Water-Soluble Binding Agents

The manufacturing of a tablet involves compressing an active pharmaceutical ingredient with several excipients. However, simple compaction of a dry powder between two punches often yields a tablet that crumbles easily.

Granulation Process for Mechanical Strength

Granulation Purpose

To produce tablets with sufficient mechanical strength, the raw powder formulation is typically subjected to granulation. This process reduces large powder particles into smaller, more uniform granules.

Wet vs Dry Granulation

Wet granulation is generally preferred over dry granulation. It results in finer, more cohesive granules that flow more easily into the dies of tablet presses. Wet granulation requires the use of a liquid and a binding agent. The binding agent facilitates particle adhesion, forming stable granules.

Liquid Selection

The liquid used must be non-toxic. Water is commonly chosen, although other solvents such as propan-2-ol or ethanol may be used when the formulation is sensitive to moisture or heat.

Compression Into Tablets

Once the granulated mixture is compressed, it forms tablets with adequate hardness to withstand packaging, storage, and transportation.

Binding Agents in Granulation

A wide range of natural and synthetic polymers and sugars are used as binding agents. This article focuses specifically on water-soluble binding agents, which are commonly employed in wet granulation.

In addition to their traditional use, certain polymers are being developed for advanced drug delivery applications. These include:

Polymer-drug conjugates (e.g., for insulin, peptides, lipids)
Soft gel capsule matrices for insoluble drugs
Hydrogels for sustained topical release

The binding agents that are discussed below divided for convenience into two categories:

Synthetic water-soluble polymers
Natural water-soluble polymers

1. Synthetic Water-soluble Polymers

Polyethylene Glycol (PEG)

PEG is synthesized from ethylene glycol and has a low polydispersivity index (PDI), giving it reliable residence times in the body. It is widely used in pharmaceutical formulations due to its favorable properties.

Low Polydispersivity Index (PDI)

Consistent and reliable residence time in the body

High Solubility

Soluble in both water and organic solvents

Hydrophilic Nature

Enhances physical stability of drugs
Prevents aggregation in vivo and during storage

Functional Uses in Formulation

Improves plasticity of other binding agents
May prolong tablet disintegration at concentrations higher than ca. 5% by weight
Acts as a meltable binder when water or alcohol is unsuitable

Chemical Flexibility

Easily modified to create various drug conjugates for use as binders or drug delivery systems

Polyvinyl Pyrrolidone (PVP or Povidone)

The most widely used synthetic binding agent, PVP is a water-soluble polymer made by polymerising vinylpyrrolidone in water or propan-2-ol.

Molecular Weight Range

40,000 to 360,000

Grades Based on MW

Available for different applications

Wet Granulation With PVP (MW 25,000–50,000) Produces:

Hard granules
Good flowability
High binding strength
Low friability

Enhances Drug Dissolution

Example: Paracetamol tablets with 4% PVP 90,000 release drug faster than those using gelatin or HPC

Improves Bioavailability

Especially effective for poorly water-soluble APIs

Other Applications

Used in hot melt extrusion to create glass solutions
Combined with citric acid trimesters to make soft, clear capsules for insoluble drugs
Some grades support sustained release tablet formulations

Polyvinyl Alcohol (PVA)

PVA is synthesized by polymerising vinyl acetate and then hydrolyzing it.

Properties Are Affected by

Degree of hydrolysis
Acetate group content

Solubility

Soluble in water, ethylene glycol, and N-methyl pyrrolidone
Often used in combination with these solvents

Pharmaceutical Applications

Gels for topical drugs
Sustained release tablets
Emulsion stabilizer

Other Synthetic Polymers

Several water-soluble synthetic polymers have been investigated as:

Binding agents
Bases for drug–polymer conjugates

Although not yet widely adopted, these materials show potential for specific oral dosage forms and advanced drug delivery applications.

Examples include:

Polyacrylamides and Polymethacrylamides

Used as carriers for drugs and bioactive molecules

Divinyl Ether–maleic Anhydride

Investigated as an antitumour agent

Polyoxazoline

Explored for use as adhesives and tablet coatings

Polyphosphates

Studied for applications in tissue engineering

2. Natural Water-Soluble Polymers

Starch

Starch is one of the earliest binding agents used in tablet manufacturing. Its appearance is white, odorless, tasteless powder.

Composed Mainly of

Amylose (linear D-glucose polymer)
Amylopectin (branched D-glucose polymer)

Starch is highly hydrophilic due to abundant hydroxyl groups and is sourced from corn, potato, wheat, and other plants.

Limitations of Native Starch

High viscosity
Poor flowability
Prone to agglomeration
Inconsistent performance

Freshly prepared starch is now rarely used in modern formulations without modification as a binding agent.

Pre-Gelatinized Starch

Modified starch offers improved properties for pharmaceutical use. Produced by hydrolysis and drying of maize, potato, or rice starch. Starch may also undergo hydroxypropylation to:

Improve water-holding capacity
Reduce starch chain re-association
Create a more stable gel

Typical Composition

5% free amylose
15% free amylopectin
80% unmodified starch

Applications

Used as:

Binder (wet or dry granulation)
Diluent
Flow aid

Common Concentrations

5–75% for wet granulation
Lower percentages for dry granulation

Liquid Glucose

Source

Made by partial hydrolysis of corn starch using acid or enzymes

Appearance

Viscous, colorless to yellow liquid

Functional Properties

Strong cohesive properties
Good water solubility

Pharmaceutical Use

Acts as an effective binding agent in tablet production

Cellulose Ethers

Microcrystalline Cellulose (MCC)

Produced via controlled hydrolysis of plant-derived cellulose
Polymerization degree typically < 400

Key Benefits

Suitable for direct compression and wet granulation
Acts as both binder and disintegrant

Limitations

Sensitive to humidity, which may soften tablets

Common Water-Soluble Cellulose Derivatives

Hydroxypropylmethyl cellulose (HPMC)
Hydroxypropyl cellulose (HPC)
Hydroxyethyl cellulose (HEC)
Sodium carboxymethyl cellulose (Na-CMC)

Uses of These Cellulose Ethers

Binding agents
Coating agents
Emulsifiers
Tablet disintegrants
Film-formers
Stabilizers
Improve water retention and pseudoplastic behavior
Facilitate drug complexation

Carnauba Wax

Carnauba wax is a safe, inert, and non-toxic plant which can be found in many other industries than the pharmaceutical industry (e.g. car wax, dental floss).

Source

Derived from Copernicia prunifera palm (native to Brazil)

Known As

Carnauba wax
Palm wax
Brazilian wax

Main Component

Fatty acid esters

Used For

Tablet coatings to improve swallowability
Binding agent in tablet manufacturing

Guar Gum

Natural polysaccharide obtained from the endosperm of the guar plant. The swelling ability of guar gum is used to delay the release of drugs from oral dosage forms.

Used As