GUMS AND MUCILAGES 1. 1 Introduction Originally, the term “gum

Chapter-1 Introduction

School of Pharmaceutical Sciences 1

GUMS AND MUCILAGES

1. 1 Introduction

Originally, the term “gum” was probably applied to natural plant exudates that had oozed

from tree barks and hardened upon exposure to air. Gums can be grouped into three major

categories, namely, natural gums, modified gums and synthetic gums. Natural gums are

found in a natural state such as the tree exudates or seaweed hydrocolloids. Examples

include gum arabic, guar gum and gum tragacanth. Natural gums are produced in response

to wounding (exudate gums) and extracted from seeds of some legumes (extractive gums).

Examples of exudate gums are gum arabic from Acacia spp., gum tragacanth from Asiatic

astraglus spp., gum karaya from Sterculia spp. and gum ghatti from Anogeissus latifolia.

Examples of extractive gums include locust gum from Certonia siliqua and guar gum from

Cyamopsis tetragonolobus.

Modified gums are chemically modified natural gums or derivatives of naturally occurring

materials such as cellulose or starch. Synthetic gums are completely synthesized chemical

products such as polyvinylpyrolidone (PVP) and ethylene oxide polymers.

Tens of thousands of people worldwide, living in regions ranging from semiarid deserts to

rainforests depend on the collection of gums, resins and latexes as a source of their income.

Equally, many millions of people around the world make use of these products in their

everyday life [1]. Nature has gifted India with great variety of flora and fauna. For centuries

man has made effective use of materials of natural origin in the medical and pharmaceutical

field. Today, the whole world is increasingly interested in natural drugs and excipients.

Natural materials have advantages over synthetic materials because they are non toxic, less

expensive and freely available. Furthermore, they can be modified to obtain tailor made

materials for drug delivery systems allowing them to compete with the synthetic products

that are commercially available. Many kinds of natural gums are used in the food industry

and are regarded as safe for human consumption. It may be noted that many ‘old’ materials

are still popular today after almost a century of efforts to replace them. It is usual to strike a

balance between economics and performance in the face of commercial realities [2-5].



1.2 What are gums and mucilages?

Gums are considered to be pathological products formed following injury to the plant or

owing to unfavorable conditions, such as drought, by a breakdown of cell walls (extra

cellular formation; gummosis) while, mucilages are generally normal products of

metabolism, formed within the cell (intracellular formation) and/or are produced without

injury to the plant. Gums readily dissolve in water, whereas, mucilage form slimy masses.

Gums are pathological products, whereas mucilages are physiological products [6]. Acacia,

tragacanth, and guar gum are examples of gums while mucilages are often found in different

parts of plants. For example, in the epidermal cells of leaves (senna), in seed coats (linseed,

psyllium), roots (marshmallow), barks (slippery elm) and middle lamella (aloe) [7]. Gums

and mucilages have certain similarities—both are plant hydrocolloids. They are also

translucent amorphous substances and polymers of a monosaccharide or mixed

monosaccharides and many of them are combined with uronic acids. Gums and mucilages

have similar constituents and on hydrolysis yield a mixture of sugars and uronic acids. Gums

and mucilages contain hydrophilic molecules, which can combine with water to form

viscous solutions or gels. The nature of the compounds involved influences the properties of

different gums. Linear polysaccharides occupy more space and are more viscous than highly

branched compounds of the same molecular weight. The branched compounds form gels

more easily and are more stable because extensive interaction along the chains is not

possible.

1.3 Disadvantages of synthetic polymers

The synthetic polymers have certain disadvantages such as high cost, toxicity,

environmental pollution during synthesis, non-renewable sources, side effects, and poor

patient compliance. Acute and chronic adverse effects (skin and eye irritation) have been

observed in workers handling the related substances methyl methacrylate and poly- (methyl

methacrylate) (PMMA) [8]. Reports of adverse reactions to povidone primarily concern the

formation of subcutaneous granulomas at the injection site produced by povidone. There is

also evidence that povidone may accumulate in organs following intramuscular injections



[9]. Carbomer dust is irritating to the eyes, mucous membranes and respiratory tract. So,

gloves, eye protection and dust respirator are recommended during handling [10].

Studies in rats have shown that 5% polyvinyl alcohol aqueous solution injected

subcutaneously can cause anemia and can infiltrate various organs and tissues [11]. Some

disadvantages of biodegradable polymers used in tissue engineering applications are their

poor biocompatibility, release of acidic degradation products, poor processing ability and

rapid loss of mechanical properties during degradation. It has been shown that poly

glycolides, polylactides and their co-polymers have an acceptable biocompatibility but

exhibit systemic or local reactions due to acidic degradation products. An initial mild

inflammatory response has been reported when using poly-(propylene fumarate) in rat

implant studies [12].

1.4 Advantages of natural gums and mucilages

The following are a number of the advantages of natural plant–based materials.

• Biodegradable—naturally available biodegradable polymers are produced by all

living organisms. They represent truly renewable source and they have no adverse

impact on humans or environmental health (e.g., skin and eye irritation).

• Biocompatible and non-toxic—chemically, nearly all of these plant materials are

carbohydrates composed of repeating sugar (monosaccharides) units. Hence, they are

non- toxic.

• Low cost—it is always cheaper to use natural sources. The production cost is also

much lower as compared with that for synthetic material.

• Environmental-friendly processing—gums and mucilages from different sources are

easily collected in different seasons in large quantities due to the simple production

processes involved.



• Local availability (especially in developing countries)—in developing countries,

governments promote the cultivation of plants for production of guar gum and

tragacanth because of the wide applications in a variety of industries.

• Better patient tolerance as well as public acceptance— there is less chance of side

and adverse effects with natural materials compared with synthetic one.

• Edible sources—most gums and mucilages are obtained from edible sources.

1.5 Disadvantages of natural gums and mucilages [13-14]

• Microbial contamination—the equilibrium moisture content present in the gums and

mucilages is normally 10% or more and, structurally, they are carbohydrates and,

during production, they are exposed to the external environment and, so there is a

chance of microbial contamination. However, this can be prevented by proper

handling and the use of preservatives.

• Batch to batch variation—manufacturing of synthetic gums is a controlled procedure

with fixed quantities of ingredients, while the production of gums and mucilages is

dependent on environmental and seasonal factors.

• Uncontrolled rate of hydration—due to differences in the collection of natural

materials at different times, as well as differences in region, species, and climate

conditions the percentage of chemical constituents present in a given material may

vary. There is a need to develop suitable monographs on available gums and

mucilages.

• Reduced viscosity on storage—Normally, when gums and mucilages come into

contact with water there is an increase in the viscosity of the formulations. Due to the

complex nature of gums and mucilages (monosaccharides to polysaccharides and

their derivatives), it has been found that after storage there is decrease in viscosity.



