CPE CREDIT 1.

Current & Practical Compounding

Information for the Pharmacist
VOLUME 18 NUMBER 1 Grant funding provided by Perrigo Pharmaceuticals

Preservatives, Antioxidants and pH

Goal: To provide information for the stability and proper preservation of compounded formulations.
Objectives: After reading and studying the article, the reader will be able to:
1. Discuss the factors to be considered in the selection of a preservative
2. List mechanisms of action and characteristics of an effective preservative
3. Describe when an antioxidant is required for a compounded formulation
4. Describe the importance of pH in pharmaceutical products and preparations
5. List common antioxidants and chelating agents used in both ophthalmic and nasal preparation

PRESERVATIVES
In addition to the stabilization of pharmaceutical prepa- growth. Generally, 15% v/v alcohol will prevent microbial
rations against chemical and physical degradation within growth in acid media and 18% v/v in alkaline media.
a formulation, certain liquid and semisolid preparations Most alcohol-containing pharmaceuticals, such as elixirs,
must be preserved against microbial contamination. spirits, and tinctures, are self-sterilizing and do not
Preservatives are typically added to either minimize require additional preservation. The same applies to
microbial growth, as is the case with oral liquids, topicals, other individual pharmaceuticals that by virtue of their
and the like, or to prevent microbial growth, as is necessary vehicle or other formulative agents may not permit the
for sterile preparations such as parenterals, ophthalmics, growth of microorganisms.
and oral inhalation solutions.
General Preservative Considerations
Sterilization and Preservation Microorganisms include molds, yeasts, and bacteria, with
Although some types of pharmaceutical products, for bacteria generally favoring a slightly alkaline medium
example, ophthalmic and injectable preparations, are and the others an acidic medium. Although few microor-
sterilized by physical methods during preparation, many ganisms can grow below pH 3 or above pH 9, most aque-
of them also require an antimicrobial preservative to ous pharmaceutical preparations are within the favorable
maintain their aseptic condition throughout storage and pH range and therefore must be protected against micro-
use. Other types of preparations that are not sterilized bial growth. To be effective, a preservative agent must be
during their preparation but are particularly susceptible dissolved in sufficient concentration in the aqueous phase
to microbial growth because of the nature of their ingre- of a preparation. Furthermore, only the undissociated
dients are protected by the addition of an antimicrobial fraction or molecular form of a preservative possesses
preservative. Preparations that provide excellent growth preservative capability, because the ionized portion is
media for microbes are most aqueous preparations, incapable of penetrating the microorganism. Thus, the
especially syrups, emulsions, suspensions, and some preservative selected must be largely undissociated at
semisolid preparations, particularly creams. Certain the pH of the formulation being prepared. Acidic preser-
hydroalcoholic and most alcoholic preparations may not vatives like benzoic, boric, and sorbic acids are more
require the addition of a chemical preservative when the undissociated and thus more effective as the medium is
alcoholic content is sufficient to prevent microbial made more acid. Conversely, alkaline preservatives are

Loyd V. Allen, Jr., Ph.D., R.Ph. Quest Educational Services Inc. is accredited by the
• Professor Emeritus, University of Oklahoma College of Pharmacy Accreditation Council for Pharmacy Education as a
• Editor in Chief, International Journal of Pharmaceutical Compounding provider of continuing pharmacy education.
ACPE Number 0748-0000-14-001-H04-P (0.1CEU)
• Dr. Allen receives an honorarium for his contribution to Secundum Artem
Initial release date: 05/30/14 Expiration date: 05/30/17

