Excipients for stabilizing / preservation of dosage forms

1. Excipients for
stabilizing /
preservation of
dosage forms
A. antioxidants,
B. chelating agents,
C. buffering agents,
D. antimicrobial
preservatives

2. Antioxidants

3. Antioxidants
• Antioxidants are substances that prevent or inhibit oxidation. They
are added to dosage forms to protect components of the dosage form
that are subject to chemical degradation by oxidation.
• Antioxidants are included in pharmaceutical solutions to enhance the
stability of therapeutic agents that are susceptible to chemical
degradation by oxidation.

4. Mechanism of action of Antioxidants
a) Some are compounds are easily oxidized; they have lower oxidation
potentials than the drugs, they are intended to protect and are
preferentially oxidized. E.g. the sulfites, ascorbic acid,
monothioglycerol, and sodium formaldehyde sulfoxylate.
b) Some antioxidants act as chain terminators. They provide a readily
available hydrogen atom or an electron and converted to free
radicals that are not sufficiently reactive. E.g Butylated
Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT)
c) Some antioxidants are reducing agents; they reduce a drug or
component that has been oxidized. Ascorbic acid and sodium
thiosulfate may act as reducing agents.

5. Types of Antioxidants
• Water soluble: Ascorbic acid, Sodium Thiosulfate, Edetate Disodium
(EDTA), Sodium Metabisulfite (see preservative)
• Oil soluble: BHT, BHA, Vitamin-E (α-Tocopherol)

6. Chelating agents

7. Chelating agents
• A chelating agents are chemical compounds
that reacts with metal ions to form stable,
water-soluble metal complexes.
• The chelating agent's molecules form several
bonds to a metal ion and prevent the metal
from reacting to other components of
formulation
• Deactivate metal ions to prevent heavy
metal poisoning and reducing metal's toxic
effects

8. Disodium Edetate (EDTA)
• Disodium edetate is used as a chelating agent in a wide range of
pharmaceutical preparations, including mouthwashes, ophthalmic
preparations, and topical preparations, typically at concentrations
between 0.005 and 0.1% w/v
• Disodium edetate forms stable water-soluble complexes (chelates) with
alkaline earth (Mg) and heavy-metal ions. The chelated form has few of
the properties of the free ion, and for this reason chelating agents are
often described as ‘removing ions’ from solution, a process known as
sequestering.
• The stability of the metal–edetate complex is dependent on the metal ion
involved and the pH.
• Disodium edetate is also used as a water softener as it will chelate
calcium and magnesium ions present in hard water. It is also used
therapeutically as an anticoagulant as it will chelate calcium and prevent
the coagulation of blood in vitro

9. Buffering agents

10. Buffering agents
• Buffers are employed within pharmaceutical solutions to control
the pH of the formulated product improve the physicochemical
performance of the product.
Generally pH control is performed:
• To maintain the solubility of the therapeutic agent in the
formulated product. The solubility of the vast number of currently
available drugs is pH-dependent and, therefore, the solubility of
the therapeutic agent in the formulation change by small changes
in pH
• To enhance the stability of products in which the chemical
stability of the active agent is pH-dependent.

11. Buffering agents
• Buffer capacity should be overcome by biological fluids following
administration. This property is particularly important for parenteral
formulations to ensure that there is no irritation or damage following
injection.
• E.g.
• Acetates (acetic acid and sodium acetate)
• Citrates (citric acid and sodium citrate):
• Phosphates (sodium phosphate and disodium phosphate)
• Care should be taken that the buffer system used in solution
formulations should not adversely affect the solubility of the API, e.g.
the solubility of drugs may be affected in the presence of phosphate
salts.

12. Buffering agents
(Dibasic Sodium Phosphate)
• Functional Category: Buffering agent; sequestering agent.
• Applications in Pharmaceutical Formulation: Dibasic sodium
phosphate is widely used as an excipient in parenteral, oral, and
topical pharmaceutical formulations as buffering agent
• Safety: Excessive administration of phosphate, particularly
intravenously, rectally, or in patients with renal failure, can cause
hyperphosphatemia that may lead to hypocalcemia. LD50 (rat, oral):
17 g/kg)
• Regulatory Status: GRAS listed.

13. Preservatives
(Antimicrobial)

14. Preservatives (Antimicrobial)
• Preservatives are included in pharmaceutical solutions to control the
microbial growth (bioburden) in the formulation.
• Ideal Properties of preservatives
• Possess a broad spectrum of antimicrobial activity (against Gram-positive and
Gram-negative bacteria and fungi)
• Chemically and physically stable over the shelf-life of the product
• Low toxicity.
• Minimum inhibitory concentration (MIC): The activity of a preservative
depends upon the correct form (dissociated/Undissociated) of the
preservative being available in the formulation at the required
concentration to inhibit microbial growth.
• E.g. Benzoic Acid, Benzalkonium Chloride, Benzyl Alcohol,
Methylparaben

15. Antimicrobial preservatives
(Sodium Metabisulfite)
• Functional Category: Antimicrobial preservative; antioxidant
• Applications: Sodium metabisulfite is used as an antioxidant in oral,
parenteral, and topical pharmaceutical formulations, at
concentrations of 0.01–1.0% w/v, and at a concentration of
approximately 27% w/v in intramuscular injection preparations.
• Sodium metabisulfite also has antimicrobial activity, which is
greatest at acid pH, and may be used as a preservative in oral
preparations such as syrups.
• In the food industry and in wine production, sodium metabisulfite is
similarly used as an antioxidant, antimicrobial preservative.

16. Sodium Metabisulfite
• Stability: On exposure to air and moisture, sodium metabisulfite is
slowly oxidized to sodium sulfate with disintegration of the crystals.
• Addition of strong acids to the solid liberates sulfur dioxide.
• In water, sodium metabisulfite is immediately converted to sodium
(Na+) and bisulfite (HSO3-) ions.
• Aqueous sodium metabisulfite solutions also decompose in air,
especially on heating. Solutions that are to be sterilized by
autoclaving should be filled into containers in which the air has been
replaced with an inert gas, suchas nitrogen

17. Sodium Metabisulfite
• Safety: Sodium metabisulfite is widely used as an antioxidant in oral,
topical, and parenteral pharmaceutical formulations; it is also widely
used in food products
• Following oral ingestion, sodium metabisulfite is oxidized to sulfate
and is excreted in urine. Ingestion may result in gastric irritation,
owing to the liberation of sulfurous acid, while ingestion of large
amounts of sodium metabisulfite can cause colic, diarrhea, circulatory
disturbances, CNS depression
• LD50 (rat, IV): 0.12 g/kg
• Regulatory Status: GRAS listed.