Pharmaceutical Excipients

Surfactants

Surfactants, or surface-active agents, lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid and increase the solubility.
They function as:
- Wetting agents
- Detergents
- Emulsifiers
Example: In tablet coating, surfactants reduce the surface tension of the coating agent in its solvent.
They facilitate drug particle wetting in suspensions, aiding dissolution.

Properties of Surfactants

Structural requirements:
- Lipophilic region
- Hydrophilic region
A balance between hydrophilic and lipophilic regions is essential for concentration at the interface and lowering surface tension.

Types of Surfactants

Classification based on ionic behavior:
1. Anionic Surfactants:
  - Hydrophilic region is negatively charged (anion).
  - Ionize in aqueous solutions into a large anion.
  - Example: Sodium lauryl sulfate is used as an excipient in some dissolvable aspirins.
2. Cationic Surfactants:
  - Hydrophilic region is positively charged (cation).
  - Ionize in aqueous solutions into a large cation.
  - Example: Cetyl trimethyl ammonium bromide (cetrimide) is an effective antiseptic agent.
3. Non-ionic Surfactants:
  - Do not ionize in aqueous solutions.
  - Examples:
    - Tween 80 (polyoxyethylene sorbitol monooleate) stabilizes aqueous formulations for parenteral administration.
    - Span (sorbitan ester of lauric acid)
4. Amphoteric Surfactants:
  - Act as wetting and stabilizing agents.

Emulsifying Agents

Reduce interfacial tension between aqueous and oily phases to make them miscible and form a stable emulsion.
Classification:
- A. Natural Emulsifying Agents (Vegetable Origin):
  - Carbohydrates including gums and mucilaginous substances.
  - Anionic in nature, produce O/W emulsion.
  - Examples: Acacia, Tragacanth, Agar, Pectin, Starch.
- B. Natural Emulsifying Agents (Animal Origin):
  - Gelatin
  - Egg yolk
  - Wool fat (Anhydrous lanolin)
- C. Semi-Synthetic Polysaccharides:
  - Methyl Cellulose
  - Sodium carboxymethyl cellulose
- D. Synthetic Emulsifying Agents:
  - Anionic: Alkali soaps, metallic soaps, sulphated alcohols, and sulphonates.
  - Cationic: Quaternary ammonium compounds (QACs).
  - Non-ionic: Glyceryl esters (e.g., Glyceryl monostearate).
- E. Inorganic Emulsifying Agents:
  - Magnesium oxide
  - Magnesium trisilicate
  - Magnesium aluminum silicate
  - Bentonite
- F. Alcohols:
  - Cholesterol
  - Carbowaxes

Stiffening Agents

Increase the hardness and thickness of preparations like ointments.
Viscosity-increasing agents for topical preparations.
Examples:
- Cetyl alcohol
- Cetyl esters wax
- Microcrystalline wax
- Paraffin
- Stearyl alcohol
- White beeswax
- Yellow beeswax

Organoleptic Additives

Affect properties sensed by organs (color, odor, taste).
Used to make pharmaceutical products more palatable and attractive, especially liquid dosage forms.
- Colour
  - Coloring agents impart color to foods, drugs, and cosmetics.
    - Increase organoleptic properties
    - Impart a preferred color
    - Enhance product quality
- Odour
- Taste

Source of Colour

Mineral: Pigments like Ferric oxide, Carbon black, Titanium dioxide, Prussian blue.
Plants: Chlorophyll, indigo, alizarin, Carotenoids, Flavones.
Animal: Tyrian blue, Cochineal.
Synthetic: Coal tar dyes like nitro-dyes, nitroso-dyes, azo-dyes, thiazines.

Flavouring Agents & Perfumes

Add a pleasant taste and smell to mask undesirable tastes, improving patient acceptance.
Four basic tastes: salty, sweet, bitter, and sour.
Examples: Clove oil, citrus, syrup, glycerin, rose oil, orange oil, raspberry flavor, vanilla flavor, anise oil, cinnamom oil, menthol, peppermint, cocoa.

Synthetic vs. Natural Flavouring Agents

Synthetic flavors are replacing natural flavors because they are:
- Constant in composition
- Readily available
- Comparatively cheap
- More stable
- More predictable in incompatibilities

General Guide to using Flavours

Water-soluble flavors: Artificial (0.2%), Natural (1%–2%).
Oil-soluble flavors: Artificial (0.1%), Natural (0.2%).
Powdered flavors: Artificial (0.1%), Natural (0.75%).
*Note: Flavors degrade by light, temperature, oxygen, water, enzymes.