1.6 Classification of gums and mucilages

Gums and mucilages are present in high quantities in certain plants, animals, seaweeds,

fungi and other microbial sources, where they perform a number of structural and metabolic

functions; plant sources however, provide the largest amounts. Various classification

systems available for gums and mucilages are as follows [15-20]:

Sr. Classification system Categories Examples

1 According to the charge

Non-ionic Guar, locust bean, tamarind

Anionic Arabic, karaya, tragacanth

2 According to the source Marine Agar, carrageenans, alginic acid

Plant Gum arabica, guar gum, locust bean

Animal Chitin, chitosan, chondrotoin sulfate,

hyaluronic acid

Microbial Xanthan, dextran, curdian

3 Semi-synthetic Starch derivatives Hetastarch, starch acetate, starch

phosphates

Cellulose derivatives Carboxy methyl cellulose (CMC),

hydroxypropyl methylcellulose

(HPMC), methylcellulose (MC),

microcrystalline cellulose (MCC)

4 According to shape Linear Algins, amylose, cellulose

Branched Xanthan, xylan, amylopectin

5. According to monomeric

units

Homoglycans Amylose, arabinanas, cellulose

Di-heteroglycans Algins, carragennans, galactomannans

Tri-heteroglycans Arabinoxylans, gellan, xanthan

Tetra-heteroglycans Gum arabic, psyllium seed gum

Penta-heteroglycans Ghatti gum, tragacanth



1.7 Applications of gums and mucilages

Gums and mucilages of different sources and their derivatives represent a group of polymers

widely used in pharmaceutical dosage forms. Their major applications are:

Applications in the food industry

Different gums are used in water retention and stabilization (guar and locust bean gum); as

stabilizers for ice-cream; in meat products and instant pudding (carrageenanas), dairy,

confectionery and meat products (agar), confectionary, beverages, backed product, and

sauces (gum arabic, tragacanth, pectins, alginates and xanthan gum) [21].

Pharmaceutical and industrial applications

Gums and mucilages are used in medicine for their demulcent properties for cough

suppression. They are ingredients of dental and other adhesives and can be used as bulk

laxatives. These hydrophilic polymers are useful as tablet binders, disintegrants, emulsifiers,

suspending agents, gelling agents, stabilizing agents, thickening agents, film forming agents

in transdermal and periodontal films, buccal tablets as well as sustaining agents in matrix

tablets and coating agents in microcapsules including those used for protein delivery.

Gums are used in cosmetics (acacia, tragacanth and karaya gum), textiles (starch, dextrin,

cellulose, pectins, and tamarind gum), adhesives (acacia gum, and tragacanth), lithography

(gum arabic, tragacanth, and locust bean gum), paints (pectins, hemicellulose, and resins)

and paper manufacture (tamarind, and cellulose).

Various gums and mucilages with their common names, biological sources and applications

are listed in Table 1.1, Table 1.2 lists the different applications of gums and mucilages in

novel drug delivery systems and Table 1.3 lists the different modified gums with their

applications.



Table 1.1: Pharmaceutical applications or uses of natural gums and mucilages.

Common

Name

Botanical

Name

Pharmaceutical Applications Reference

Abelmoschus

mucilage

Abelmoschus

Esculentus

Binder in tablets 34, 35

Agar Gelidium

amansii

Suspending agent, emulsifying

agent, gelling agent in

suppositories, surgical lubricant,

tablet disintegrants, medium for

bacterial culture, laxative

36

Albizia gum Albizia zygia Tablet binder 37

Aloe

mucilage

Aloe species Gelling agent 38

Asario

mucilage

Lepidum

sativum


agent

39, 40

Bavchi

mucilage

Ocimum

canum


agent

39

Carrageenan Chondrus

cryspus

Gelling agent, stabilizer in

emulsions and suspensions, in

toothpaste, demulcent and laxative

41, 42, 43

Cashew gum Anacardium

Occidentale

Suspending agent 44, 45

Cassia tora Cassia tora

Linn

Binding agent 46

Fenugreek

mucilage

Trigonella

foenumgraecu

m

Gelling agent, tablet binder,

sustaining agent, emollient and

demulcent

22, 47, 48

Guar gum Cyamompsis

tetraganolobus

Binder, disintegrant, thickening

agent, emulsifier, laxative

49, 50,

51, 52

Gum acacia Acacia arabica Suspending agent, emulsifying

agent, binder in tablets, demulcent

and emollient in cosmetics

53

Gum ghatti Anogeissus

latifolia

Binder, emulsifier, suspending

agent

54



Gum

tragacanth

Astragalus

gummifer


agent, demulcent, emollient in

cosmetics

55

Hibiscus

mucilage

Hibiscus

esculentus

Emulsifying agent, suspending

agent

56, 57

Hibiscus

mucilage

Hibiscus

rosasinensis

Suspending agent 58, 59, 60

Ispagol

mucilage

Plantago

psyllium,

Plantago ovata

Cathartic, lubricant, demulcent,

laxative, sustaining agent, binder,

emulsifying and suspending agent

61, 62, 63,

64, 65

Karaya gum Sterculia urens Suspending agent, emulsifying

agent, dental adhesive, sustaining

agent in tablets, bulk laxative

66, 67

Khaya gum Khaya

grandifolia

Binding agent

68

Leucaena

seed gum

Leucaena

Emulsifying agent, suspending

agent, binder in tablets,

disintegrating agent in tablets

69, 70, 71,

72, 73

Ocimum

seed

Mucilage

Ocimum

gratissimum

Linn

Suspending agent, binding agent 74, 75

Pectin Citrus

aurantium

Thickening agent, suspending

agent, protective agent

76, 77

Sodium

alginate

Macrocytis

pyrifera

Suspending agent, gelation for

dental films, stabilizer, sustained

release agent, tablet coating

79, 80, 81,

82, 83

Satavari

mucilage

Asparagus

racemosus

Binding agent and sustaining agent

in tablets

78

Tamarind

seed

polysaccharide

Tamarindus

indica

Binding agent, emulsifier,

suspending agent, sustaining agent

84

Xanthan gum Xanthomonas

lempestris

Suspending agent, emulsifier,

stabilizer in toothpaste and

ointments, sustained release agent

66, 85

Gellan gum Pseudomonas

elodea

Disintegrating agent 86



Table: 1.2: Applications of gums and mucilages in NDDS.

