1.5 Formulation

Ø What will you gain? 1.5.1 Excipient and their functionalities 1.5.2 Diluents 1.5.3 Binders 1.5.4 Disintegrants 1.5.5 Antifrictional Agents 1.5.6 Miscellaneous Excipients

1.5.1 Excipient and their functionalities ^(13-15)

Excipient means any
component other than the active pharmaceutical ingredient(s) intentionally
added to the formulation of a dosage form. Many guidelines exist to aid in
selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS
(Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others.

While selecting excipients
for any formulation following things should be considered wherever possible:
keep the excipients to a minimum in number minimize the quantity of each
excipients and multifunctional excipients may be given preference over
unifunctional excipients.

Excipients play a crucial role in design of the
delivery system, determining its quality and performance. Excipients though
usually regarded as nontoxic there are examples of known excipient induced
toxicities which include renal failure and death from diethylene glycol,
osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from
lanolin and cardiotoxicity induced by propylene glycol.

Excipients are chosen in
tablet formulation to perform a variety of functions like

i) For providing essential manufacturing technology functions (binders, glidants,
lubricants may be added),

ii) For enhancing patient acceptance (flavors, colourants may be added),

iii) For providing aid in product identification (colourants may be added),

iv) For Optimizing or modifying drug release (disintegrants, hydrophilic polymers,
wetting agents, biodegradable polymers may be added),

v) For enhancing stability (antioxidant, UV absorbers may be added)

Various excipients used in tablet formulation and their functionalities.
^{(1, 4, 16)}

Table.2. Excipient With Their Functions In Tablet Formulation

EXCIPIENT	FUNCTION
Diluents or Fillers	Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size.
Binders or Granulating agents or Adhesives	Binders are added to tablet formulations to add cohesiveness to powders, thus providing the necessary bonding to form granules, which under compaction form a cohesive mass or a compact which is referred to as a tablet.
Disintegrants	A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment.
Antifrictional Agents
Lubricants	Lubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity.
Antiadherents	Antiadherents are added to reduce sticking or adhesion of any of the tablet granulation or powder to the faces of the punches or to the die wall.
Glidants	Glidants are intended to promote the flow of tablet granulation or powder mixture from hopper to the die cavity by reducing friction between the particles.
MISCELLANEOUS
Wetting agents	Wetting agents are added to tablet formulation to aid water uptake during disintegration and assist drug dissolution.
Dissolution retardants	Dissolution retardants as the name suggest, retards the dissolution of active pharmaceutical ingredient(s).
Dissolution enhancers	Dissolution enhancers as the name suggest, enhance the dissolution rate of active pharmaceutical ingredient(s).
Adsorbents	Adsorbents are capable of retaining large quantities of liquids without becoming wet; this property of absorbent allows many oils, fluid extracts and eutectic melts to be incorporated into tablets.
Buffers	Buffers are added to provide suitable micro environmental pH to get improved stability and / or bioavailability.
Antioxidants	Antioxidants are added to maintain product stability, they act by being preferentially oxidized and gradually consumed over shelf life of the product.
Chelating agents	Chelating agents are added to protect against autoxidation; they act by forming complexes with the heavy metal ions which are often required to initiate oxidative reactions.
Preservatives	Preservatives are added to tablet formulation in order to prevent the growth of micro-organisms.
Colours	Colours are added to tablet formulation for following purposes: to disguise off colour drugs, product identification and for production of more elegant product.
Flavours	Flavours are added to tablet formulation in order to make them palatable enough in case of chewable tablet by improving the taste.
Sweeteners	Sweeteners are added to tablet formulation to improve the taste of chewable tablets.

 

Ø Key Phrases Ø Tablet formulations are usually designed to satisfy following criteria- Patient acceptability; accuracy and uniformity of drug content; manufacturability; optimal drug dissolution and stability. Ø Excipients are any component other than active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Ø Excipients play a crucial role in design of the delivery system, determining its quality and performance. Ø Various excipients used in tablet formulation are diluents, binders, disintegrants, lubricants, antiadherents, glidants, wetting agents, dissolution retardants, dissolution enhancers, absorbents, buffers, antioxidants, chelating agents, preservatives, colours, flavours, sweeteners, etc.

1.5.2 Diluents (Fillers)

What will you gain? 1.5.2.1 Introduction 1.5.2.2 Classification of diluents 1.5.2.2.1 Organic diluents 1.5.2.2.2 Inorganic diluents 1.5.2.2.3 Co-processed diluents

1.5.2.1 Introduction ^{(1, 17)}

In order to facilitate tablet
handling during manufacture and to achieve targeted content uniformity, the
tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Many
potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such
cases diluents provide the required bulk of the tablet when the drug dosage
itself is inadequate to produce tablets of adequate weight and size. Usually
the range of diluent may vary from 5-80%. Diluents are also synonymously known
as fillers. Diluents are often added to tablet formulations for secondary
reasons like to provide better tablet properties such as:

i)To provide improved cohesion

ii)To allow direct compression manufacturing

iii)To enhance flow

iv)To adjust weight of tablet
as per die capacity

No matter for what purpose they (diluents) are added
they must meet certain basic criteria for satisfactory performance in tablet
dosage form. They are as follows:
Diluent should not react with the drug substance and moreover it should
not have any effect on the functions of other excipients, it should not have
any physiological or pharmacological activity of its own, it should have
consistent physical and chemical characteristics, it should neither promote nor
contribute to segregation of the granulation or powder blend to which they are
added, it should be able to be milled (size reduced) if necessary in order to
match the particle size distribution of the active pharmaceutical ingredient,
it should neither support microbiological growth in the dosage form nor
contribute to any microbiological load, it should neither adversely affect the
dissolution of the product nor interfere with the bioavailability of active
pharmaceutical ingredient, it should preferably be colourless or nearly so.

1.5.2.2 Classification of diluents ^(16,17)

Tablet
diluents or fillers can be divided into following categories:

i)Organic materials - Carbohydrate and modified carbohydrates.

ii)Inorganic materials – Calcium phosphates and others.

iii)Co-processed Diluents.

Carbohydrate substances such as sugars, starches and celluloses may also function
as binders during wet granulation process. Whereas when used in direct compression
system, they serve as the diluent. The inorganic diluents, do not exhibit binding
properties when used in wet granulation and direct compression.

Tablet diluent or filler
may also be classified on the basis of their solubility in water as soluble and
insoluble.

Table.3. Classification Of Diluents Based On Their Solubility

INSOLUBLE TABLET FILLERS OR DILUENTS	SOLUBLE TABLET FILLERS OR DILUENTS
Starch Powdered cellulose Microcrystalline cellulose Calcium phosphates, etc.	Lactose Sucrose Mannitol Sorbitol, etc.

Selection of diluent should
be done after considering properties of diluent such as: Compactibility,
flowability, solubility, disintegration qualities, hygroscopicity, lubricity
and stability.

1.5.2.2.1 Organic diluents ^(1,17-20)

Carbohydrates

Sugar and Sugar
alcohols

Lactose α-lactose
monohydrate, spray dried lactose and anhydrous lactose are widely used as
diluent.