Disclaimer: The content and opinions of this article are those of the author and are for educational purposes only. Although the material is based on review of multiple sources of information,
it is not all inclusive of information available. Readers should review and consider other publications and materials on this topic and not rely solely upon the information in this article.
less effective in acid or neutral media and more effective Preservative Selection
in alkaline media. Thus, it is meaningless to suggest Preservation involves the addition of a substance to a
preservative effectiveness at specific concentrations preparation; the choice of preservative to be added
unless the pH of the system is mentioned and the undis- depends on the characteristics of the preparation and its
sociated concentration of the agent is calculated or other- acceptability to the patient.
wise determined. Also, if formulative materials interfere
with the solubility or availability of the preservative Selection Factors
agent, its chemical concentration may be misleading, Factors that must be considered in selecting a preserva-
because it may not be a true measure of the effective tive include concentration, pH, taste, odor, and solubility.
concentration. It is essential for the compounding phar- Some preparations, such as syrups are inherently
macist to examine all formulative ingredients as one preserved by their high concentration of sugar, which
affects the other to ensure that each agent is free to do its acts as an osmotic preservative. For most preparations,
job. In addition, the preservative must not interact with a however, a suitable preservative is necessary. In choosing
container or closure. a preservative, the pharmacist must ensure that the com-
pounded preparation is stable. A preservative must be
In the pharmaceutical development process, the lowest
nontoxic, stable, compatible, inexpensive and have an
effective concentration of an antimicrobial preservative
acceptable taste, odor, and color. It should also be effec-
that is demonstrated to be effective by an antimicrobial
tive against a wide variety of bacteria, fungi, and yeasts.
preservative effectiveness test should be used. The
concentration used should be validated in terms of When experience or shelf storage experiments indicate
efficacy and safety, with the effectiveness confirmed to that a preservative is required in a pharmaceutical prepa-
last throughout the intended shelf life of the preparation. ration, its selection is based on many considerations,
including some of the following:
Mode of Action
Preservatives interfere with microbial growth, multipli- • The preservative prevents the growth of the type
cation, and metabolism through one or more of the of microorganisms considered the most likely
following mechanisms: contaminants of the preparation.
• The preservative is sufficiently soluble in water to
• Modification of cell membrane permeability and
achieve adequate concentrations in the aqueous
leakage of cell constituents (partial lysis)
phase of a system with two or more phases.
• Lysis and cytoplasmic leakage
• The proportion of preservative remaining
• Irreversible coagulation of cytoplasmic constituents undissociated at the pH of the preparation makes it
(e.g., protein precipitation) capable of penetrating the microorganism and
• Inhibition of cellular metabolism, such as by interfering destroying its integrity.
with enzyme systems or inhibition of cell wall
• The required concentration of the preservative does
synthesis
not affect the safety or comfort of the patient when
• Oxidation of cellular constituents the pharmaceutical preparation is administered by
• Hydrolysis the usual or intended route; that is, it is nonirritating,
Examples of the preservatives and their concentrations nonsensitizing, and nontoxic.
commonly employed in pharmaceutical preparations are • The preservative has adequate stability and will not be
listed in Table 1. For each type of preparation to be reduced in concentration by chemical decomposition
preserved, the compounding pharmacist must consider or volatilization during the desired shelf life of the
the influence of the preservative on the comfort of the preparation.
patient. For instance, a preservative in an ophthalmic • The preservative is completely compatible with all
preparation must have an extremely low degree of other formulative ingredients and does not interfere
irritant qualities, which is characteristic of chlorobutanol, with them, nor do they interfere with the effectiveness
benzalkonium chloride, and phenylmercuric nitrate, of the preservative agent.
frequently used in ophthalmic preparations. In all instances,
the preserved preparation must be biologically tested to • The preservative does not adversely affect the
determine its safety and efficacy and shelf-tested to preparation’s container or closure.
determine its stability for the intended shelf life of the
preparation.