Common

Name

Botanical

Name

Pharmaceutical Applications Reference

Acacia Acacia Senegal Osmotic drug delivery 87, 88

Bhara gum Terminalia

bellerica roxb

Microencapsulation 89

Chitosan ---- Colonspecific drug delivery,

microspheres, carrier for protein

as nanoparticles

90, 91

Cordia gum Cordia obliqua

willed

Novel oral sustainedrelease matrix

forming agent in tablets

92

Cactus

mucilage

Opuntia ficus-

indica

Gelling agent in sustained drug

delivery

93

Guar gum Cyamompsis

tetraganolobus

Colon targeted drug delivery,

cross-linked microspheres

94, 95, 96

Gellan gum Pseudomonas

elodea

Ophthalmic drug delivery,

sustaining agent, beads, hydrogels,

floating in-situ gelling, controlled

release beads

97, 98, 99,

100,

101, 102

Hakea Hakea gibbosa Sustained release and peptide

mucoadhesive for buccal delivery

103, 104

Ispagol Plantago

psyllium,

Plantago ovata

Hydrogels, colon drug delivery,

gastroretentive drug delivery

105, 106,

107, 108

Karaya gum Sterculia urens Mucoadhesive and buccoadhesive 109

Locust bean

gum

Ceratania

siliqua

Controlled release agent 110

Mucuna

gum

Mucuna

flagillepes

Microspheres 111

Okra Hibiscus

esculentus

Hydrophilic matrix for controlled

release drug delivery

112

Pectin Citrus

aurantium

Beads, floating beads, colon drug

delivery, pelletization by extrusion

/spheronization, microparticulate

delivery, transdermal delivery,

Iontophoresis, hydrogels

113, 114,

115, 116,

117, 118,

119, 120

Sodium

alginate

Macrocytis

pyrifera

Bioadhvesive microspheres,

nanoparticles, microencapsulation

121

Tamarind Tamarindus

indica

Hydrogels, mucoadhesive drug

delivery for ocular purposes,

spheroids, nasal drug delivery

122, 123

Xanthan

gum

Xanthomonas

lempestris

Pellets, controlled drug delivery

system

124, 125



Table 1.3: Examples of modified gums with their applications.

Gums and

mucilage

Modification technique Application Reference

Karaya gum Heat treatment at various

temperatures in a hot air

oven

Disintegrating

agent

126, 127

Agar and Guar

gum

Heat treatment at various

temperatures in a hot air

oven along with co-grinding

of both materials

Disintegrating

agent

128

Hypochlorite

potato starch

Chemical modification of

potato starch carried out in

presence of hypochloride

Disintegrating

agent

129

Tragacanth Chemical modification of

tragacanth using

epichlorhydrine

Disintegrating

agent

130

Acacia gum Chemical modification of

acacia gum using

epichlorhydrine

Disintegrating

agent

131

Guar gum Chemical modification of

guar gum

Disintegrating

agent

132

Cross-linked

amylase


amylase by substituting it in

a one step reaction

Disintegrating &

binding agent

133

Cross-linked

cellulose


cellulose by epichlorhydrine

Disintegrating &

binding agent

134

Polyalkylamine Chemical modification of

polyalkylamine

Disintegrating

agent

135

Cyclodextrin Physical modification - co-

drying of micro crystalline

cellulose with cyclodextrin

Disintegrating

agent

136

Starch Physico-chemical treatment

of to starch for modification

Disintegrating &

binding agent

137

Sesbania gum


Sesbania gum with tartaric

acid for a sustained release

formulation and chemical

modification of gum with

acetone: chloroform

mixture for gelling agent

Sustained release

formulation,

gelling agent

138, 139



Guar gum


guar gum with

glutaraldehyde for colonic

delivery, chemical

modification using

isopropanol as a filmcoating

material

Colonic delivery,

film coating,

hydrogel

140,141,

142,

143, 144

Tamarind

powder


tamarind powder using

epichlorohydrin for a

sustained release

formulation and partial

degradation of β-

galactosidase for rectal drug

delivery

Sustained release

formulation,

rectal drug

delivery

145, 146

Psyllium


psyllium was carried out to

form N- hydroxymethyl

acrylamide based hydrogels,

chemical modification with

tartaric acid

N- hydroxyl

methyl

acrylamide based

hydrogels, oral

insulin drug

delivery

147, 148,

149, 150

Okra fruits

(pods) of

Hibiscus

esculentus

Chemical modification with

acrylamide synthesis

Controlled drug

delivery

151

Ipomoea

dasysperma,

Ipomoea

hederacea, and

Ipomoea

palmate


ipomoea with poly-

(acrylonitrile) grafted drug

delivery

Poly

(acrylonitrile)

grafted drug

delivery

152

Pectins Chemical modification of

pectin with acetyl chloride

in ethanol for modified drug

delivery, chemical

modification with

ethanolamine for hydrogels

and chemical modification

of pectin for colonic drug

delivery

Modified drug

delivery.

hydrogels,

colonic drug

delivery

153, 154,

155



1.8 Reasons for developing new excipients

For a number of reasons there has been an increase in interest in the development of new

excipients/diluents.

Incompatibilities with many of the current range of excipients

One of the more common drug-excipient incompatibilities is the reaction between aldehydic

sugars, such as lactose and primary and secondary amines, leading to the formation of Schiff

bases. These complex series of reactions lead to browning and discoloration of the dosage

form. Despite being a carrier of choice for dry powder aerosol formulations, lactose may

need to be replaced with a different carrier, such as mannitol or sucrose, when formulating

primary and secondary amines. Atenolol- PVP, atenolol-magnesium-stearate [27],

magnesium-stearate is incompatible with aspirin, some vitamins and most alkaloidal salts

[28].

Need for excipients that will allow faster manufacturing of formulations

In the present times, in tablet dosage forms, new excipients having better compressibility at

very high compression speeds are needed. Today, it is not unheard of to have tableting

equipment compressing 8000 to 10000 tablets per min. It is critical under these conditions to

have an exceptionally efficient flowing granulation/powder blend. Many sugar-based

excipients, such as maltose, mannitol, and sorbitol are not compressible in their natural state

and need to be modified for use in direct compression tableting.

Requirements for new delivery system

New drug delivery systems for oral administration of biotechnology products need new

excipients which will avoid the inconvenience of multiple daily injections. Progress in the

development of peptides as therapeutic drugs has been impeded in part by their rapid

excretion, resulting in short circulating lifetimes. This has generated considerable interest in

improving the duration of action of drugs through conjugation with the water-soluble,

biocompatible excipient, poly (ethylene glycol). Such conjugates have reduced enzymatic

degradation rates and lengthened circulating lifetimes compared with the native compounds.