Characteristics of α -Lactose monohydrate (hydrous)

Lactose monohydrate is not directly compressible and therefore it is suitable for use in wet granulation. It has poor flow properties. α-lactose monohydrate is water soluble. It produces a hard tablet and the tablet hardness increases on storage. Disintegrant is usually needed in lactose containing tablets. Drug release rate is usually not affected. It is usually unreactive, except for discoloration when formulated with amines and alkaline materials (i.e. browning or maillard reaction). It contains approximately 5% moisture and hence is a potential source of instability especially with moisture sensitive drugs. It is inexpensive. It is commercially available under the trade name of: PharmatoseÒ and Respitose® manufactured by DMV International.

Characteristics of Lactose spray dried

It is directly compressible diluent. It exhibits free flowing characteristics. It needs high compression pressures in order to produce hard tablets. Its compressibility is adversely affected if dried below 3% moisture. It has high dilution potential. It is more prone to darkening in the presence of excess moisture, amines and other compounds due to the presence of a furaldehyde. Usually, neutral or acid lubricant should be used when spray dried lactose is employed. Expensive compared to anhydrous and hydrous lactose. It is commercially available as Spray Process 315® manufactured by Foremost Farms USA.

Characteristics of Lactose anhydrous

Lactose anhydrous is a directly compressible diluent. It does not exhibit free flowing property. It can pick up moisture at elevated humidity as a result of which changes in tablet dimensions may occur. It does not undergo a maillard reaction to the extent shown by spray dried lactose, although this may occur in some cases to a slight degree. It is inexpensive. It is commercially available as Pharmatose® DCL 21 manufactured by DMV Pharma.

Starch

Characteristics of Compressible Starch (Pregelatinized)

It is a directly compressible diluent. It has better flow compared to unmodified starch. It also shows high compressibility as the aggregated granules undergo plastic deformation on compression. It possesses good binding properties. It also possesses disintegrant activity. It requires high pressure in order to produce a hard tablet. For good flow, it requires a flow promoter. It is prone to softening when combined with large amounts of magnesium stearate. It is commercially available under the trade name of Starch 1500 LMÒ manufactured by Colorcon.

Sucrose

Characteristics of Sucrose or sugar

It requires high machine pressures, especially in cases with over wetted granulations. It is water soluble. It possesses good binding properties. It is slightly hygroscopic. It is inexpensive. It produces gritty mouth feel (i.e., it is not free from grittiness). It is a calorie contributor and is cariogenic.

Mannitol

Characteristics of Mannitol

Mannitol a sugar alcohol is an optical isomer of Sorbitol. It exhibits poor flow properties. It requires high lubricant content. It is probably the most expensive sugar used as a tablet diluent and is water soluble. It is widely used in chewable tablets because of its negative heat of solution, its slow solubility and its mild cooling sensation in mouth. It can be used in vitamin formulation, where moisture sensitivity may create a problem. It is comparatively non hygroscopic. It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available under the brand name ParteckÒM manufactured by EMD Chemicals .Other commercial products are PearlitolÒ and MannogemÒ.

Sorbitol

Characteristics of Sorbitol

Sorbitol is often combined with mannitol formulations in order to reduce diluent cost. It is highly compressible diluent and is water soluble. It is hygroscopic in nature. It has good mouth feel and sweet cooling taste. It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available as SorbifinÒ and NeosorbÒ .

Poorly
absorbed sugar alcohols such as Sorbitol and mannitol can decrease small
intestinal transit time. Therefore absorption may be altered for the drugs that
are preferentially absorbed from this region.

Celluloses ^(1,17,
21)

Powdered
cellulose

Characteristics of Powdered cellulose

Powdered cellulose products consist of finely divided amorphous and crystalline α-cellulose particles. Powdered cellulose may be used alone or together with other fillers such as lactose, calcium phosphates, dextrans and others. It possesses poor compressibility and exhibits poor flow properties. It has poor binding properties and low dilution potential. It is water insoluble. It possesses some degree of inherent lubricity. It is inexpensive. It is commercially available under the trade name of ElcemaÒG-250 manufactured by Degussa Corporation.

Microcrystalline
cellulose

Characteristics of Microcrystalline cellulose

Microcrystalline cellulose (MCC) is highly compressible and is perhaps the most widely used direct-compression tablet diluent. Hard tablets, at low compression pressures, are usually obtained when MCC is used as tablet diluent. It undergoes plastic deformation on compression and hence it is more sensitive to lubricants. It exhibits fair flowability. It exhibits binding properties. It also possesses disintegrant activity and thus promotes fast tablet disintegration. It is water insoluble. MCC is expensive. Silicified MCC (SMCC- ProsolvÒ) provides increased compactibility, enhanced flow and improved uniformity compared to MCC (AvicelÒ manufactured by FMC Biopolymer) SMCC is more suitable for cohesive poorly compressible ingredients in direct compression formulation. Other commercial product is EmcocelÒ manufactured by Penwest Pharmaceutical Co.

1.5.2.2.2 Inorganic diluents ^(17,22)

Calcium phosphates

The calcium phosphates, here includes, the dihydrate
and anhydrous form of dibasic calcium phosphate and tribasic calcium phosphate.
They are granular insoluble materials.
They are widely used both as wet granulation and direct compression
diluents in tablet formulation. Bulk density of calcium phosphates is higher
than that of organic fillers. They are used extensively in vitamin and mineral
preparations. Dibasic calcium phosphate dihydrate is also commonly known as
dicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calcium
phosphate dihydrate.

Dibasic calcium phosphate is available commercially
under the trade name Di-Tab^Ò (manufactured by Rhone-Poulenc) and Emcompress^Ò (Manufactured by E.Mendell
Co.).An anhydrous form of dibasic calcium phosphate is available commercially
under the trade name A-Tab^Ò (manufactured by Rhone-Poulenc). Fujicalin^®,
a novel commercially available free flowing spherically granulated dicalcium
phosphate anhydrous (SGDCPA) for direct tableting was compared with directly
compressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPA
exhibited same good flowability and better compactibility. Whereas in contrast
to DCPD, SGDCPA exhibited significant uptake of moisture when exposed to
relative humidity exceeding 70 %.Tribasic calcium phosphate is also commonly
referred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite.
Tribasic calcium phosphate is available under the trade name Tri-Tab^Ò.

Characteristic of Calcium Phosphates

They are directly compressible and are characterized by brittle fracture on compression during tableting process. Hard tablets are produced when calcium phosphates are used as diluents. They exhibit good flow properties. They are non hygroscopic. They are inexpensive. They are abrasive in nature and hence can cause wear of tablet tooling. Sometimes their alkalinity is a major source of drug instability.

1.5.2.2.3 Co-processed diluents ^(17,23)

Co-processing means combining two or more materials
by an appropriate process. The products so formed are physically modified in
such a special way that they do not loose their chemical structure and
stability. Now a days direct compression technique has been one of the
well-accepted methods of tablet manufacture. An extensive range of materials from
various sources have been developed and marketed as directly compressible
diluents such as lactose, starch, cellulose derivatives, inorganic substance,
polyalcohols, and sugar-based materials. In addition to the development of
directly compressible excipients by modifying just a single substance,
co-processing of two or more components has been applied to produce composite
particles or co-processed excipients. The composite particles or co-processed
excipients are introduced in order to provide better tableting properties than
a single substance or the physical mixture.