Preservatives, Antioxidants and pH Page 2

Table 1: Preservatives Used in Selected Pharmaceutical Preparations
Concentration (%)
Ointments/ Ophthalmic/
Preservative Liquids Emulsions Creams Parenterals Nasal/Otic
Alcohol/ethanol 15–20 15–20
Benzalkonium chloride 0.004–0.02 0.002–0.1 0.01 0.013 0.004 – 0.02
Benzethonium chloride 0.004–0.02 0.005–0.02 0.01 0.01 0.004 – 0.01
Benzoic acid and salts a 0.1–0.3 0.1–0.3
Sodium benzoate 0.1–0.3 0.1–0.3
Benzyl alcohol 1.0–3.0 1.0–4.0 1 1-2
Boric acid and salts 0.5–1
Cetylpyridinium chloride 0.01–0.02 0.01–0.02
Cetyltrimethyl ammonium bromide — 0.01–0.02
Chlorobutanol b 0.3–0.5 0.5 0.25–0.5 0.5
Chlorocresol 0.05–0.1 0.1–0.3
Cresol 0.3–0.5 0.3–0.5 0.3–0.5 0.3-0.5
Imidazolidinyl urea — 0.05–0.5
Metacresol 0.1–0.3 0.1-0.3
Myristylgamma picolinium chloride 0.17
Nitromersol 0.001–0.1
Parabens c 0.001–0.2 0.05-0.3 0.001–0.2 0.02–0.2 0.1
Benzyl 0.015
Butyl 0.02-0.2 0.015
Methyl 0.05-0.3 0.1–0.2
Propyl 0.02-0.2 0.02–0.2
Phenol d 0.2–0.5 0.2–0.5 0.2–0.5 0.25-0.5
o-Phenyl phenol 0.005–0.01
β-phenylethyl alcohol 0.2–1
Phenylmercuric acetate/nitrate 0.002–0.005 0.002–0.005 0.002 0.002-0.004 0.004
Sorbic acid and salts 0.05–0.2 0.05–0.2
Thimerosal 0.001–0.1 0.005–0.02 0.01 0.01 0.01
a Benzoic acid/sodium benzoate are most effective at a pH of 4 or below.
b The anhydrous form of chlorobutanol should be used if a clear solution is desired in liquid petrolatum. Chlorobutanol needs a pH <5; also, it will sorb to plastic.
c Parabens are usually used in pairs. They have low water solubility and poor taste. May degrade at a pH >8; they are best used at a pH range of 4–8. The parabens may interact
with certain macromolecular compounds and bind, resulting in a loss of some effectiveness.
d Phenol forms an eutectic mixture with a number of compounds and may soften cocoa butter in suppository mixtures. Phenol may precipitate albumin, gelatin, and collodion.
A green color may be produced in the presence of alum or borax.

Table 2: Binding Percentages of Parabens with Macromolecular Compounds

Compound % of Methylparaben Bound % of Propylparaben Bound

Gelatin 8 11
Methylcellulose 9 13
Polyethylene glycol 4000 16 19
Polyvinylpyrrolidone 22 36
Polyoxyethylene monostearate 45 84
Polyoxyethylene sorbitan monolaurate 57 86
Polyoxyethylene sorbitan monooleate 57 90

