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:

1. Synthetic water-soluble polymers

2. Natural water-soluble polymers

 

1. Synthetic Water-soluble Polymers

1. 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

2. 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

 

3. 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

 

4. 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

1. 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.

 

2. 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

 

3. 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

 

4. 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

5. 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

 

6. 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

• Tablet binder

• Stabilizer, thickener, emulsifier, suspending agent in liquids

7. Pectin

Mixture of polysaccharides from citrus peel or apple pomace, both of which are byproducts of juice production.

Applications

• Additive in convenience foods

• Binder in tablets (often combined with HPMC)

• Matrix for drug, protein, or cell entrapment/delivery

Additional Functional Benefits

• May reduce cholesterol

• Can bind and remove heavy metals like lead and mercury from the gastrointestinal tract and respiratory organs

 

8. Xanthan Gum

• Free-flowing powder

• Soluble in hot and cold water

• Forms a viscous solution at low concentrations

• Commonly used in controlled-release and suspension formulations