Table.4. List Of Co-Processed Excipients Used To Achieve
Better Tableting Properties

TRADE NAME	MANUFACTURER	DESCRIPTION
Fast Flo lactose®	Foremost Whey Products	It is spray processed lactose which is a mixture of crystalline α-lactose monohydrate and amorphous lactose.
Microcellac®		75% lactose and 25% MCC (MicroCrystalline Cellulose)
Ludipress®		93% α-lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone.
Nu-Tab®	Ingredient Technology	Sucrose 95-97%, invert sugar 3-4% and magnesium stearate 0.5%
Di-Pac®	Amstar Corp.	Sucrose 97% and modified dextrins 3%
Sugartab®	E.Mendell Co. Inc.	Sucrose 90-93% and invert sugar 7-10%.
Emdex®	E.Mendell Co. Inc.	Dextrose 93-99% and maltose 1-7%
Cal-Tab®	Ingredient Technology	Calcium sulfate 93% and vegetable gum 7%
Cal-Carb®	Ingredient Technology	Calcium carbonate 95% and maltodextrins 5%
Calcium 90®	Ingredient Technology	Calcium carbonate (minimum) 90% and Starch, NF (maximum) 9%

Key Phrases Ø Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Ø Diluents are often added to tablet formulations for secondary reasons like to provide better tableting properties. Ø Tablet diluents or fillers can be divided into following categories: i) Organic materials ii) Inorganic materials iii) Co-processed diluents Ø Tablet diluents or fillers may also be classified on the basis of their solubility in water as soluble diluent and insoluble diluent. Ø Microcrystalline cellulose (MCC) is perhaps the most widely used direct-compression tablet filler. Ø Co-processing means combining two or more materials by an appropriate process. Ø The composite particles or co-processed excipients are introduced to provide better tableting properties than a single substance or the physical mixture.

1.5.3 Binders ( Adhesives, Granulating agent)

What will you gain? 1.5.3.1 Why to go for Granulation? 1.5.3.2 Granulation Processes 1.5.3.3 Types of Binders 1.5.3.4 Direct compression (DC) Binders 1.5.3.5 Mechanism of granule formation 1.5.3.6 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement 1.5.3.7 Factors to be considered in Granulation 1.5.3.8 Evaluation tests for Binders/Granules

Binder is one of
an important excipient
to be added
in tablet formulation.
In simpler words, binders or
adhesives are the
substances that promotes
cohesiveness. It is utilized
for converting powder
into granules through
a process known
as Granulation. Granulation
is the unit
operation by which
small powdery particles
are agglomerated into
larger entities called
granules.

1.5.3.1 Why to go for Granulation? ⁽²⁴⁾

Powders/Granules intended for compression into tablets must possess
two essential properties : flow property and compressibility.

Flow
property/Fluidity is required
to produce tablets
of a consistent
weight and uniform
strength. Compressibility is required
to form a
stable, intact compact mass
when pressure is
applied. These two objectives
are obtained by
adding binder to
tablet formulation and
then proceeding for
granulation process. Granules so
formed should possess acceptable flow property and compressibility. Some
drugs exhibit poor fluidity and
compressibility. In such
cases binders have
to be added
for improving flow
property and compressibility.

Other reasons for
Granulation process are to improve
appearance, mixing properties,
to avoid
dustiness, to densify material, to
reduce segregation, in general
to either eliminate
undesirable properties or to improve
the physical and
chemical properties of
fine powders.

1.5.3.2 Granulation Processes ⁽²⁴⁾

The standard methods frequently used today in tablet manufacturing
are granulation and direct compression. Granulation technique includes
wet granulation and dry granulation/slugging methods wherein binders
are added in solution/suspension form and in dry form respectively.
In Direct Compression, binders possessing direct compressibility characteristics
are used. Binder when used in liquid form gives better binding action
as compared to when used in dry form.

1.5.3.3 Types of Binders ^(18,25-28)

Table.5. Classification Of Binders

Sugars	Natural  Binders	Synthetic/Semisynthetic  Polymer
Sucrose	Acacia	Methyl Cellulose
Liquid glucose	Tragacanth	Ethyl Cellulose
	Gelatin	Hydroxy Propyl Methyl Cellulose ( HPMC)
	Starch Paste	Hydroxy Propyl Cellulose
	Pregelatinized Starch	Sodium Carboxy Methyl Cellulose
	Alginic Acid	Polyvinyl Pyrrolidone (PVP)
	Cellulose	Polyethylene Glycol (PEG)
		Polyvinyl Alcohols
		Polymethacrylates

Table.6. Commonly Used Binders

BINDER	CATEGORY	MANUFACTURER
Starch 1500Ò	Partially Pregelatinized Maize Starch	Colorcon
MethocelÒ	Hydroxy Propyl Methyl Cellulose	Dow Chemicals
WalocelÒHM	Hydroxy Propyl Methyl Cellulose	Wolff-Cellulosics Natural Starch and Chemical Company
LuvitecÒ	Polyvinylpyrrolidone	BASF Company
LuvicrossÒ	Polyvinylpyrrolidone	BASF Company
LuvicaprolactamÒ	Polyvinylcaprolactam	BASF Company

Table.7. Characteristics Of Commonly Used Binder

BINDER	SPECIFIED CONCENTRATION	COMMENTS
Starch Paste	5-25%w/w	- Freshly prepared starch paste is used as a binder. - Its method of preparation is very crucial.
Pregelatinized Starch (PGS) [Partially and Fully PGS]	5-10%w/w (Direct Compression) 5-75%w/w (Wet Granulation )	- It is starch that have been processed chemically and/or mechanically to rupture all or part of the granules in the presence of water and subsequently dried. - It contains 5% free amylose, 15% free amylopectin and 80% unmodified starch. - Obtained from maize, potato or rice starch. - It is multifunctional excipient used as a tablet binder, diluent, disintegrant and flow aid. - They enhance both flow and compressibility and can be used as binders in Direct Compression as well as Wet Granulation. - High purity PGS allow simplified processing as they swell in cold water and therefore reduce time/costs compared with traditional starch paste preparation.
Hydroxypropyl Methyl Cellulose (HPMC)	2-5%w/w	- Comparable to Methyl Cellulose. - Used as a binder in either wet or dry granulation processes.
Polyvinyl Pyrrolidone (PVP)	0.5-5%w/w	- Soluble in both water and alcohol. - Used in wet granulation process. - It is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol or hydroalcoholic solution. - Valuable binder for chewable tablets. - The drug release is not altered on storage.
Polyethylene Glycol (PEG) 6000	10-15%w/w	- Used as a meltable binder. - Anhydrous granulating agent where water or alcohol cannot be used . - It may prolong disintegration time when concentration is 5% or higher - It improves the plasticity of other binders.

1.5.3.4 Direct compression (DC) Binders ⁽²⁹⁾

Due
to ease of manufacture, product stability and high efficiency, the use of
Direct Compression for tableting has increased. For Direct Compression,
directly compressible binders are required which should exhibit adequate powder
compressibility and flowability. Direct Compression binders should be selected
on the basis of compression behavior, volume reduction under applied pressure
and flow behavior in order to have optimum binding performance. The choice and
selection of binders is extremely critical for Direct Compression tablets.