Preservatives, Anitoxidants and pH Page 3

Physicochemical Considerations for Common carboxymethylcellulose or polysorbate 80 because of
Preservatives sorption or complex formation. Greater antimicrobial
Preservatives have unique characteristics that must be effectiveness can be obtained by combining 0.5% chloro-
taken into account during the selection process. For butanol with 0.5% phenylethanol. The anhydrous form
example, the anhydrous form of chlorobutanol should be of chlorobutanol should be used if a clear solution is
used if a clear solution is desired in liquid petrolatum. desired in a liquid petrolatum vehicle.
Ethylenediamine may irritate the skin and mucous mem- Parabens
branes and thus should be used with caution; sodium Methylparaben is most effective in solution between pH
benzoate is most effective at a pH of 4 or below, and a 4 and 8; its efficacy decreases at higher pH levels. In
green color may be produced in the presence of alum or aqueous solution it can be autoclaved and it is stable in
borax. The parabens may interact with certain macromo- aqueous solution in the pH range of 3 to 6 for up to 4
lecular compounds, binding and thereby losing some of years at room temperature. Methylparaben is incompati-
their effectiveness (Table 2). Phenol forms a eutectic ble with nonionic surfactants (its antimicrobial activity is
mixture with a number of compounds and may soften reduced), bentonite, magnesium trisilicate, talc, traga-
cocoa butter in suppository mixtures. Also, phenol may canth, sodium alginate, essential oils, sorbitol, and
precipitate albumin, gelatin, and collodion. atropine. It may sorb to some plastics and is discolored in
Quaternary Ammonium Compounds the presence of iron.
Benzalkonium chloride is an antimicrobial agent com- Propylparaben is also most effective in solution between
monly used as a preservative. It acts by emulsification of pH 4 and 8; its efficacy decreases at higher pH levels. It
the bacterial cell walls, probably the cell membrane can be autoclaved in aqueous solutions of pH 3 to 6 with-
lipids. Ethylenediaminetetraacetic acid (EDTA) is often out decomposition; aqueous solutions within this pH
added in concentrations ranging from 0.01% to 0.1% to range are stable for up to 4 years. Propylparaben is
enhance the activity of benzalkonium chloride against incompatible with nonionic surfactants (reduced effec-
Pseudomonas aeruginosa. Listed incompatibilities include tiveness); in addition, sorption has been reported to mag-
aluminum, anionic materials, citrates, cotton, fluorescein, nesium aluminum silicate, magnesium trisilicate, yellow
hydrogen peroxide, hydroxypropyl methylcellulose, iron oxide, and ultramarine blue. Discoloration in the
iodides, kaolin, lanolin, nitrates, high concentrations of presence of iron and hydrolysis by weak alkalis and
nonionic surfactants, permanganates, protein, salicylates, strong acids can also occur. Some plastics will adsorb
silver salts, soaps, sulfonamides, tartrates, zinc oxide, propylparaben. Sodium propylparaben is a more
and zinc sulfate. water-soluble form that may be used in place of propyl-
Benzethonium chloride is a detergent antiseptic with the paraben, but the pH of the formulation may be increased.
same limitations and behavior characteristics as benzal- Phenylmercuric Acetate/Nitrate
konium chloride. It is incompatible with soaps. One Phenylmercuric acetate should be protected from light. It
advantage of benzethonium chloride is that its germi- is reported to be incompatible with anionic emulsifying
cidal activity increases with an increase in pH. For exam- agents and suspending agents, tragacanth, starch, talc,
ple, at pH 10 it is several times more active against select- sodium metabisulfite, sodium thiosulfate, disodium edetate,
ed bacteria than at pH 4. the silicates, halides, and some types of filter membranes
Chlorobutanol used for sterilization. Phenylmercuric nitrate is effective
Chlorobutanol is both antibacterial and antifungal. Its over a broad pH range against both bacteria and fungi
antibacterial effectiveness is reduced above pH 5.5. and is the preferred form in acidic solutions.
Aqueous solutions of chlorobutanol will degrade in the The phenylmercuric salts are used in preference to
presence of hydroxide ions. Chlorobutanol aqueous benzalkonium chloride in solutions of salicylates and
solutions have good stability at pH 3, but stability nitrates, as well as in solutions of physostigmine and
decreases with an increase in pH. Chlorobutanol may epinephrine that contain sodium sulfite. Its solutions can
diffuse through polyethylene or other porous containers, be autoclaved, but significant amounts of the salt may be
resulting in a decreased concentration and effectiveness. lost; therefore, they are best sterilized by filtration.
Incompatibilities include plastic vials, rubber stoppers, Incompatibilities include anionic emulsifying agents and
bentonite, magnesium trisilicate, polyethylene, and poly- suspending agents, tragacanth, starch, talc, sodium
hydroxyethylmethacrylate (in some soft contact lenses). metabisulfite, sodium thiosulfate, disodium edetate, the
Some antimicrobial activity is lost on contact with silicates, halides, and some types of filter membranes
used for sterilization.

