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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].
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.
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].
• Low cost—it is always cheaper to use natural sources. The production cost is also
much lower as compared with that for synthetic material.
• 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.
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]:
Gums and mucilages of different sources and their derivatives represent a group of polymers
widely used in pharmaceutical dosage forms. Their major applications are:
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].
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.
For a number of reasons there has been an increase in interest in the development of new
excipients/diluents.
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].
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.
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.
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.
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].
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.
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.
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
Different pharmacopoeias, like USP, PhEur, and JP contain pharmacopoeial standards for
specific gums [26], as shown in Table 1.5.
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.
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].
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].
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].
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.
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.
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]:
12 – 16 good flow,
A similar index has been defined by Hausner (1967) by the equation [168]:
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.
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.
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].
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.
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].
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 /DtΠ
Π
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 / D2Π
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].
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
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)]
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
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