There are six FDA-approved PEGylated products on the market, vouching for the safety and

commercial viability of this technology. Other novel lipophilic carbohydrate excipients,

termed oligosaccharide ester derivatives (OEDs), have been used to modify the

pharmacokinetic profiles of drugs. This technology is quite flexible, offering the ability to

formulate drug molecules with modified release characteristics and improved

bioavailability. In other areas of technology, selected carbohydrate excipient, such as

trehalose and sucrose are used to stabilize molecules in the dry state, thereby preventing

their physical and chemical degradation at ambient temperatures and above. These patent-

protected drug delivery technologies are suited to the delivery of macromolecules, such as

proteins and peptides by the pulmonary, oral and injectable routes. Drug targeting systems,

like liposome delivery systems, need newer excipient, because the existing excipients for

liposomes are too expensive.

1.9 Isolation and purification of gums/mucilages

Plant material is dried in sunlight (preferably) or in an oven at 105˚C to retain its properties.

Generally, chlorophyll or pigments are present in the plant which have to be removed before

isolating the mucilage so the plant material must be treated with petroleum ether,

chloroform and then with distilled water. Care should be taken when drying the final

isolated/extracted mucilage. It must be dried at a low temperature (not more than 50˚C) or in

a vacuum. The dried material is stored carefully in desiccators to prevent further moisture

uptake or degradation. The general isolation and purification process for gums and

mucilages is shown in Fig. 1.1.

Baveja et al., [22] and Wahi et al., [23] reported the following method for the isolation of

mucilage. The fresh plant material is collected, washed with water to remove dirt and debris,

and dried. Then, the powdered material is soaked in water for 5–6 h, boiled for 30 min, and

allowed to stand for 1 h so that all the mucilage releases into the water. The material is then

squeezed from an eight fold muslin cloth to remove the marc from the solution. Following

this, three volumes of acetone are added to the filtrate to precipitate the mucilage. The

mucilage is separated, dried in an oven at a temperature less than 50˚C, and the dried

powder is passed through a sieve # 80 and stored in a desiccator until required.



Figure 1.1: General isolation/extraction procedure for mucilages.

Selection of part of plant

Plant identification and characterization

Drying, Grinding and Sieving

Stirring in distilled water

Heating initially for complete dispersion in distilled water

Storing for 6–8 h at room temperature,

Centrifugation

Separation of the Supernatant

Washing of residue and its addition to the supernatant

procedure repeated four times

Selection of solvents for moistening and precipitation.

Mixing of the supernatant with twice the volume of acetone by continuous stirring.

Washing the precipitated material with distilled water and drying at 50–60˚C under vacuum.

The isolated mucilage from the plant is then subjected to some preliminary confirmative

testing. Table 1.3 shows the preliminary confirmative test for dried mucilage [6, 15, 16].



Table: 1.4: Preliminary confirmative tests for dried mucilage powder.

Test Observation Inferences

Molisch’s test: (100 mg dried mucilage

powder + Molisch’s reagent + conc. H2SO4

on the side of a test tube)

Violet green color

observed at the junction

of the two layers

Carbohydrate

present

Ruthenium test: Take a small quantity of

dried mucilage powder, mount it on a slide

with ruthenium red solution, and observe

under microscope.

Pink color develops Mucilage

present

Iodine test: 100mg dried mucilage powder

+ 1 ml 0.2 N iodine solution.

No color observed in

solution

Polysaccharides

present

(starch absent)

Enzyme test: Dissolve 100 mg dried

mucilage powder in 20 ml-distilled water;

add 0.5 ml of benzidine in alcohol (90%).

Shake and allow to stand for few minutes

No blue color produced

Enzyme absent

(distinction

between dried

mucilage and

acacia)

Extraction is one of the most crucial procedures to achieve complete recovery of target

compounds from plants. Recently, microwave energy has been used for the extraction of

phyto-constituents from plants [24]. It is a simple, fast, clean, eco-friendly and efficient

method and saves energy, fuel and electricity. Microwave extraction follows the same

principle as maceration or percolation, but the speed of breaking up of the plant cells and

tissues is much higher. Microwave assisted extraction methods require a shorter time and

less solvent, and provide a higher extraction rate and better products at a lower cost. Plant

material is powdered in a mechanical blender for 5 m and then soaked in distilled water for

24 h in a beaker. It is kept in a microwave oven along with a glass tube to prevent bumping

when subjected to microwave irradiation. The beaker is removed from the oven and allowed

to stand for 2 h to allow the mucilage to be released into the water. It is then processed in a

similar way to the conventional procedure, weighed and stored.



1.10 Characterization of gums and mucilages

A suitable strategy is required to save money and time. Over-characterization is not

desirable, because excessive use of time and resources could actually delay the launch of

innovative excipients. The characterization of gums and mucilages is initially achieved by

only a multiple-technique approach [25]. For excipient analysis, analytical techniques can be

classified according to the type of information generated.

Structural Characterization—Gums and mucilages are polysaccharides and contain sugars.

So, confirmation of the different sugars is carried out by chromatography and structure

elucidation can be carried out by NMR and mass spectroscopy.

Purity—To determine the purity of the extracted/ isolated gum and mucilage, tests for the

presence of alkaloids, glycosides, carbohydrates, flavanoids, steroids, amino acids, terpenes,

saponins, tannins, phenols, oils and fats are carried out.

Impurity profile—Testing for impurities must be carried out using suitable analytical

techniques.

Physico-chemical properties—The estimation in terms of color, odor, shape, taste, touch,

texture, solubility, pH, swelling index, loss on drying, hygroscopic nature, angle of repose,

bulk and true densities, porosity and surface tension is carried out. Different ash values are

also determined. The microbial load and presence of specific pathogens are also determined.

In-vitro cyto-toxicity is also determined. As gums and mucilages are highly viscous in

nature, so, the rheological properties of excipients are important criteria for deciding their

commercial use. The flow behavior of the samples is determined.

Toxicity— The acute toxicity of gums and mucilages is determined by the fixed-dose

method as per OECD guideline no. 425. A sub-acute toxicity study, determination of the

LD50 etc., is carried out in rats and guinea pigs of both sexes. Once analysis is complete,

determination of the structure, composition and impurity profile enables a scientific dossier

to be prepared describing the excipient. This information is of value for the regulatory

dossier of the final pharmaceutical product that would contain the given excipient. Finally,

as gums and mucilages are added to pharmaceutical formulations, so a compatibility study is



important. The compatibility studies of gum/mucilage/ drugs are performed using

spectrophotometry/FTIR/ DSC.

1.11 Pharmacopoeial standard specifications of gums and mucilages

Different pharmacopoeias, like USP, PhEur, and JP contain pharmacopoeial standards for

specific gums [26], as shown in Table 1.5.

Table 1.5: Pharmacopoeial specifications for gums.