Preservatives, Anitoxidants and pH Page 4

Thimerosal
Thimerosal is an antibacterial agent with weak bacterio- The actual selection of an antioxidant depends on the (1)
static and mild fungistatic properties. It is affected by light. type of product, (2) route, dose, and frequency of admin-
istration, (3) physical and chemical properties of the
Preservative Effectiveness Testing (USP General Chap-
preservative used, (4) presence of other components, and
ter <51>)
(5) properties of the closure and container. The effectiveness
United States Pharmacopeia (USP) tests for the effective- of antioxidants may actually be decreased in complex
ness of antimicrobial preservatives may be conducted on systems such as suspensions and emulsions. This decrease
any formulation that is expected to be prepared in quantity may be due to sorption of the antioxidant onto suspended
and used for an extended period of time. The purpose of particles or to partitioning of the antioxidant between
the tests, which can be conducted by a testing laboratory, the phases of an emulsion. Also, it should be noted that
is to demonstrate preservative effectiveness against five antioxidants may sorb to containers and closures.
different organisms (Candida albicans, Aspergillus niger,
In general, antioxidants are used in relatively low
Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus
concentrations, usually from 0.001% to 0.2%. The lowest
aureus). Test results are applicable only to the specific
effective concentration should be used. When formulating
preparation, packaged in the original, unopened containers.
a preparation, pharmacists should remember to incorporate
ANTIOXIDANTS the antioxidant early in the compounding process to
Oxidation and Antioxidants minimize the extent of oxidation, rather than at the end of
preparation when some of the antioxidant will be needless-
Antioxidants are added to minimize or retard oxidative ly used up in counteracting the oxidation that has already
processes that occur with some drugs or excipients on occurred. Also, it is usually advisable to use a chelating
exposure to oxygen (air) or in the presence of free agent (See Table 4) along with an antioxidant to chelate
radicals. These processes can often be catalyzed by light, trace metals that may catalyze an oxidative process.
temperature, hydrogen ion concentration, presence of trace
metals, or peroxides. Oxidation of a preparation may be The formulation of an antioxidant system is accomplished
manifested as an unpleasant odor or taste, discoloration primarily through trial and error. With some experimen-
or other change in appearance, precipitation, or even a tation and patience, a suitable, stable system with the
slight loss of activity. required antioxidant properties can be developed.
It is important to remove oxygen from the ingredients pH EFFECT
before formulation and to minimize the entrapment of The pH is one of the most important factors affecting the
air during formulation. To minimize air entrapment, care stability of a preparation. The pharmacist can use
should be taken to not foam, whip, mix too vigorously, or published pH/stability profiles to determine the pH that
form a vortex during mixing. Mixing ingredients at will ensure maximum stability. After determining the pH
lower-than-normal speed in sealed containers works well. range, the pharmacist can prepare buffers to maintain the
For emulsions, a hand homogenizer (producing strong pH for the expected shelf life.
shear forces in a closed space) works well if the product
is collected carefully and protected from air. Degradation The pH is important in drug formulations, especially
can be also minimized by filling the container as full as because it affects drug solubility, activity, absorption,
possible, thereby decreasing the headspace, or by replacing stability, sorption, and patient comfort. pH is related to
the headspace with nitrogen. certain physical characteristics, such as the viscosity of
some polymers used as gel-forming agents and in
The most common approach to minimizing oxidation is to suspensions.
add an antioxidant to the system (Table 3). The selection
of an appropriate antioxidant is dependent on several So that a desired solution pH for both solubility and
factors, including solubility, location of the agent in the stability can be maintained, many preparations contain
formulation (emulsions), chemical and physical stability buffer systems. The buffer capacity (i.e., the resistance to
over a wide pH range, compatibility, odor, discoloration, change on the addition of either an acid or a base) is
toxicity, irritation, potency, effectiveness in low concen- generally low so that these systems will not alter the pH
trations, and freedom from toxicity, carcinogenicity, and of the body fluids on injection. Buffer systems are suffi-
sensitizing effects. ciently strong, however, to resist changes in pH under
normal storage and use.