Table.8. Commonly Used Dc Binders

Dc  Binder	Class	Manufacturer
AvicelÒ (PH 101)	MCCa	FMC Corporation
SMCCÒ (50)	SMCCb	Penwest Pharmaceutical
UNI-PUREÒ(DW)	Partially PGSc	National Starch & Chemical
UNI-PUREÒ (LD)	Low density starch	National Starch & Chemica
DC LactoseÒ	DC lactose anhydrous	Quest International Group
DI TABÒ	DC-DCPDd	Rhodi

a
– Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c –
Pregelatinized Starch, d – Dibasic Calcium Phosphate Dihydrate

Table.9. Characteristics Of Dc Binders

Flow Behavior	DI TABÒ> SMCCÒ(50) > DC LactoseÒ , UNI PUREÒ(DW) > AvicelÒ (PH 101) > UNI PUREÒ(LD)
Compressibility	UNI PUREÒ(LD) > SMCCÒ(50) , AvicelÒ(PH 101) > UNI PUREÒ(DW) , DC LactoseÒ > DI TABÒ
Crushing Strength	UNI PUREÒ(LD) > SMCCÒ(50) > UNI PUREÒ(DW) > AvicelÒ(PH 101) > DC LactoseÒ > DI TABÒ

1.5.3.5 Mechanism of
granule formation ⁽³⁰⁾

Granules
are formed in three stages:

Nucleation:
Here, the particles adhere due to
liquid bridges which are the initiation step of Granulation. These adhered
particles play a role of nucleus for further enlargement of granules.

Transition: Enlargement of nucleus takes place by two possible
mechanisms. Individual particle adhere to the nucleus or two or more nuclei
combine among themselves.

Ball growth or enlargement of the
granule:
Ball growth occurs either by Coalescence or Breakage or Abrasion Transfer or
Layering. In Coalescence a larger granule is formed when two or more granules
are united. In Breakage granules break and the fragments of granule adhere to
other granules. This forms a layer of material over intact granules. In
Abrasion Transfer granule material are abraded through attrition by the
agitation of granule bed and abraded material adheres to other granules
resulting into enlarged granules. In layering particles adheres to the already
formed granules increasing their size.

1.5.3.6
Near Infrared (NIR)
spectroscopy : A tool for
granulation end point
measurement ⁽³¹⁾

NIR Spectroscopy is applicable for
monitoring of wet granulation process when impeller torque method cannot be
applied. Watano et al determined the granulation end point using agitated
fluidized bed where in IR moisture sensor was installed. The properties of the
wet mass obtained from NIR are independent of granulator equipment variables
such as impeller design. Even the powder blending efficiency in the dry mixing
phase can be monitored inline by NIR. NIR spectroscopy could be an excellent
tool in wet granulation measurement.

1.5.3.7 Factors to be considered in Granulation ^(24,30,32)

Compatibility

The primary criteria is the compatibility of binder with the
API & other tablet components. This is traditionally found by
choosing appropriate stability study design. Currently Differential Scanning
Calorimetry (DSC) is used to ascertain compatibility.

Characteristics of
drugs and other excipients

The drugs characteristics like its
compressibility, particle size,
surface area, porosity,
hydrophobicity, solubility in
binder are important
while fixing a
granulation process. The
drug that exhibits
poor compressibility requires
the use of
a strong binder (liquid glucose, sucrose, etc.) while
the drugs that
exhibit good compressibility can
be successfully handled
using a weak
binder ( starch paste etc.,).
Fine and porous
particles requires higher
amount of liquid
binder as compared
to coarse particles. Hydrophilic drug/excipients exhibiting
absorption characteristics require
higher volume of
binder as compared
to hydrophobic drug/excipients. The granule
quality (size , friability) is
governed by the
solubility of the
drug in the
granulation solution.

Spreading of Binder

Spreading
of binder/granulation solution
on the powder
blend is of
paramount importance in
successful granulation. A binder
that spreads easily
on particles is
superior as compared
to that which
shows poor wetting
quality. HPMC is a
superior binder for
paracetamol as compared
to PVP.

Type and quantity of
Binder

The uniformity
of the particle
size, hardness, disintegration
and compressibility of
the granulation depends on type
and quantity of binder added to formulation. As for example hard granulations
results due to stronger binder or a highly concentrated binder solution which
require excessive compression force during tableting. On the
other hand, fragile granulations
results due to insufficient quantity
of binder which
segregates easily. Larger quantities
of granulating liquid
produce a narrower
particle size range
and coarser and
hard granules i.e.
The proportion of fine granulates particle decreases. Therefore the
optimum quantity of
liquid needed to
get a given
particle size should
be known in
order to keep
a batch to batch variations
to a minimum.

Temperature and
Viscosity

The temperature and viscosity of binder is also
important. Fluid (less viscous) binder exhibit good spreading behavior.

Method of Addition of
Binder

The
method of addition of binder is also important. PVP can
be used as
solution as a
binder or it
may be dry
blended with powders
and later activated
by adding water. Distribution of
binder is favored
if it is
dispersed instead of
pouring it.

Mixing Time

The mixing time also determines quality of
granules. If the wet
massing time is
higher (resulting into hard
granules), the tablets may
fail the dissolution
test in certain
cases since drug
release from hard
granules is altered.

Material of
Construction of Granulator

The
material of construction
of granulator determines
the volume of
binder required as
well as granule
size distribution. Any
vessel wall which
are wetted easily
by binder demands
the need of
higher volume of
binder. As for example
vessel wall made
up of Stainless Steel
require higher volume
of binder as
compared to vessel
made up of
plastics (PMMA – Polymethylmethacrylate
and PTFE –
Polytetrafluoroethylene i.e. Teflon).
In case of
PMMA and PTFE
due to high
contact angle, all
granulating liquid is
forced immediately into
the powder bed
and gives narrow
particle size distribution.
While in case
of steel, due to
less contact angle
liquid layer formed
on the wall
surface which in
turn causes inhomogeneous
distribution of liquid
over the powder
bed resulting into broader
granule size.

Type of Granulator

Fluidized
Bed Granulator produces
porous granules as
compared to High
Shear Granulators.

Process Variables

Higher
degree of densification
of the granules results due to higher impeller
speed as well
as longer wet
massing time. And also there is
tendency of agglomeration since liquid saturation increases. Consequently,
impeller speed and wet massing time affect the granule size.

Apparatus Variables

The
apparatus variables in
High Shear Mixer
have a larger
effect on granule
growth than in
Fluidized Bed Granulators
because the shear
forces are dependent
on the mixer
construction. The size and
shape of the
mixing chamber, impeller and
chopper vary in
different High Shear
Mixers.

Impeller Movement

Adhesion
of wetted mass to the vessel is less if impeller movement is helical. This
gives a narrower granule size and few lumps. In case of High Shear Mixers,
adhesion of wetted mass to the vessel is a problem which can be reduced by
proper construction of the impeller or by coating the vessel with
Polytetrafluoroethylene i.e. Teflon.

1.5.3.8 Evaluation
tests for Binders/Granules ⁽¹⁾

Compactness, physical and chemical stability,
rapid production capability, efficacy are some of the characteristics that make
tablet a ruling dosage form. These characteristics depend on the quality of
granules from which it is made. The characteristics of granules produced are
affected by formulation and process variables. So it becomes essential to
evaluate the granule characteristics to monitor its suitability for tableting.

Particle Size and Particle
Size Distribution

The particle size
of granules affect
the average tablet
weight, tablet weight variation, disintegration time,
granule friability,
granulation flowability and
the drying rate
kinetics of wet
granulations. Therefore the effects
of granule size
and size distribution
on the quality of tablet should
be determined by formulator. The
methods usually adopted
for measurement of
particle size and
particle size distribution
includes Microscopy, Sieving, Conductivity test.