Excipient Test Pharmacopeia

Acacia Microbial limit, ash values, USP, JP, PhEur

Alginic acid Microbial limit, pH, loss on drying USP, PhEur

Carrageenan Solubility, viscosity, loss on drying, ash value USP

Dextrin Loss on drying, residue on ignition, reducing sugars USP, BP, JP

Gelatin Isoelectric point, microbial limit, residue on

ignition,

loss on drying, total ash, jelly strength

USP, JP, PhEur

Guar gum pH, microbial contamination, apparent viscosity,

loss on drying, ash, galactomannans, organic

volatile impurities,

USP, PhEur

Lecithin Water, arsenic, lead, acid value, heavy metals USP

Sodium

alginate

Microbial limit, appearance of solution, loss on

drying, ash, heavy metals

USP, PhEur

Tragacanth Microbial limits, flow time, lead, acacia and other

soluble gums, heavy metals

USP, JP, PhEur

Xanthan gum pH, viscosity, microbial limits, loss on drying, ash,

heavy metals,

organic volatile impurities

USP, PhEur

Gellan gum pH, microbial limit, loss on drying, moisture

content,

specific gravity, solubility, bulk density

USP



1.12 TABLET EXCIPIENTS

The ingredients or excipients used to make compressed tablets are numerous and can be

classified by their use or function as: fillers, binders, disintegrants, lubricants, glidants,

wetting agents, antioxidants, preservatives, colouring agents and flavouring agents. Fillers,

binders, glidants and lubricants help to impart satisfactory processing and compression

characteristics to the formulation. Disintegrants, wetting agents, antioxidants, preservatives,

colouring and flavouring agents help give additional desirable physical characteristics to the

finished tablets. It is becoming increasingly apparent that there is an important relationship

between the properties of the excipients and the dosage forms containing them.

Preformulation studies demonstrate their influence on stability, bioavailability and the

process by which the dosage forms are prepared. This calls for the need for acquiring more

information and use standards for excipients [156, 157, 158].

Pharmaceutical binders

Pharmaceutical binders are materials added dry or in liquid form to form granules or to

promote cohesive compacts for directly compressed tablets. These include natural gums,

alginic and alginates, starches, liquid glucose, cellulose derivatives and polyvinylpyrolidone.

Natural gums like acacia and tragacanth are employed in solutions ranging from 10-25%

concentration alone or in combination. These materials are more effective when they are

added as solutions than when they are added dry to a direct compression formula. These

natural gums have the disadvantage of being variable in their composition and performance

based on their origin and they are heavily contaminated with bacteria. Therefore their wet

granulation masses are quickly dried at a temperature above 37oC to reduce bacteria

proliferation.

Alginic acid and alginates: Alginic acid is a hydrophilic colloid extracted with dilute alkali

from various species of brown seaweed (phaeophyceae). It is odourless and tasteless. It is

best incorporated or blended into a tablet granulation by dry mixing processes up to a

concentration of 1 – 5%. Sodium alginate is the sodium salt of alginic acid which is easily

gelled in the presence of a divalent cation as calcium ion [159, 160, 161].



Starches: Starch, in the form of paste or mucilage, has long been the most common

granulating agent since the introduction of conventional tablet formulation. Its use is based

on its adhesive, thickening, gelling, swelling and film forming properties as well as its ready

availability, low cost and controlled quality. Potato and maize starches are widely used in

Europe and the USA. Despite its wide use, the effects of starch paste preparation add

variables on granulation or tableting quality. Viscosity or thickness of the paste is one

variable. The pregelatinization degree of starch paste influences the properties of the

resulting tablets. A properly made paste is translucent rather than clear (which would

indicate virtually complete conversion to glucose) and produces cohesive tablets that are

readily disintegrated when properly formulated. Concentration of starch paste varies from 10

– 20% [162,163].

Starches from different botanical sources may not have identical properties with respect to

their intended use. Indeed the chemical composition and physical characteristics of a starch

are typical of its biological origin. Hence the starch from each plant source will vary

somewhat in appearance, composition and properties.

Liquid glucose: Liquid glucose is prepared by the incomplete acidic or enzymatic

hydrolysis of starch. It is a 50% solution in water, and is a fairly common wet granulating

agent at concentrations of 5-10%.

Cellulose derivatives: Various cellulose derivatives have been used as binders in solution

form. Carboxymethylcellulose (CMC), methylcellulose (MC), ethyl cellulose (EC),

hydoxymethylcellulose (HMC), hydroxylpropylcellulose (HPC), hydroxypropyl

methylcellulose (HPMC)) are common binders and adhesives. HPMC has been widely used

in this regard. It is more soluble in cold water than hot. Other water-soluble cellulosics such

as HPC have been used successfully in solution as binder at concentration 2 – 4% w/v. HPC

may also be used as an alcohol solution to provide an anhydrous adhesive. Not all

cellulosics are soluble in water. EC can be used effectively when dissolved in alcohol or as a

dry binder, which then is wetted with alcohol. It is used as a binder for materials that are

moisture sensitive. Fibrous cellulose obtained from sugar-cane bagasse has also been

evaluated as tablet binder [165,166].



Polyvinylpyrolidone: Polyvinylpyrolidone (PVP) is a synthetic polymer that is used as an

adhesive in either an aqueous solution or alcohol. This versatility has increased its

popularity. Its concentration ranges from 0.5 - 5% w/v solution. Many traditional materials

compete successfully today after almost a century of effects to replace them. It is the usual

balance of economics and performance that determines the commercial reality. Natural

polysaccharides do hold advantages over the synthetic polymers, generally because they are

non-toxic, less expensive and freely available. Natural gums can also be modified to have

tailor-made materials for drug delivery systems and thus can compete with the synthetic

biodegradable excipients available in the market [166,167,168].

1.13 Methods of incorporation of binders

Tablet cohesion is best achieved when the binding component is used in solution as an

adhesive. In solution form, the binder is well distributed in the other materials of the tablet

and results in better bonding at a lower concentration of binder. Moreover, since powders

differ with respect to the ease with which they can be wetted, and their rate of solubilization,

it is preferable to incorporate the binding agent in solution. Some poorly compressible drugs

like paracetamol, metronidazole and acetazolamide can be successfully tableted only when a

liquid adhesive and wet granulation procedure is employed. The method of liquid addition

can change from pouring the total amount of liquid at once, to the pumping of liquid for a

specific period of time during granulation. Binder solutions are prepared on weight basis

rather than volume basis. This enables the formulator to determine the weight of the solids,

which have been added to the tablet granulations in the binding solution [155].