Preservatives, Anitoxidants and pH Page 5

Table 3: Suggested Antioxidants for Use in Pharmacy Compounding
Solubility Usual Concentration
Antioxidant Mechanism Water Alcohol Oil Range/Comments
Acetone sodium bisulfite Reducing Yes No No 0.2%–0.4%
Acetylcysteine True Yes Yes No 0.1%–0.5%
α-Lipoic acid (sodium salt) — Yes — Yes —
α-Tocopherol (synthetic) True No Yes Yes
α-Tocopherol acetate True No Yes Yes ≤0.001%
D-α-Tocopherol (natural) True No Yes Yes 0.05%–0.075%
DL-α-Tocopherol (synthetic) True No Yes Yes 0.01%–0.5%
Ascorbic acid Reducing/Synergy Yes Yes No Soluble in glycerin/propylene glycol
Ascorbyl palmitate True Yes Yes Yes
Butylated hydroxyanisole True No Yes Yes 0.005%–0.02%/Soluble in propylene glycol
Butylated hydroxytoluene True No Yes Yes 0.005%–0.02%/Soluble in mineral oil
Calcium ascorbate Reducing Yes Yes —
Calcium bisulfite Reducing Yes — —
Calcium sulfite Reducing Yes Yes —
Cysteine True Yes Yes No 0.1%–0.5%
Cysteine HCl True/Synergy Yes Yes No 0.1%–0.5%/Bad odor
Dilauryl thiodipropionate True No Yes Yes
Dithiothreitol True Yes Yes No 0.01%–0.1%
Dodecyl gallate True No Yes Yes
Ethoxyquin True — — Yes
Ethyl gallate True SlS Yes No
Gallic acid — Yes Yes Yes
Glutathione True Yes — —
Gossypol True No Yes Yes
Hydroquinone Reducing Yes Yes Yes
4-Hydroxymethyl-2,6-di-tert-butylphenol — Yes Yes Yes
Hypophosphorus acid — Yes — —
Isoascorbic acid Reducing Yes — —
Lecithin True Yes Yes Yes
Monothioglycerol Reducing Yes Yes — 0.1%–1.0%/Slight odor
β-Naphthol True Yes Yes Yes
Nordihydroguaiaretic acid True No Yes Yes 0.001%–0.01%
Octyl gallate True No Yes Yes
Potassium metabisulfite Reducing Yes No No
Propyl gallate True SlS Yes SlS 0.001%–0.15% (≤2.5 mg/kg body weight)
Sesamol — — — —
Sodium ascorbate Reducing Yes Yes No
Sodium bisulfite Reducing Yes SlS No 0.05%–1.0%
Sodium formaldehyde sulfoxylate Reducing Yes SlS — 0.005%–0.15%
Sodium metabisulfite Reducing Yes SlS — 0.01%–1.0%/Soluble in glycerin
Sodium sulfite Reducing Yes No No 0.01%–0.2%
Sodium thiosulfate Reducing Yes No —
Sulfur dioxide Reducing Yes Yes Yes
Tannic acid Reducing Yes — —
Thioglycerol Reducing Yes Yes —
tert-Butyl-hydroquinone True — — —
Thioglycolic acid Reducing Yes Yes Yes
Thiolactic acid Reducing Yes Yes Yes
Thiosorbitol Reducing Yes Yes Yes
Thiourea Reducing Yes Yes No 0.005%
Tocopherols True — — Yes 0.05%–0.5%