Surface Area

Surface
area of the
drug effects upon
dissolution rate especially
in cases where
drug have limited
water solubility. The
two most common
methods for surface
area determination are Gas
Adsorption and Air
Permeability.

Density

Granule
density, True Density, Bulk Density
may influence compressibility, tablet porosity, flow property, dissolution and
other properties. Higher compression
load is required in case of dense and hard granules which in turn increases the
tablet disintegration and
drug dissolution times.
Density is usually determined by pycnometer.

% Compressibility

Compressibility is
the ability of
powder to decrease
in volume under pressure. Compressibility is a measure that is
obtained from density determinations.

% Compressibility =
(Tapped density – Bulk density/Tapped density)*100

Compressibility measures
gives idea about
flow property of
the granules as
per CARR’S Index
which is as
follows :

Table.10. Carr’s Index

% Compressibility	Flow  Description
5 – 15	Excellent
12 – 16	Good
18 – 21	Fair
23 – 28	Poor
28 – 35	Poor
35 – 38	Very Poor
> 40	Extremely Poor

Flow Properties

It is very
important parameter to be measured
since it affects
the mass of
uniformity of the
dose. It is
usually predicted from
Hausner Ratio and
Angle Of Repose
Measurement.

Hausner Ratio = Tapped
Density / Bulk Density

Table.11. Hausner Ratio

HAUSNER RATIO	TYPE OF FLOW
Less than 1.25	Good Flow
1.25 – 1.5	Moderate
More than 1.5	Poor Flow

Angle of Repose (Φ) is the
maximum angle between
the surface of
a pile of
powder and horizontal
plane. It is
usually determined by
Fixed Funnel Method
and is the
measure of the
flowability of powder/granules.

Φ = tan^-1
(h / r) where, h = height of heap of pile

r = radius of base of pile

Table.12.Angle Of Repose (Φ)

ANGLE OF REPOSE	TYPE OF FLOW
< 25	Excellent
25 – 30	Good
30 – 40	Passable
> 40	Very Poor

Friability

Friability
is important since
it affects in
particle size distribution
of granules affecting compressibility into
tablet, tablet weight variation,
granule flowability. Friability is
determined carrying out
Tumbler Test or
using Friability Tester
( Roche Friabilator ) and
% loss is
determined.

Moisture Content

It affects the granule flowability,
compressibility as well as the stability of moisture sensitive drug and
therefore should be determined to evaluate the quality of granule.

Key Phrases ØBinders are added in tablet formulation to have required flow property and compressibility of powders. ØWet Granulation, Dry Granulation/Slugging, Direct Compression are major granule manufacturing methods. ØDirect Compression Binders are more efficient than conventional binders. ØPregelatinized Starch is used as multifunctional excipient: tablet binder (wet granulating agent as well as direct compression binder), diluent, disintegrant and flow aid. ØPolyethylene Glycol used as meltable binder. ØGranules are formed in three stages: Nucleation, Transition and Ball Growth. ØNIR a tool for granulation end point measurement and is better than torque impeller method. ØCompatibility of binder with API and other excipients, characteristics of binder, process variables, and apparatus variables affects the quality of granules. ØGranules have to be evaluated in order to measure its suitability for tableting.

1.5.4
Disintegrants

What will you gain?

1.5.4.1
Introduction

1.5.4.2
Mechanism of tablet disintegrants

1.5.4.3
Methods of addition of disintegrants

1.5.4.4
Types of disintegrants

1.5.4.5
Factors affecting disintegration

1.5.4.1 Introduction

Bioavailability
of a drug depends in absorption of the drug, which is affected by solubility of
the drug in gastrointestinal fluid and permeability of the drug across
gastrointestinal membrane. The drugs solubility mainly depends on physical –
chemical characteristics of the drug. However, the rate of drug dissolution is
greatly influenced by disintegration of the tablet.

The
drug will dissolve at a slower rate from a nondisintegrating tablet due to
exposure of limited surface area to the fluid. The disintegration test is an
official test and hence a batch of tablet must meet the stated requirements of
disintegration.

Disintegrants, an important excipient of the
tablet formulation, are always added to tablet to induce breakup of tablet when
it comes in contact with aqueous fluid and this process of desegregation of
constituent particles before the drug dissolution occurs, is known as
disintegration process and excipients which induce this process are known as
disintegrants.

The objectives behind addition of
disintegrants are to increase surface area of the tablet fragments and to
overcome cohesive forces that keep particles together in a tablet.

Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent Drug Dissolution

1.5.4.2 Mechanism of tablet disintegrants ^{(16,29,33-39)}

The tablet breaks to primary particles by
one or more of the mechanisms listed below:-

I.By capillary action

II.By swelling

III.Because of
heat of wetting

IV.Due to disintegrating particle/particle repulsive forces

V.Due to
deformation

VI.Due to
release of gases

VII.By enzymatic
action

By Capillary Action

Disintegration by capillary action
is always the first step. When we
put the tablet into suitable aqueous medium, the medium penetrates into the
tablet and replaces the air adsorbed on the particles, which weakens the
intermolecular bond and breaks the tablet into fine particles. Water uptake by
tablet depends upon hydrophilicity of the drug /excipient and on tableting
conditions. For these types of
disintegrants maintenance of porous structure and low interfacial tension
towards aqueous fluid is necessary which helps in disintegration by creating a
hydrophilic network around the drug particles.

By Swelling

Perhaps the most widely accepted general mechanism of
action for tablet disintegration is swelling Tablets with high porosity show
poor disintegration due to lack of adequate swelling force. On the other hand,
sufficient swelling force is exerted in the tablet with low porosity. It is
worthwhile to note that if the packing fraction is very high, fluid is unable
to penetrate in the tablet and disintegration is again slows down.

Figure.17. Disintegration Of Tablet By Wicking And Swelling

Because of heat of wetting (air expansion)

When
disintegrants with exothermic properties gets wetted, localized stress is
generated due to capillary air expansion, which helps in disintegration of
tablet. This explanation, however, is limited to only a few types of
disintegrants and can not describe the action of most modern disintegrating
agents.

Due to disintegrating particle/particle repulsive
forces

Another
mechanism of disintegration attempts to explain the swelling of tablet made
with ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particle
repulsion theory based on the observation that nonswelling particle also cause
disintegration of tablets. the
electric repulsive forces between particles are the mechanism of disintegration
and water is required for it. Researchers found that repulsion is secondary to
wicking.

Due to deformation

Hess
had proved that during tablet compression, disintegranted particles get
deformed and these deformed particles get into their normal structure when they
come in contact with aqueous media or water. Occasionally, the swelling
capacity of starch was improved when granules were extensively deformed during
compression. This increase in size of the deformed particles produces a break
up of the tablet. This may be a mechanism of starch and has only recently begun
to be studied

Figure.18. Disintegration By Deformation And Repulsion

Due to release of gases

Carbon
dioxide released within tablets on wetting due to interaction between
bicarbonate and carbonate with citric acid or tartaric acid. The tablet
disintegrates due to generation of pressure within the tablet. This
effervescent mixture is used when pharmacist needs to formulate very rapidly
dissolving tablets or fast disintegrating tablet. As these disintegrants are
highly sensitive to small changes in humidity level and temperature, strict
control of environment is required during manufacturing of the tablets. The
effervescent blend is either added immediately prior to compression or can be
added in to two separate fraction of formulation.

