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Water-soluble binding agents

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The manufacturing of a tablet includes compressing a drug with several excipients. Mere compaction of a dry powder between two punches yields a tablet that easily crumbles.To achieve successful tablet production, the raw powder formulation is usually subject to granulation, a process which breaks down the large particles of powder into smaller particles of more uniform size.Wet granulation is generally preferred over the granulation of dry powders as it can achieve a fine powder that more easily flows into the dies of tableting machines.Wet granulation utilizes a liquid and a binding agent, and it is the binding agent that helps to hold the powder particles together as tiny granules.The liquid should be non-toxic and is preferably water, although various other solvents may be considered, such as propan-2-ol and ethanol for materials that are sensitive to moisture or heat. When a granulated mixture is subjected to compression, it results in the production of a tablet that is sufficiently hard to withstand the rigors of subsequent packing and transportation.

Certain natural and synthetic polymers and sugars are commonly used as binding agents.This article focuses on widely used water-soluble binding agents.Having said that, polymers are increasingly developed to solve specific problems associated with novel drug delivery systems.These include, for example, polymer-drug conjugates for a variety of drugs (insulin, peptides and lipids), to obtain clear soft gel capsules for transporting insoluble drugs, and as hydrogels for sustained release of topical drug. The binding agents that are discussed below divided for convenience into two categories (1) synthetic and (2) natural.

1. Synthetic water-soluble polymers

1.1Polyethylene glycol (PEG)

This polymer is synthesised by from ethylene glycol and has a lower polydispersivitiy index (PDI) than most polymers meaning that PEG has a reliable residence times in the body.It is soluble in water and organic solvents and is non-toxic, making it a widely used polymer in pharmaceutical products. The high hydrophilic nature of PEG enhances the physical stability of drugs and prevents aggregation of drugs in vivo, as well as during storage. It can be used to improve the plasticity of other binding agents, and may prolong disintegration times of tablets when the concentration is higher than ca. 5% by weight.PEG has been used as a meltable binder as an anhydrous binding agent where water or alcohol cannot be used.It is chemically easy to modify PEG and a variety of drug conjugates have been synthesised and applied as binding agents or drug delivery systems.

1.2Polyvinyl pyrrolidone (PVP, or Povidone).

This, the most widely used synthetic binding agent, is a water-soluble polymer having a molecular weight ranging from 40,000 to 360,000. It is synthesised by polymerisation of vinylpyrrolidone in water or propan-2-ol and is available in different graded based on molecular weights.Wet granulation with PVP having a molecular weight between 25,000 and 50,000 generally gives hard granules with good flowability, high binding and low friability.Another advantage of PVP is that is increases the dissolution of the active ingredient (API).For example, research has shown that paracetamol tablets formulated with 4% PVP 90,000 as binder, released the drug more quickly than tablets with gelatin or hydroxypropyl cellulose as binder. Soluble grades of PVP have been shown to improve the bioavailability of many poorly water-soluble drugs.As well as improving bioavailability of tablets, PVP can also be used to formulate drugs as glass solutions by hot melt extrusion (HME).Povidone and trimesters of citric acid can also be combined to obtain clear soft gelatin-like capsules of insoluble drug substances. Some grades of PVP are also useful for the preparation of sustained release tablets.

1.3Polyvinyl alcohol (PVA)

This polymer is synthesised by the polymerisation of vinyl acetate to give an acetate polymer which is then hydrolysed.The extent of hydrolysis and content of acetate groups affect the crystallizability and solubility of PVA in water.This polymer is also soluble in ethylene glycol, and n-methyl pyrollidone, and is therefore often in mixtures with these materials. PVA is often used in hydrolysed form as a gel for topical pharmaceuticals, in sustained release tablets, and as a stabiliser in emulsions.

1.4Other synthetic polymers

A number of water-soluble synthetic polymers have been trialled as binding agents or as the basis of drug-polymer conjugates for drug deliver systems.Whilst not yet widely used, their importance may grow for specific oral dosage forms.They include, polyacrylamides and poly-methyacrylamides (as carrier for drugs and bioactive molecules), divyinly ether-maleic anhydride (as antitumour agent), polyoxazoline (as adhesives or coatings), and various types of polyphosphates (used in tissue engineering).