1.14 Granulation

For the powder mixture to flow evenly and freely from the hopper into the dies, it is usually

necessary to convert the powder mixture to free flowing granules. A granule is an

aggregation of component particles that is held together by the presence of bonds of finite

strength. The strength of a wet granule is due mainly to the surface tension of the

granulation liquid and capillary forces. These forces are responsible for initial agglomeration

of the wet powder. Granulation usually refers to processes whereby agglomerates with sizes



ranging from 0.1 to 2 mm are produced. The most important reasons for a granulation step

prior to tableting are to improve the flow properties of the mix and hence the uniformity of

the dose, to prevent segregation of the ingredients in the hopper of tablet machines, to

improve the compression characteristics of the tablet mixture and to reduce dust during

handling. There are various techniques of producing granules such as dry and wet

granulation, extrusion [155, 156] or spray drying.

Dry granulation

Dry granulation is a valuable technique in situations where the effective dose of a drug is

too high for direct compaction and the drug is sensitive to heat, moisture or both, which

precludes wet granulation [155]. The blend of powders is forced into dies of a large heavy-

duty tableting press and compacted to slugs. The slugs or roller compacts are then milled

and screened in order to produce a granular form of tableting material which flows more

uniformly than the original powder mix [156,157].

Wet granulation

Tableting by the wet granulation process is the most widely used method for pharmaceutical

materials. This is accomplished by adding a liquid binder or an adhesive to the powder

mixture, passing the wetted mass through a screen of the desired mesh size, drying the

granulation and then passing through a second screen of smaller mesh to reduce further the

size of the granules. Granulation is mainly performed in planetary mixers with low speed

and low shear forces. Now there is a trend toward using machines that can carry out the

entire granulation sequence in a single piece of equipment – the mixer- granulator – dryer,

for example the fluidized bed granulation. Advantages of these machines include reduced

handling of excipients, reduced exposure of excipients to heat, and a better opportunity to

precisely control the moisture level in the granulation and reduced granulation time [155].

High shear mixers are also recently introduced with short process time and production of

very dense granules with low porosity [155,156,157]. In wet granulation, liquid bridges are

developed between particles, and the resulting tensile strength of these bonds increases as

the amount of liquid increases. During drying, inter-particulate bonds result from fusion or



re-crystallization and curing of the binding agent. The formation of crystal bridges has been

shown to be a major influence on the physical characteristics of tablets especially if the solid

is more soluble in the granulating fluid [155].

Direct compression

Although this is not a granulation method, some drugs like aspirin require the addition of

direct compressible diluents such as microcrystalline cellulose, dibasic calcium phosphate.

Dry methods and in particular direct compression are superior to those methods employing

liquids, since dry processes do not require the equipment and handling expenses required in

wetting and drying procedures and can avoid hydrolysis of water-sensitive drugs. Tablets are

produced by mixing the drug with the compression vehicle in a blender. The powder mix is

then compressed directly on a tableting machine. Direct compression vehicles should be free

flowing, physiologically inert, tasteless, colourless and have a good mouth feel [156,157].

Variables that affect granulation properties

The pharmaceutical elegance and ease of compression of tablets are related directly to the

granulations from which the tablets are compressed. Granulation quality in turn, is

dependent on the materials used (formulation), processing techniques and equipment

employed [155]. Of these variables, the materials used especially the binding agent

employed are fundamental to granulation particle size uniformity, inter-granular porosity,

adequate hardness, compressibility and general quality. Binders are evaluated on different

bases, such as mechanical properties of films, granules, tablets, and compressional

properties of granules [155,156].

Effect of binders on granule properties

None of the pharmaceutical ingredients is more fundamental than the binding agents used in

the formulation of granules. Most binding agents used for wet granulations, such as starch

paste, acacia mucilage, gelatin solution, simple syrup, methylcellulose solution and corn

syrup are hydrophilic in nature. These binders increase the bulk density and reduce the

porosity of the powder, thereby diminishing the effective surface area for evaporation.



Hydrophilic binders also retard the rate of evaporation of moisture by lowering the vapour

pressure of liquid moisture. In addition, the amount of moisture introduced into the granules

and retained by them after drying varies greatly with different binding agents. It has been

also reported that the amount of moisture retained by granules after drying increased with

the increasing concentration of the binding agents used [155]. Many studies have been done

on the effect of different binders: acacia, gelatin, PVP, HPC, methylcellulose solution,

Eudragit at various concentrations on the mechanical and physical properties of granules and

correlating these with the characteristics of the corresponding tablets [156-58]. It was found

that increasing the binder concentration was followed by an increase in the mean particle

size, harder granules, decreased granule flowability and reduction in tapped density and

hence reduction in granule porosity [155-56]. The reduced flow rate of granulations

produced at higher binder concentrations is associated with the increase in their average

size. Investigations on the effects of using different grades of PVP and gelatin binders in

granules also showed that increasing the molecular mass of binder (or bloom number for

gelatin) resulted in a decrease in granule friability but in an increase in granule size and

porosity [166].

The most significant changes in the physical properties affected by binder dilution were

found in granule friability and bulk density. Specifically, the more dilute binder solution

resulted in less friable granules. Also considerable influence was observed on inter-

particulate porosity and thus on flow rate while insignificant effects were observed on

average particle size and granule density [166]. A change in the intra-particulate pore spaces

of the granules is needed to effect change in granule density [167]. The mechanical

properties of the granules and the corresponding compacts are basically determined by the

physicochemical interactions of the substrate-binder interfacial layer. The mechanical

properties of granules and subsequent compacts were correlated with the physicochemical

characteristics (contact angle, surface tension and binder concentration) of the granulating

liquid made of PVP. Results indicated that the mechanical properties of the single particles

as well as of the compressed compact increased when the binder concentration in the

granulation liquid increased until a certain limit above which the increasing granulation



contact angle hindered the binder spreading, creating weak regions in the compact and

decreasing its mechanical strength.

Effect of processing variables on granule properties

Granule characteristics are reported to be influenced by equipment employed and processing

variables such as method of granulation, volume of granulating fluid, massing time and

method of compressing the granules to tablets [155].

Investigations on influence of various processing variables (impeller speed, granulating

solution addition rate, total amount of solution added in the granulation step, wet massing

time, moisture content of the granulation after drying, and screen size used for the dry

milling) in granulation characteristics using high shear mixer indicated that granulation

growth (size) was enhanced by the increase in the amount of added water, high impeller

speeds and short wet massing time [155]. It was also found that moisture content had the

largest impact on granulation compressibility. Increasing wet massing time decreased

granule porosity and fragmentation propensity hence increased granule strength, which led

to granulation compressibility. It was reported granulation compressibility was extremely

sensitive to processing conditions.