By enzymatic reaction

Here,
enzymes presents in the body act as disintegrants. These enzymes destroy the
binding action of binder and helps in disintegration

Table.13. Disintegrating Enzymes

ENZYMES	BINDER
Amylase	Starch
Protease	Gelatin
Cellulase	Cellulose and it’s derivatives
Invertase	Sucrose

1.5.4.3 Methods of addition of disintegrants

The method of
addition of disintegrants is also a crucial part. Disintegrating agent can be
added either prior to granulation (intragranular) or prior to compression
(after granulation i.e. extragranular) or at the both processing steps.
Extragranular fraction of disintegrant (usually, 50% of total disintegrant
requires) facilitates breakup of tablets to granules and the intragranular
addition of disintegrants produces further erosion of the granules to fine
particles.

1.5.4.4 Types of
disintegrants ^(34,40-42)

Starch

Starch
was the first disintegrating agent widely used in tablet manufacturing. Before
1906 potato starch and corn starch were used as disintegrants in tablet
formulation. However, native starches have certain limitations and have been
replaced by certain modified starches with specialized characteristics.

The mechanism of action of starch is wicking
and restoration of deformed starch particles on contact with aqueous fluid and
in doing so release of certain amount of stress which is responsible for
disruption of hydrogen bonding formed during compression.

Lowenthal
& Wood proved that the rupture of the surface of a tablet employing starch
as disintegrant occurs where starch agglomerates were found. The conditions
best suited for rapid tablet disintegration are sufficient number of starch
agglomerates, low compressive pressure and the presence of water.

The
concentration of starch used is also very crucial part. If it is below the
optimum concentration then there are insufficient channels for capillary action
and if it is above optimum concentration then it will be difficult to compress
the tablet.

Pregelatinized starch

Pregelatinized
starch is produced by the hydrolyzing and rupturing of the starch grain. It is
a directly compressible disintegrants and its optimum concentration is 5-10%.
The main mechanism of action of Pregelatinized starch is through swelling.

Modified starch

To
have a high swelling properties and faster disintegration, starch is modified
by carboxy methylation followed by cross linking, which is available in market
as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low
substituted carboxymethyl starches are also marketed as Explotab^Ò and Primojel^®.

Mechanism
of action of this modified starches are rapid and extensive swelling with
minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its
limit, then it produces viscous and gelatinous mass which increases the
disintegration time by resisting the breakup of tablet. They are highly
efficient at low concentration because of their greater swelling capacity.

Table.14. List Of Disintegrants

DISINTEGRANTS	CONCENTRATION IN GRANULES (%W/W)	SPECIAL COMMENTS
Starch USP	5-20	Higher amount is required, poorly compressible
Starch 1500	5-15	-
Avicel®(PH 101, PH 102)	10-20	Lubricant properties and directly compressible
Solka floc®	5-15	Purified wood cellulose
Alginic acid	1-5	Acts by swelling
Na alginate	2.5-10	Acts by swelling
Explotab®	2-8	Sodium starch glycolate, superdisintegrant.
Polyplasdone®(XL)	0.5-5	Crosslinked PVP
Amberlite® (IPR 88)	0.5-5	Ion exchange resin
Methyl cellulose, Na CMC, HPMC	5-10	-
AC-Di-Sol®	1-3	Direct compression
	2-4	Wet granulation
Carbon dioxide	_	Created insitu in effervescent tablet

Cellulose and its
derivatives

Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic
structure and is soluble in water. But when it is modified by internally
crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium
which is nearly water insoluble due to cross linking. It rapidly swells to 4-8
times its original volume when it comes in contact with water.

Microcrystalline cellulose (MCC)

MCC exhibit very good disintegrating properties because MCC is insoluble and act by
wicking action. The moisture breaks the hydrogen bonding between adjacent
bundles of MCC. It also serves as an excellent binder and has a tendency to
develop static charges in the presence of excessive moisture content.
Therefore, sometimes it causes separation in granulation. This can be partially
overcome by drying the cellulose to remove the moisture.

Alginates

Alginates
are hydrophilic colloidal substances which has high sorption capacity.
Chemically, they are alginic acid and salts of alginic acid. Alginic acid is
insoluble in water, slightly acidic in reaction. Hence, it should be used in
only acidic or neutral granulation. Unlike starch and MCC, alginates do not
retard flow and can be successfully used with ascorbic acid, multivitamin
formulations and acid salts of organic bases.

Ion-exchange resin

Ion
exchange resin (Ambrelite^Ò IPR-88) has highest water uptake capacity than other
disintegrating agents like starch and Sodium CMC. It has tendency to adsorb
certain drugs.

Miscellaneous

This
miscellaneous category includes disintegrants like surfactants, gas producing
disintegrants and hydrous aluminium silicate. Gas
producing disintegrating agents is used in soluble tablet, dispersible
tablet and effervescent tablet.

Polyplasdone^ÒXL and Polyplasdone^ÒXL10 act by wicking, swelling and possibly some
deformation recovery. Polyplasdone^®XL do not reduce tablet hardness,
provide rapid disintegration and improved dissolution. Polyplasdone^®
as disintegrating agent has small particle size distribution that impart a
smooth mouth feel to dissolve quickly. Chewable tablet does not require
addition of disintegrant.

Superdisintegrants

As day’s passes, demand for faster disintegrating formulation is increased. So,
pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low
concentration and have greater disintegrating efficiency and they are more
effective intragranularly. But have one drawback that it is hygroscopic
therefore not used with moisture sensitive drugs.

And this superdisintegrants act by swelling and due to swelling pressure exerted in
the outer direction or radial direction, it causes tablet to burst or the
accelerated absorption of water leading to an enormous increase in the volume
of granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling

Table.15. List Of Superdisintegrants

SUPERDISINTEGRANTS	EXAMPLE OF	MECHANISM OF ACTION	SPECIAL COMMENT
Crosscarmellose®   Ac-Di-Sol®   Nymce ZSX® Primellose® Solutab®   Vivasol®	Crosslinked cellulose	-Swells 4-8 folds in < 10 seconds. -Swelling and wicking both.	-Swells in two dimensions. -Direct compression or granulation       -Starch free
Crosspovidone Crosspovidon M® Kollidon® Polyplasdone®	Crosslinked PVP	-Swells very little and returns to original size after compression but act by capillary action	-Water insoluble and spongy in nature so get porous tablet
Sodium starch glycolate Explotab® Primogel®	Crosslinked starch	-Swells 7-12 folds in <30 seconds	-Swells in three dimensions and high level serve as sustain release matrix
Alginic acid NF Satialgine®	Crosslinked alginic acid	-Rapid swelling in aqueous medium or wicking action	-Promote disintegration in both dry or wet granulation
Soy polysaccharides Emcosoy®	Natural super disintegrant		-Does not contain any starch or sugar. Used in nutritional products.
Calcium silicate		-Wicking action	-Highly porous, -light weight -optimum concentration is between 20-40%

1.5.4.5 Factors affecting
disintegration

Effect of fillers ^(43,44)

The
solubility and compression characteristics of fillers affect both rate and mechanism
of disintegration of tablet. If soluble fillers are used then it may cause
increase in viscosity of the penetrating fluid which tends to reduce
effectiveness of strongly swelling disintegrating agents and as they are water
soluble, they are likely to dissolve rather than disintegrate. Insoluble
diluents produce rapid disintegration with adequate amount of disintegrants.