Preservatives, Anitoxidants and pH Page 6

 Table 4: Common Chelating Agents and Synergists Used in Pharmacy Compounding

Solubility Usual Concentration

Chelating Agent Water Alcohol Oil Range/Comments
Alkyl gallates Yes Yes Yes
Ascorbic acid Yes Yes No 0.02%-0.1%
Boric acid Yes Yes No
Citric acid Yes Yes - 0.005%-0.01%
Citraconic acid Yes Yes No 0.03%-0.45%
Cysteine Yes Yes No
EDTA and salts Yes Yes No 0.02%-0.1%
Gluconic acid Yes Yes No
Glycine Yes Yes -
Hydroxyquinoline sulfate Yes Yes - 0.005%-0.01%
Maleic acid Yes Yes No
Phosphoric acid Yes Yes - 0.005%-0.01%
Polysorbates Yes Yes No
Saccharic acid Yes Yes No
Tartaric acid Yes Yes - 0.01%-0.02%
Tryptophan - Yes No

Adjustment of pH is critical for maintaining drugs in DOSAGE FORM CONSIDERATIONS

solution. A slight increase or decrease in pH can cause
Emulsions
some drugs to precipitate from a solution. Conversely, a
slight adjustment of pH can aid in solubilizing some Preservatives may partition into the oil phase of an emul-
drugs. Drug activity can be related to pH, depending on sion and lose their effectiveness. The preservative should
whether the ionized or the nonionized form is desired. be concentrated in the aqueous phase, since this is where
Drug stability, in many cases, directly depends on the pH bacterial growth usually occurs. In addition, since the
of the environment (dosage form). pH:degradation un-ionized form of the preservative is more effective
profiles are of great value in selecting the proper pH for against bacteria, most of the preservative should be present
optimum stability of a preparation. Sorption of a drug to in the nonionized state. In order to be effective, the
various excipients, packaging components, and adminis- preservative must be neither bound nor adsorbed to any
tration devices can occur. The sorption can be pH related, agent in the emulsion or the container. Generally, only
depending on which species, ionized or nonionized, is preservative in the aqueous phase in the free, unbound,
sorbed to the material. Patient comfort and, ultimately, unadsorbed, un-ionized state will be effective in emulsions.
compliance can depend on the proper pH of the prepara- The parabens (methylparaben, propylparaben, butylpara-
tion. In some cases, a compromise must be reached ben) are among the most satisfactory preservatives for
between the drug requirements and patient preferences. emulsions. Antioxidants used in emulsions include ascorbic
Often, pH can be adjusted for optimum drug stability acid, ascorbyl palmitate, butylated hydroxyanisole,
and a low buffer capacity can be used, so that, upon butylated hydroxytoluene, gallic acid 4-Hydroxymethyl-2,
administration, the patient’s physiologic buffers will 6-di-tert-butylphenol, propyl gallate, sulfites and L-To-
quickly move the pH to the physiologic range. copherol.
Oils and fats can become rancid, which causes the prepa-
ration to have an unpleasant odor, appearance, and taste;
antioxidants can prevent rancidity.

Preservatives, Anitoxidants and pH Page 7

Ophthalmics Parenterals
Because most ophthalmic solutions and suspensions are In compounding parenteral admixtures, pharmacists
prepared in multiuse containers, they must be preserved. must be cognizant of adjuvants such as vehicles, cosol-
The preservative must be compatible with the active drug vents, buffers, preservatives, antioxidants, inert gases,
as well as with all the other excipients in the preparation. surfactants, complexation agents, and chelating agents.
Antioxidants may also be required for some active drug The addition of a preserved solution of active drug to
ingredients. Common antioxidants and chelating agents sterile water for injection, dextrose 5% in water or 0.9%
used in ophthalmic and nasal preparations include sodium chloride injection may decrease the concentra-
ethylenediamine tetraacetic acid (0.1%), sodium bisulfite tion of the preservative so it is no longer effective.
(0.1%), sodium metabisulfite (0.1%), and thiourea (0.1%).
Preparations that are packaged in multiple-dose vials are
Oral Inhalations required to contain a preservative to prevent the growth
Any oral inhalation preparation that is not in unit dose of microorganisms that may be introduced when the
containers should contain a preservative, especially since container is manipulated. However, the preservatives
they are required to be sterile. The minimum amount of may not always be compatible with other drugs to which
preservative that is effective should be used. If too high a the drug may be added. For example, benzyl alcohol is
concentration is used, it may initiate a cough reflex in the incompatible with chloramphenicol sodium succinate,
patient. Also, too high a concentration of certain preser- and the parabens and phenol preservatives are incom-
vatives that are also surfactants may cause foaming that patible with nitrofurantoin, amphotericin B, and erythro-
can interfere with the delivery of the complete dose. mycin. When bacteriostatic water for injection is used for
reconstitution, it is important to select a product with a
Ointments preservative that will be compatible with the solution.
Antioxidants, such as butylated hydroxy toluene, are Preservatives must also be compatible with the container
sometimes required to delay the rate of rancidification of to which the preparation is added and with its closure.
selected bases.
SUMMARY
Gels
Preservatives, antioxidants and pH are all factors that are
When added to an aqueous system, 0.1% methylparaben
critically important in compounding stable preparations
or propylparaben is generally an acceptable preservative
and efficacious preparations. Each formulation must be
and does not affect the efficiency of the polymer to main-
evaluated based on its composition and characteristics.
tain viscosity.