2.Natural water-soluble polymers

2.1Starch

Starch is one of the earliest known binding agents to be used in tablet manufacturing. It is a white powder having no odour or taste. Chemically starch is mainly composed of two homopolymers of D-glucose:amylase, and branched amylopectin.Starch polymers have many functional hydroxyl groups and the material is therefore hydrophilic in nature.Native starches can be prepared from a wide variety of plant sources such as corn, potato and wheat.Careful preparation is required to achieve reproducible performance.Native starches tend to be highly viscous, to agglomerate, and have poor flow properties, making their handling difficult during the tablet manufacturing process.For these reasons, freshly prepared starch is now rarely used as a binding agent.

2.2Pre-gelatinized starch

Starch can be chemically and physically modified to improve its properties such as clarity and cold-storage stability.Maize, potato or rice starch can easily be hydrolyzed or partly hydrolyzed by heating with water.The process ruptures all or part of the starch structure, and after subsequent drying is used as a pre-gelatinized gel.Starch is also commonly modified by a hydroxypropylation process.The presence of hydroxypropyl groups on the starch molecules increases their water-holding capacity and reduces the re-association of starch chains. The result is a more stable starch gel.

Pre-gelatinized starch typically contains 5% free amylase, 15% free amylopectin and 80% unmodified starch.It is a widely used excipient in tablet making and functions as a binder, diluent and flow aid.It can be used in a concentration of between 5 and 75% as a binder for wet granulation, or for dry granulation at lower concentrations.

2.3Liquid glucose

Liquid glucose is a colourless to yellow-coloured viscous liquid that is obtained from corn starch.The process of manufacture includes partially hydrolyzing starch using an acid or enzyme. Being a viscous liquid with strong cohesive property, it acts as a good binding agent in tablet manufacture.

2.4 Cellulose ethers

Pure cellulose, which is a naturally polymer that occurs in plant fibres and is insoluble in both hot and cold water due to strong intramolecular hydrogen bonding.Cellulose can be chemically modified by controlled hydrolysis. This process yields a partially depolymerized form of cellulose called microcrystalline cellulose (MCC).Generally, this product has a polymerization degree less than 400. MCC and is useful in the preparation of tablets prepared by direct compression as well as wet granulation methods. Unlike other traditional binders that slow down the process of tablet disintegration, MCC acts both as a binding and disintegrating agent. Tablets containing MCC should not be exposed to high humidity conditions, which tend to soften the tablets. This form of cellulose is one of the most widely used tablet binders..

Further chemical modification of cellulose can produce water-soluble ethers, the most common of which are:

  • Hydroxypropylmethyl cellulose(HPMC)
  • Hydroxypropyl cellulose (HPC)
  • Hydroxyethyl cellulose (HEC)
  • Sodium carboxy methyl cellulose (Na-CMC)

These modified cellulose derivatives are used in a wide range of applications to enhance water retention and pseudoplastic behaviour, for their film forming properties and their ease of complexing with active drug ingredients.They are commonly used as binding agents, coating agents, emulsifying, stabilising agents and as tablet disintegrants.Of the synthetic binding agents, the derivatives of cellulose are perhaps the most common water-soluble binding agents used throughout pharmaceutical products.

2.5 Carnuaba wax

Carnauba wax is used in the pharmaceutical industry as a binder and coating material for tablets.It is produced from the leaves of the Copernicia prunifera palm grown only in Brazil. Carnauba wax is also known as palm wax or Brazil wax.Carnauba wax primarily consists of fatty acid esters. Coating tablets with the wax enables easier swallowing of the tablet. Carnauba wax has many other uses, including uses from car wax to dental floss. Carnauba wax is a safe, non-toxic and inert ingredient.

2.6 Guar Gum

This natural polysaccharaide is obtained from the endosperm of the guar plant.It is widely used as a binding agent in tablets and also acts as a stabilizer, thickening agent, emulsifier and suspending agent in liquid formulations.The swelling ability of guar gum is used to delay the release of drugs from oral dosage forms.

2.7 Pectin

Pectin is a mixture of polysaccharides, and is obtained from citrus peel or apple pomades, both of which are byproducts of juice production.Pectin is widely used as an additive in convenience foods, and as a binding agent in the manufacture of tablets along with hydroxymethyl cellulose.Pectin also has several unique propertiese which have enabled it to be used as a matrix for the entrapment and /or delivery of a variety of drugs, proteins and cells.Pectin has been shown to reduce cholesterol in a diverse group of subjects, and has been reported to remove lead and mercury from the gastrointestinal tract and respiratory organs.

2.8 Xanthan Gum

Xantham is a free-flowing powder soluble in both hot and cold water to give a viscous solution at low concentrations.

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