Chebli
and cartilier proved that tablets made with spray dried lactose (water soluble
filler) disintegrate more slowly due to its amorphous character and has no
solid planes on which the disintegrating forces can be exerted than the tablet
made with crystalline lactose monohydrate.

Effect of binder

As
binding capacity of the binder increases, disintegrating time of tablet
increases and this counteract the rapid disintegration. Even the concentration
of the binder can also affect the disintegration time of tablet.

Effect of lubricants^(16,34)

Mostly lubricants are hydrophobic and they are usually used in smaller size than any
other ingredient in the tablet formulation. When the mixture is mixed,
lubricant particles may adhere to the surface of the other particles. This
hydrophobic coating inhibits the wetting and consequently tablet
disintegration.

Lubricant
has a strong negative effect on the water uptake if tablet contains no
disintegrants or even high concentration of slightly swelling disintegrants. On
the contrary, the disintegration time is hardly affected if there is some
strongly swelling disintegrants are present in the tablet. But there is one
exception like sodium starch glycolate whose effect remains unaffected in the
presence of hydrophobic lubricant unlike other disintegrants.

Effect of surfactants

Table.16. The Effects Of Various Surfactants

Surfactant	Remarks
Sodium lauryl sulfate	Good-various drugs Poor - various drugs
Polysorbate 20	Good
Polysorbate 40 & 60	Poor
Polysorbate 80	Good
Tweens	Poor
Poly ethylene glycol	Poor

(Good – decrease in
disintegration time, Poor – increase in disintegration time)

Sodium
lauryl sulphate increased absorption of water by starch or had a variable
effect on water penetration in tablets. Surfactants are only effective within
certain concentration ranges. Surfactants are recommended to decrease the
hydrophobicity of the drugs because the more hydrophobic the tablet the greater
the disintegration time.

Aoki
and fukuda claimed that disintegration
time of granules of water-soluble drugs did not seem to be greatly
improved by the addition of nonionic
surfactant during granulation , but the desired effect of a surfactant appeared when granule were
made of slightly soluble drugs. The speed of water penetration was increased by
the addition of a surfactant.

Key Phrases Ø Disintegrants are added to tablet to induce breakup when it comes in contact with aqueous fluid. Ø Disintegration by capillary action or by swelling is the major mechanism for disintegrants. Ø Disintegrant can be added intragranular or extragranular or at both stages. Ø Superdisintegrants have greater efficiency at low concentration and hence, their demand is increasing day by day.

1.5.5
Antifrictional Agents

What will you gain? 1.5.5.1 Lubricants 1.5.5.1.1 Classification of lubricants 1.5.5.1.1.1 Water Insoluble Lubricants 1.5.5.1.1.2 Water Soluble Lubricants 1.5.5.2 Antiadherents 1.5.5.3 Glidants

1.5.5.1 Lubricants^(4,16)

Lubricants
are the agents that act by reducing friction by interposing an intermediate
layer between the tablet constituents and the die wall during compression and
ejection. Solid lubricants, act by boundary mechanism, results from the
adherence of the polar portions of molecules with long carbon chains to the
metal surfaces to the die wall. Magnesium stearate is an example of boundary
lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where two
moving surfaces are separated by a finite and continuous layer of fluid
lubricant. Since adherence of solid lubricants to the die wall is more than
that of fluid lubricants, solid lubricants are more effective and more
frequently used.

Since
primarily lubricants are required to act at the tooling or material interface,
lubricants should be incorporated in the final mixing step, after granulation is complete. When hydrophobic
lubricants are added to a granulation, they form a coat around the individual
particles (granules), which may cause an increase in the disintegration time
and a decrease in the drug dissolution rate. Presence of lubricants may results
in a less cohesive and mechanically weaker tablet because it may interfere with
the particle – particle bonding.

Surface
area is important parameter for deciding lubricant efficiency. Lubricants with
high surface area are more sensitive to changes in mixing time than lubricant
with low surface area. Therefore lubricant mixing time should be kept minimum.

Tooling
used to compress the tablet is important for deciding type and level of
lubricant used. Additional lubricant is often added to the tablet formulations
that are to be compressed with curved face punches.

Further,
the amount of lubricant increases as the particle size of the granulation
decreases but its concentration should not exceed to 1% for producing maximum
flow rate.

Lack
of adequate lubrication produces binding which can results in tablet machine
strain and can lead to damage of lower punch heads, lower cam track, die seats
and the tooling itself. And it may also yield tablets with scratched edges and
are often fractured at the top edges. With excessive binding the tablet may be
cracked and fragmented by ejection.

1.5.5.1.1 Classification
of lubricants

Lubricant
are classified according to their water solubility i.e. water insoluble and
water soluble. Selection of lubricant is depends partly on mode of
administration, type of tablet, desired disintegration and dissolution
properties, physicochemical properties of granules or powder and cost.

1.5.5.1.1.1 Water Insoluble Lubricants

Water
insoluble lubricants are most effective and used at reduced concentration than
water soluble lubricants. Since these
lubricants function by coating ,
their effectiveness is related with their surface area, extent of particle size
reduction, time, procedure of addition
and length of mixing.

Table.17. List Of Insoluble Lubricants

INSOLUBLE LUBRICANTS	CONCENTRATION	COMMENTS
Stearates(Magnesium Stearate, Calcium Stearate, Sodium stearate)	0.25 -1	Reduce tablet strength; prolong disintegration; widely used.
Talc	1 -2	Insoluble but not hydrophobic; moderately effective.
Sterotex	0.25 – 1	-
Waxes	1 - 5	-
Stearowet	1 - 5	-
Glyceryl behapate(Compritol®888)	1 - 5	Both lubricant and binder;
Liquid paraffin	Up to 5	Dispersion problem; inferior to stearates

1.5.5.1.1.2 Water Soluble Lubricants

Water
Soluble Lubricants are used when a tablet is completely soluble or when unique
disintegration and dissolution characteristics are required. Tablet containing
soluble lubricant shows higher dissolution rate than tablet with insoluble
lubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearates
can lead to the best compromise in terms of lubricity, tablet strength and
disintegration.

Table.18. List Of Soluble Lubricants

WATER SOLUBLE LUBRICANTS	CONCENTRATION RANGE (%W/W)
Boric acid	1
Sodium benzoate	5
Sodium oleate	5
Sodium acetate	5
Sodium Lauryl sulfate (SLS)	1 – 5
Magnesium lauryl sulfate (MLS)	1 - 2

1.5.5.2 Antiadherents ^{(4, 16)}

Some
material have strong adhesive properties towards the metal of punches and dies
or the tablet formulation containing excessive moisture which has tendency to
result in picking and sticking problem. Therefore antiadherents are added,
which prevent sticking to punches and die walls.

Talc,
magnesium stearate and corn starch have excellent antiadherent properties.
Vegan had suggested that silicon oil can be used as antiadherent.