Process variables associated with the fluidized bed granulation technique include binder

solution addition rate, air pressure to the binary nozzle, inlet air temperature and nozzle

position with respect to the fluidized solids. When the rate at which the aqueous binder

solution added to a fluidized bed of powders was increased, the ability of the solution to wet

and penetrate the solids was enhanced, resulting in large average size, less friable

granulation, a more fluid granulation and decreased granulation bulkiness. Granule density

was unaffected by varying the rate of binder addition. Influence of drying temperature,

drying process (tray- or freeze-drying), granulation liquid viscosity on the inter- and intra-

granular drug migration were studied on both soluble and poorly soluble drugs. It was found

that the drying temperature had no influence on inter and intra-granular drug distribution

whereas a homogeneous distribution of drug in granules and in compacts was obtained by

the use of freeze-drying. Intra-granular migration was decreased as the granulation liquid



viscosity increased. It was also reported that fluidized-bed and infra-red dryers were found

to have a 2- to 5-fold advantage in thermal efficiency and better physical properties over tray

dryers in granule drying with the fluidized bed dryer being the most efficient.

The drying rate kinetics of pharmaceutical granulations depends on the physicochemical

nature of the ingredients as well as the solutions of the binding agents used to form them.

Studies on granulations of lactose and sulfathiazole prepared using various commonly used

binders: starch, gum acacia, corn syrup, CMC, povidone, gelatin and simple syrup showed

that binders and diluents affected the drying rate curves of these granulations both

qualitatively and quantitatively. Granules made with starch paste and gelatin solution

required maximum time and energy for drying and those made with simple syrup USP

required the least among the binders studied.

Granule flow

Studies indicate that the rheological behaviour of granules is closely related to tablet

property [155]. Glidants and lubricants such as talc, magnesium stearate are added to

promote flow of the tablet granulation. These glidants often possess a coefficient of friction

less than that of the bulk solid and hence improve the flowability thereby decreasing inter-

particulate friction. Adequate mixing is needed for homogenous distribution of lubricants

and satisfactory granulation flow. The percent of fines, amount and type of granulating

agent, particle size distribution, and type of glidant all had a measurable effect on granule

flow. Granules with higher amount of fine (<100) and large particle size distribution will

have poor flow from hoppers and will cause weight variation of the dosage form. This is

mainly caused from the segregation of the fines. The smaller particles may fall through the

voids between larger particles and thus make their way towards the bottom of the mass.

Many methods are available to measure the extent of inter-particle forces as index of flow.

Some of the more common are measurements of bulk density (poured density), angle of

repose, shear strength and hopper flow rate measurements. The former three are indirect

measures while the hopper flow rate is a direct measure of flow. Bulk density is the density

calculated from the volume of a poured granule of known weight. Tapped density is



calculated from the volume obtained by tapping the measuring cylinder mechanically at

constant speed. A useful empirical guide is given by the Carr’s compressibility index (1965),

which is given by the equation [168]:

Carr’s index (%) = [(tapped density – bulk density)/tapped density] x 100

� Carr’s index of 5 – 15% indicate excellent flow,

� 12 – 16 good flow,

� and >23% indicate poor flow.

A similar index has been defined by Hausner (1967) by the equation [168]:

Hausner ratio = Tapped density/ bulk density

� Values less than 1.25 indicate good flow,

� Values greater than 1.25 indicates poor flow.

Angle of Repose (φ)

The angle of repose is used to characterize a flow property of the powder material. It was

determined by conventional fixed height funnel method. Repose angle increases with

increases in percentage of fines.

� angles of repose < 300 usually indicate a free flowing material

� angles > 400 suggest a poorly flowing material.

Flow rates are also a function of particle diameter. Tablet weight variation may be

influenced by hopper flow rates if material flow to the feed frame is not consistent.

1.15 Tablet compression

In the process of compression in pharmaceutical tableting, an appropriate volume of

granules in a die cavity is compressed between an upper and lower punch to consolidate the

material into a single solid matrix, which is subsequently ejected from the die cavity as an

intact tablet. The subsequent events that occur in the process of compression are



� Transitional repacking,

� Deformation at points of contact,

� Fragmentation and/or deformation,

� Bonding,

� Deformation of the solid body and

� Decompression and finally ejection of the tablet.

The process of compression is described in terms of the relative volume (ratio of volume of

the compressed mass to the volume of the mass at zero voids) and applied pressure. This

may be expressed by the Heckel equation in terms of relative density rather than volume;

ln (1/(1-D)) = kP +A

Where D is packing fraction of the tablet, P is applied pressure, constants k and A are

determined from the slopes and intercepts respectively of the extrapolated linear portion of

the plot of ln (1/(1-D)) vs P. Materials have been characterized by comparing the behavior

of a material in the compression and decompression phase [156].

Compressional characteristics of granules

Information on the compression properties of drugs is extremely useful. Plastic materials

deform by changing shape while there is very little permanent change in elastic materials

during compression. While it is true that the tableted material should be plastic, i.e., capable

of permanent deformation, it should also exhibit a degree of brittleness (fragmentation).

Accordingly if the drug behaves plastically, the chosen excipients should fragment. If the

drug is brittle or elastic, the excipients should be plastic, or plastic binders could be used in

wet massing.

1.16 Tablet properties

Conventional tablets in general should have a certain amount of hardness, resistance to

friability to withstand the rigors of mechanical shocks encountered during their production,

packaging, transportation and handling prior to use. These tablet properties together with

uniformity of weight, disintegration and dissolution depend on tableting conditions



employed, on size and distribution of the granules and predominantly on the formulation

(granulation binding agent, moisture content). Generally, a correlation exists between the

granule properties and those of their compressed tablets. Granules possessing best

mechanical and physical characteristics will produce tablets with best pharmaceutical

property. It is apparent that the type and concentration of binder used in the granulation step

would influence the corresponding tablet properties [156].

The effect of drying time, compression force, size of particles and moisture content of wet

granules on tablet properties indicate that the formation and disintegration of tablets were

related to the effect of the formation of solid bridges between particles. Several forces that

can act between small neighboring particles have been identified. Among these, van der

Waals forces play the most important role in the formation of common compressed tablets.

Hydrogen bonding and also moisture for tablets prepared by wet granulation method also

play a key role in the tableting process.

Tablet hardness and friability

Hardness and friability are the most common measures used to evaluate tablet strength.

Factors that may alter tablet hardness are alterations in machine speed, changes in particle

size distribution of the granulation mix and lubricants. Dies having a light fill (large

particles, low density) will produce a softer tablet than dies receiving a heavy fill (small

particle, high density). Lubricants can have a significant effect on tablet hardness when used

in too high a concentration or when mixed too long. The lubricants will coat the granulation

particles and interfere with tablet bonding, reducing tablet strength. It was also reported that

the duration of lubricant mixing significantly changed the apparent bulk volume of the mix,

ejection force during tableting, hardness and disintegration and dissolution properties of

tablets. The application method of lubricants also has influence on tablet hardness and

ejectability after compression. It was found that mixing of lubricants with the granulation

gave better results for ejectability and hardness than the incorporation into the

granulation[156].