Preservatives, Anitoxidants and pH Page 8

Send this completed form in for CE credit today!
Please circle the most appropriate answer for each of the following questions. There is only ONE correct answer per question.
1. All but which of the following provide excellent growth media for 8. Which two classes are commonly used together to provide antioxidant effect?
bacteria and may require a preservative in the formula? I. Suspending agents
A. Emulsions D. Creams II. Antioxidants
B. Suspensions E. Tinctures III. Chelating agents
C. Syrups A. I only D. II and III only
B. III only E. I, II and III
2. To be effective, a preservative should be: C. I and II only
I. In an aqueous phase
II. In sufficient concentration 9. pH is an important consideration for:
III. Be in the dissociated state A. Preservative effectiveness D. Antioxidant activity
A. I only D. II and III only B. Drug solubility E. All the above
B. III only E. I, II and III C. Drug stability
C. I and II only 10. Common antioxidants and chelating agents used in both ophthalmic and nasal
3. Preservatives act by which of the following mechanism(s): preparations include:
I. Inhibiting cellular metabolism I. Ethylenediamine tetraacetic acid
II. Lysis and cytoplasmic leakage II. Sodium bisulfite
III. Oxidation of cellular constituents III. Thiourea
A. I only D. II and III only A. I only D. II and III only
B. III only E. I, II and III B. III only E. I, II and III
C. I and II only C. I and II only
4. For an oral liquid, which of the following characteristic(s) must a 11. My practice setting is:
preservative possess? A. Community-based C. Manage-care based
I. Acceptable taste B. Hospital-based D. Consultant and Other
II. Acceptable odor
III. Acceptable color 12. Did this article effectively cover the topic and meet your educational needs?
A. I only D. II and III only A. Yes B. No If no, please comment:
B. III only E. I, II and III 13. Did you find that the learning assessment questions met your understanding
C. I and II only of the information covered in this article?
5. What is sometimes added to a solution containing benzalkonium A. Yes B. No If no, please comment:
chloride to enhance its effectiveness?
14. Do you think that the information provided in this article is current and
A. Benzyl alcohol D. Methylparaben potentially useful to you in your pharmacy practice?
B. Chlorobutanol E. Soap
C. EDTA A. Yes B. No C. Not Applicable

6. Which of the following is incompatible with sodium thiosulfate? 15. Does the article convey perceptions of bias or commercialism?
A. Phenylmercuric nitrate D. Benzalkonium chloride A. Yes B. No If yes, please comment:
B. Methylparaben E. All of the above 16. Approximately how long did it take you to read the article AND respond to
C. Chlorobutanol the test questions?
7. Oxidation of a chemical can be catalyzed by:
A. Light D. Trace metals 17. What topics would you like to see in future issues of Secundum Artem?
B. Temperature E. All of the above
C. pH

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