Sweetening Agents

Mask unpleasant or bitter tastes, making preparations sweet.
Used in liquid formulations for oral administration.
Examples: Sucrose, Lactose, Aspartame, Sorbitol, Mannitol.

Sweetening Agents (cont.)

Aspartame is an artificial sweetening agent.
Use of artificial sweetening agents is increasing.
Sugars should be avoided in oral formulations for children and patients with diabetes mellitus.
- Commonly used in chewing tablets, lozenges, oral disintegrating tablets, dispersible tablets, oral solutions, emulsions, and oral suspensions.

Humectant

Hygroscopic substances that keep things moist, preventing preparations from drying.
Examples: Glycerin, Propylene glycol, Sorbitol.
Function: Retard evaporation of aqueous vehicle in dosage forms.
- Prevent drying of product after application to the skin.
- Prevent drying of product in the container after first opening.
- Prevent cap-locking caused by condensation onto the container neck.
These materials are hygroscopic and should be stored in well-closed containers prior to use.

Ideal properties of Humectant

Absorbs moisture from the atmosphere and retains it under normal humidity conditions.
Colorless or not of too intense color.
Good odor and taste.
Nontoxic and non-irritant.
Noncorrosive to packaging materials.
Does not solidify under normal conditions.
Not too costly.

Plasticizers (coating agents)

Components of film-coating solutions that make the film pliable and flexible.
Used for solid-oral dosage forms like tablets.
Enhance the spread of coats over tablets, beads, and granules.
Examples: Diethyl phthalate and Glycerin.

Wetting or Solubilizing agents

Reduce the surface tension of water, allowing it to spread more easily, and/or improves the solubility of poorly water-soluble drugs.
Increase spreading and penetrating properties by lowering surface tension.
Examples:
- Oral: polysorbates (Tweens), sorbitan esters (Spans)
- Parenteral: polysorbates, poloxamers, lecithin
Excessive levels can cause excessive foaming and deflocculation (undesirable physical instability and sedimentation).
Hydrophilic colloids (e.g., bentonite, tragacanth, alginates, cellulose derivatives): Used as suspending agents and can encourage deflocculation if levels are too low.

Stabilizer

Maintain the physical, chemical, microbiological, therapeutic, and toxicological specifications of a formulation within specific limits.
Important stabilizers:
1. Antioxidants
2. Preservatives

Antioxidant

Inhibit the oxidation of other molecules.
Prevent the oxidative degradation of the drug in the presence of oxygen or peroxides by blocking an oxidative chain reaction.
Compete for oxygen, protecting oxygen-sensitive drugs.
Examples:
- Quinol group: Hydroquinone, Tocopherols, Hydroxychromans
- Catechol group: Catechol, Pyrogallol, Gallic Acid, Ethyl Gallate
- Nitrogen-containing Substance: Alkanolamine, Diphenylamines, Casein
- EDTA (Ethylenediamine tetra-acetic acid), Ascorbic acid, Sod. Bisulfite, Sodium Metabisulfite, Sodium Formaldehyde sulfoxylate, and Ascorbic acid esters.

Drugs Sensitive to Oxidation

Ascorbic acid (Vitamin C)
Chlorpromazine
Cyanocobalamine (Vitamin B12)
Gentamicin
Heparin
Hydrocortisone
Resorcinol
Riboflavin (Vitamin E)
Streptomycine
Methyldopa
Morphine
Penicillin
Tetracycline
Thiamine (Vitamin B1)
Vitamin A, D and E
Paracetamol

Preservatives

Prevent or inhibit the growth of microorganisms in pharmaceutical formulations to prolong their shelf life.
Prevent increased risk of contamination and proliferation by opportunistic microbes (from excipients or externally introduced), that would result in potential health issues.

Definition

Protect drugs from undergoing undesirable chemical changes and microbial spoilage (bacteria, fungi, etc.).
Commonly used in liquid and semi-solid formulations.
Anti-fungal preservatives: Butylparaben, Propylparaben, and Ethylparaben.
Anti-bacterial preservatives: Benzoic acid

Ideal properties of Preservatives

Wide spectrum of antimicrobial activity at low inclusion levels.
Maintain activity throughout product manufacture, shelf life, and usage.
Not compromise the quality or performance of the product, pack, or delivery system.
Not adversely affect patient safety or tolerance of the product.
Chemically compatible with other ingredients of the formulation.
Nontoxic and non-sensitizing.
Soluble in the aqueous phase when used in emulsions.
Odorless, tasteless, and should not impart color to the formulation.
Stable and effective over a wide range of pH.
The preservative does not adversely affect the container or closure.