Tablet tensile strength

The strength of a tablet may also be expressed as a tensile strength (breaking stress of a solid

unit cross section in kg/cm2). Tablet tensile strength, measured using the diametral

compression test, allows the dimensions of the tablets to be taken into account while tablet

hardness is only a measure of the force at which the tablet breaks. Since the radial tensile

strength measurements considers the thickness of a tablet, and only tensile stress and axial

tensile strength express the strength in the direction in which capping may occur, the tensile

strength characterises the strength of a tablet more completely than hardness. The radial

tensile strength is expressed as;

σx = 2F /DtΠΠΠΠ

in which F is crushing load, D is the diameter and t is the thickness of the tablet. The axial

tensile strength is expressed as:

σz = 4F / D2ΠΠΠΠ

Reports indicate that flat-faced tablets have slightly higher tensile strength than deep

biconcave tablets compressed to the same packing fraction. Moreover, increasing the

compression speed generally decreased the tensile strength of tablets. In common

compressed tablets, the number of contact points between particles plays important role in

tablet tensile strength. With decrease in tablet porosity, the number of contact points

increase, and tensile strength of the tablets shows a higher value. The tensile strength

increases linearly with the log of porosity because more solid bridges are formed between

particles [169].

Maximum tensile strength occurs when the tablet contained moisture between 2.5% and

4.5%, which is the optimum moisture range [100-104]. The increase in tablet hardness with

increase in water content up to the optimum range could be attributed to the lubricating

effect of water. Increasing the water content above the optimum range causes a reduction in

tablet crushing strength due to the hydrodynamic resistance to consolidation [169,170].



Tablet disintegration and porosity

The importance of tablet disintegration was recognized as early as 1879 when a patent

recommended that pills be perforated to admit gastric juice for better disintegration.

Complete tablet disintegration is defined as that state in which any residue of the tablet,

except fragments of insoluble coating, remaining on the screen of the test apparatus is a soft

mass having no palpably firm core. For tablets to be disintegrated, it is necessary to

overcome the cohesive strength introduced into the mass by compression and by any binder

present. It is therefore usual practice to incorporate a disintegrant, which will induce this

process. Among the disintegrants, several types acting by different mechanism may be

distinguished. Disintegrants that enhance the action of capillary forces in a rapid uptake of

aqueous liquids and those that swell in contact with water are considered more important.

Whatever could be the mechanism, to obtain rapid disintegration, a disintegrant force is

generated by the replacement of solid/air with solid/liquid interfaces. The displacement of

air by water or aqueous liquids is a wetting process that may lead to hydration of the

involved particles [156]. Disintegrants can be incorporated extra-granularly, intra-granularly

or distributed between the two phases. Studies show that porosity, hydrophilicity, swelling

ability of particles and inter-particle forces are important factors for tablet disintegration.

Tablet porosity is clearly related to water absorption, which is a very important step of the

disintegration process. For conventional tablets, when tablet porosity is high, water can be

absorbed easily and destruction of tablets is not very difficult. Disintegration is hardly

affected by tablet formulation. However, when tablet porosity is not high, disintegration will

be influenced by the properties of the excipients used [157]. The disintegration time of

tablets was found to increase linearly with the log of porosity. Generally, disintegration time

increases with increasing compression force. The wettability of the formulation plays a vital

role in the process of disintegration and dissolution, which lead to release of the drug into

the blood stream. Wetting is closely related to the inner structure of tablets and to the

hydrophilicity of excipients. The wetting and subsequent penetration of liquid into the

capillary structure of the tablets are controlled, respectively, by the contact angle of the

liquid on the solid surface q, and by its surface tension g and the pore radius. The adhesion

tension, which is a measure of tablet wetability, could be useful in providing information



about the wetting and disintegration characteristics of tablet formulations. Although

disintegration is frequently considered a prerequisite for drug dissolution, it in no manner

assures that a drug will dissolve and hence have the potential for satisfactory bioavailability.

Tablet Dissolution

A drug given as an orally administered tablet must undergo dissolution before it can be

absorbed and transported into the systemic circulation. Although characteristics of granules

by pore or void size analysis is useful in assessing the penetration of fluids into matrices, as

well as compact strength, whenever a solid is in contact with a fluid particle, surface area is

of paramount importance [156]. Disintegration of tablets plays a vital role in the dissolution

process since it determines the area of contact between the solid and liquid [171,172]. On

coming into contact with water, a tablet disintegrates into granules and then de-aggregates

into fine particles. Dissolution thus occurs from intact tablet, granules and fine particles.

Assuming that the dissolution rate is proportional to the surface area available, the amount

dissolved from the intact tablet will be negligible compared with that dissolved from the

granules and fine particles. This has been described by Noyes and Whitney equation which

is given by:

dc/dt = [AD/hv(Cs-Ct)]

where, dc/dt is the dissolution rate, A is surface area, D is diffusion coefficient, h is

thickness of diffusion layer, v is volume of dissolution medium, Cs is the saturation

concentration and Ct concentration at a given time t. It is also reported that T50 showed

direct correlation with the disintegration time [172,173].

Effect of binders on tablet properties

Binders are added to a material to increase bonding. Granulations with a more homogenous

distribution of binder in the granules generally produce tablets of a higher mechanical

strength than granulations with a peripheral localization of binder [174]. Studies on the

effect of various formulations and processing factors on the properties of some tablets by

various authors revealed that at a constant moisture level and packing fraction, an increase in



binder concentration generally results in increased tensile strength, disintegration and

dissolution times (decreased dissolution rates), reduced capping tendency, ER/PC (elastic

recovery/plastic compression) ratio and the brittle fracture index value (BFI- a measure of

the lamination tendency of tablets) of the tablets [175, 176,177]. Increasing molecular mass

of binder (bloom number for gelatin for example) increases tablet tensile strength when

compressed to fixed apparent density. The radial strength is little affected but the axial

tensile strength is increased by increased concentration of binder to strength greater than the

radial strength. The results have been explained in terms of the effects of moist and binder

bridges on bonding of particles in tablets [177]. The role of binders in the moisture-induced

hardness increase in compressed tablets containing lactose as a major excipient was studied.

Results showed that the increase in moisture-induced hardness in compressed tablets is

related linearly to the amount of moisture loss from the tablets after compression [177, 178].

It was also reported that the magnitude of the hardness increase is related to the type and

concentration of the binder used in wet granulation. This moisture-induced hardness

increase in the tablets had no effect on the tablet disintegration time and in vitro drug

dissolution.



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Documents

GUMS AND MUCILAGES 1. 1 Introduction Originally, the term “gum