Table.19. List Of Antiadherents

ANTIADHERENT	RANGE(%W/W)	COMMENT
Talc	1 – 5	Lubricant with excellent antiadherents properties
Cornstarch	3 – 10	Lubricant with excellent antiadherents properties
Colloidal silica	0.1 – 0.5	Does not give satisfactory results due to small surface area. Cab-O-Sil® and Syloid®
DL-Leucine	3 – 10	Water soluble lubricant; excellent antiadherents properties
Sodium lauryl sulfate	<1	Antiadherents with water soluble lubricant
Stearates	<1	Antiadherents with water insoluble lubricant

1.5.5.3 Glidants ^{(4, 16)}

GLIDANTS
are added to the formulation to improve the flow properties of the material
which is to be fed into the die cavity and aid in particle rearrangement within
the die during the early stages of compression. If the flow properties are
extremely poor then glidants are ineffective and consideration of force free
mechanisms may be necessary. Starch is a popular glidant because it has
additional value of disintegrant. Concentration of starch is common up to 10%,
but should be limited otherwise it will worsen the flow of material. Talc is a
glidant which is superior to starch; its concentration should be limited
because it has retardant effect on dissolution-disintegration profile.

Silaceous
material like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydrated
sodium silioaluminate (0.75%) are also successfully used to induce flow.

Glidants
act by interposing their particles between those of material and lower the
overall interparticulate friction of the system by virtue of their reduced
adhesive tendencies. Similar to lubricants, they are required at the surface of
feed particles and they should be in fine state of division and appropriately
incorporated in the mixture.

Key Phrases Ø Lubricants are added to reduce the friction during compression. Ø Antiadherents avoid sticking to die walls and picking by punches. Ø Glidants improve the flow property of material/granules.

1.5.6 Miscellaneous Excipients

What will you gain? 1.5.6.1 Wetting Agents 1.5.6.2 Dissolution Retardants 1.5.6.3 Dissolution Enhancers 1.5.6.4 Adsorbents 1.5.6.5 Buffers 1.5.6.6 Antioxidants 1.5.6.7 Chelating Agents 1.5.6.8 Preservatives 1.5.6.9 Colourants 1.5.6.10 Flavours 1.5.6.11 Sweeteners

1.5.6.1 Wetting Agents

Wetting Agents in tablet formulation
aid water uptake and thereby enhancing disintegration and assisting in drug
dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate
(SLS) is known to enhance the dissolution.It has been established that SLS
improves permeation of drug through biological membrane since it destroys the
path through which drug has to pass and thus minimizing the path length for the
drug to travel. Wetting agents are mainly added when hydrophobic drug is to be
formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as
wetting agent in tablet formulation.

1.5.6.2 Dissolution
Retardants

Dissolution Retardants are incorporated into tablet
formulation only when controlled release of drug is required. Waxy materials
like stearic acid and their esters can be used as dissolution retardants.

1.5.6.3 Dissolution Enhancers

They are the agents that alter the
molecular forces between ingredients to enhance the dissolution of solute in
the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.

1.5.6.4 Adsorbents ⁽⁴⁾

Adsorbents are the agents that can
retain large quantities of liquids. Therefore liquids like Vitamin E can be
incorporated into tablets by addition of adsorbents .Most commonly used
adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch,
magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and
silicon dioxide. Generally the liquid to be adsorbed is first mixed with the
adsorbent prior to incorporation into the formulation. Silicon dioxide when
added can play as both glidant and an adsorbent role in the formula.

1.5.6.5 Buffers

Buffers are added to maintain a required pH since a
change in pH may cause significant alteration in stability. Most commonly used
buffering agent in tablet formulation includes sodium bicarbonate, calcium
carbonate, and sodium citrate.

1.5.6.6 Antioxidants

Antioxidants are added in tablet formulation to
protect drug from undergoing oxidation. Antioxidants undergo oxidation in place
of drug or they block the oxidation reaction or they act as synergists to other
antioxidants. Chelators may also act as antioxidant. Most commonly used
antioxidants include ascorbic acid and
their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium
metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated
Hydroxy Anisole (BHA) , citric acid , and tartaric acid .

1.5.6.7 Chelating Agents

Chelating agents tend to form complexes with trace
amount of heavy metal ions inactivating their catalytic activity in the
oxidation of medicaments. Ethylenediamine tetracetic acid and its salts,
Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used
chelators.

1.5.6.8
Preservatives

Preservatives may be a part of tablet formulation in
order to prevent the growth of microorganisms in tablet formulation. Parabens
like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as
preservatives.

1.5.6.9 Colourants^{(1, 4,16)}

Colourants neither contribute to therapeutic activity
nor do they improve product bioavailability or stability but are incorporated
into tablets for purposes like to facilitate identification of similar looking
products with in a product line to avoid mix ups, to facilitate identification
of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on
aging, disguising of off-colour drugs, for brand image in the market, to
enhance the aesthetic appearance of the product to have better patient
acceptance. Most widely used colourants are dyes and lakes which are FD & C
and D & C approved. Dyes are generally applied as solution especially in
the granulating agent. Lakes are usually employed as dry powders for colouring.
In general, direct compression tablets are coloured with lakes because no
granulation step is used. Natural colourants can be used and generally they do
not require the FDA certification before use in drug products. One of the
important advantage in using lakes is reduced risk of interaction between the
drug and other ingredients as well as colour development is rapid which reduces
processing time .While employing wet granulation , care should be taken to
prevent colour migration during drying . In any coloured tablet, the
formulation should be checked for resistance to colour changes on exposure to
light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements
and Microreflectance Photometer used to measure the colour uniformity and gloss
on a tablet surface.

Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic)

FD & C COLOUR	COMMON NAME
Red 3	Erythrosine
Red 40	Allura red AC
Yellow 5	Tartrazine
Yellow 6	Sunset Yellow
Blue 1	Brilliant Blue
Blue 2	Indigotine
Green 3	Fast Green

1.5.6.10 Flavours^(1,4)

Flavors are commonly used to improve
the taste of chewable tablets as well as mouth dissolved tablets. Flavors are
incorporated either as solids (spray dried flavors) or oils or aqueous (water
soluble) flavors. Solids that is dry flavors are easier to handle and generally
more stable than oils. Oil is usually added at the lubrication step because of
its sensitivity to moisture and their tendency to volatilize when heated during
drying. It may also be adsorbed onto an excipient and added during the
lubrication process. The maximum amount of oil that can be added to granulation
without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous
flavors are less used because of its instability on aging.

1.5.6.11 Sweeteners^(1,4,45)

Sweeteners are added primarily to chewable
tablets.

Table.21. Some Of The Sweeteners Used In Tablet Formulation

NATURAL SWEETENERS	ARTIFICIAL SWEETENERS
Mannitol Lactose Sucrose Dextrose	Saccharin Cyclamate Aspartame

Saccharin
is 500 times sweeter than sucrose. Its major disadvantages are that it has a
bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic
.Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of
aspartame is its lack of stability in the presence of moisture. When aspartame
is used with hygroscopic components, it will be necessary to determine its
stability under conditions in which the product can adsorb atmospheric
moisture. Aspartame is available in market under the brand Nutrasweet^Ò manufactured and marketed by Nutrasweet Company.

Key Phrases ØOnly FD&C and D&C approved colourants can be incorporated into tablet formulation. ØFlavours and Sweeteners are one of the important ingredients of chewable and mouth dissolving tablet formulation.