Preservatives- General Considerations

Acidic preservatives (benzoic, boric, and sorbic acids) are more effective as the medium is made more acid (more undissociated).
Alkaline preservatives are less effective in acid or neutral media and more effective in alkaline media.
Formulas interfering with solubility or availability may mislead the effective concentration.
Tragacanth can attract and hold preservatives like parabens, rendering them unavailable for preservative function.
Preservatives must not interact with the container (metal ointment tube, plastic medication bottle) or closure (rubber or plastic cap or liner).

Mode of Action

Interfere with microbial growth, multiplication, and metabolism through one or more of the following mechanisms:
- Modification of cell membrane permeability
- Lysis and cytoplasmic leakage
- Irreversible coagulation of cytoplasmic constituents (e.g., protein precipitation)
- Inhibition of cellular metabolism via enzyme systems or inhibition of cell wall synthesis
- Oxidation of cellular constituents
- Hydrolysis

Preservative Concentrations

Low volatility to ensure that loss does not occur during storage.
Examples:
- Methyl paraben and Propyl paraben (0.1-0.2%)
- Ethyl parabens, Propylparaben, Butylparaben (0.1- 0.2%)
- Benzoic acid and sodium benzoate (0.1-0.2%)
- Sorbic acid and its salts (0.05-0.2%)
- Alcohol (15-20%)
- Benzalkonium chloride (0.002-0.01%)
- Phenol (0.2-0.5%)
- Cresol (0.1% to 0.5%)

Antimicrobial Agent

Any agent that destroys microorganisms or suppresses their multiplication or growth.
Can be used both as an active pharmaceutical ingredient (API) and as excipients.
When used as an excipient, antimicrobial agents help preserve formulations.
Examples:
- Benzalkonium Chloride (BKC): quaternary ammonium compound and a cationic (positively charged) surfactant
- Phenolics
- Saponins
- Terpinoids
- Tannins, etc

Chelating agents

Form a chelate (water-soluble complex) when they react with metals.
Used as stabilizers to complex heavy metals that lead to instability in liquid formulations.
Examples: Edetic acid and Edetate disodium.

Solvents & Co-Solvency

Water is determinant to interactions of biological systems, dissociating in $H+$ and $OH-$
Ions interfering with ions and charged biomolecules, also interacting by Van de Wahl binding to solvate biomolecules and by hydrophobic interactions to form micelles or precipitates.
Polar solvents: Water and hydrophilic molecules; mineral or organic (ethanol).
- Used in large areas because water and water-soluble compounds are present in biosciences.
- Organisms, tissues, cells, biomolecules, and proteins need a polar environment to maintain their structure.
Organic solvents may be helpful to solubilize hydrophobic compounds prior to mixing with aqueous buffers.
Apolar solvents (nonpolar solvent): Components of petrol (obtained by fractionated condensation), having more or less long carbonated saturated chains.
- Organic solvents in chemistry dissolve apolar chemicals or achieve high concentrations.
- Protein tolerance levels depend on their nature.
Organic solvents are often harmful because they dissolve in lipidic biological structures, denaturing them.
Even very low concentrations (ppm) can concentrate in cell membranes, with major targets such as neural cells (neurological disorders).

Pharmaceutical water

Water for injection (WFI) is used in the production of parenterals and other formulations where endotoxin content must be controlled.
Also used for cleaning certain equipment used in the production of parenteral preparations.
Water is highly used as an ingredient and solvent in several pharmaceutical formulations.

Viscosity Enhancer

Agents that elevate (increase) the viscosity by reducing the sedimentation rate of particles in a vehicle in which they are insoluble.
Purpose:
- To trap particles
- Improve viscosity at high and low temperatures
- Improve resistance to oxidation
Examples:
- Emulsifiers: Tragacanth, Acacia, Veegum
- Silicones and Derivatives
- Solvents: Aliphatic hydrocarbons
- Thickeners: Cellulose ethers, magnesium aluminum silicate and Carbopol resins, Agar, Bentonite