly substituted phenols that are used to preserve oil-in-water creams.
C. Biochemical

• Sometimes the bactericide acts on a specific metabolic pathway in the organism; this
usually results in reversible blockage of the synthesis of an essential metabolite.

• But if the metabolite or its intermediates can be produced from alternative starting
materials sufficient of these may overcome the blockage.
 SURFACE EFFECT
• Surface active agents are often used in cosmetic formulations that require preservation.

A. Bactericide with Marked Surface Activity

(i) Surfactant with same charge as bactericide

There are three possibilities: firstly, the surfactant may not affect the bactericidal activity; secondly, the effects of
bactericide and surfactant may be additive; and thirdly, there maybe synergism. i.e. a more marked effect than
would be expected from addition of the two actions.

(ii) Surfactant with opposite charge to bactericide

• This reduces the antibacterial effect to a degree that depends on the relative proportion of ions of the two
substances.
• Where the proportion of bactericide is greater than 1, compared with the surfactant, some antibacterial action
will remain, but if it is less than 1 the antibacterial activity will be lost through precipitation.
B. Bactericide without Marked Surface Activity
i. Effects of ions of bactericide on ions of surfactant
They are of great importance in the formulation of creams, as vehicles for ionic bactericidal agents
such as the medicinal dyes, where incompatibilities between bactericide/medicaments and
surfactants can have serious effects on activity and appearance.

ii. Non-ionic surfactants

Often non-ionic surfactants contain hydroxy groupings, e.g. all of the sorbitans. Hydrogen
bonding takes place between these types of compound and -OH, -NH2, and -COOH groups in
bactericides. Because this bonding is reversible it does not completely inactivates the
bactericide but the effects are hard to predict.
Consequently, when a system containing such agents is being formulated, it is necessary to
check the effectiveness of anti microbial preservatives by inoculation with a suitable range of
microorganisms and storage under conditions similar to those that the product will encounter in
practice.

Colloidal electrolytes
• Many antimicrobial substances are only slightly soluble in water and must be solubilised by
the use of colloidal electrolytes; alkali soaps of long chain fatty acids are often used.
Formulations of this type are issued as concentrates and diluted before use.