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Tablet:Formulation of tablets/Binders

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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.
Contents
[hide]

• 1 Why to go for Granulation?


• 2 Granulation Processes
• 3 Types of Binders
o 3.1 Direct compression (DC) Binders
o 3.2 Mechanism of granule formation
o 3.3 Near Infrared (NIR) spectroscopy : A tool for granulation end point
measurement
o 3.4 Factors to be considered in Granulation
 3.4.1 Compatibility
 3.4.2 Characteristics of drugs and other excipients
 3.4.3 Spreading of Binder
 3.4.4 Type and quantity of Binder
 3.4.5 Temperature and Viscosity
 3.4.6 Method of Addition of Binder
 3.4.7 Mixing Time
 3.4.8 Material of Construction of Granulator
 3.4.9 Type of Granulator
 3.4.10 Process Variables
 3.4.11 Apparatus Variables
 3.4.12 Impeller Movement
o 3.5 Evaluation tests for Binders/Granules
 3.5.1 Particle Size and Particle Size Distribution
 3.5.2 Surface Area
 3.5.3 Density
 3.5.4 % Compressibility
 3.5.5 Flow Properties
 3.5.6 Friability
 3.5.7 Moisture Content

o 3.6 Key Phrases


[edit]

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.
[edit]

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.
[edit]

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

Partially Pregelatinized
Starch 1500 Colorcon
Maize Starch
Hydroxy Propyl Methyl
Methocel Dow Chemicals
Cellulose

Wolff-Cellulosics
Hydroxy Propyl Methyl
Walocel Natural Starch and
Cellulose
Chemical Company

Luvitec Polyvinylpyrrolidone BASF Company

Luvicross Polyvinylpyrrolidone BASF Company

Luvicaprolactam Polyvinylcaprolactam BASF Company

TABLE.7. CHARACTERISTICS OF COMMONLY USED BINDER


COMMENTS
BINDER SPECIFIED
CONCENTRATION

Starch Paste 5-25%w/w - Freshly prepared starch paste is used as


a binder.
- Its method of preparation is very crucial.

Pregelatinized 5-10%w/w It is starchthat have been processed


Starch (PGS) chemically and/ormechanically to rupture
(Direct Compression)
all or part of the granules in the presence
[Partially and Fully
5-75%w/w of water and subsequently dried.
PGS]
(Wet Granulation ) - It contains 5% free amylose, 15% free
amylopectin and 80%unmodifiedstarch.
- 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 2-5%w/w - Comparable to Methyl Cellulose.


Methyl Cellulose
- Used as a binder in either wet or dry
(HPMC)
granulation processes.

Polyvinyl Pyrrolidone 0.5-5%w/w - Soluble in both water and alcohol.


(PVP)
- 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 10-15%w/w - Used as a meltable binder.


(PEG) 6000
- 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.

[edit]

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

Avicel (PH 101) MCCa FMC Corporation

SMCC (50) SMCCb Penwest Pharmaceutical

UNI-PURE(DW) Partially PGSc National Starch


& Chemical

UNI-PURE (LD) Low density starch National Starch & Chemica

DC Lactose DC lactose anhydrous Quest International Group

DI TAB 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 TAB > SMCC(50) > DC Lactose , UNI PURE(DW) >
Avicel (PH 101) > UNI PURE(LD)

Compressibility UNI PURE(LD) > SMCC(50) , Avicel (PH 101) > UNI
PURE(DW) , DC Lactose > DI TAB
Crushing Strength UNI PURE(LD) > SMCC(50) > UNI PURE(DW) >
Avicel(PH 101) > DC Lactose &gt DITAB
[edit]

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.
[edit]

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.
[edit]

Factors to be considered in Granulation


(24,30,32)

[edit]

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.
[edit]

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.

[edit]

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.
[edit]

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.
[edit]

Temperature and Viscosity


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

[edit]

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.
[edit]

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.
[edit]

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.
[edit]

Type of Granulator
Fluidized Bed Granulator produces porous granules as compared to High Shear
Granulators.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]

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.
[edit]
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.
[edit]

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.
[edit]

% 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

[edit]

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

[edit]

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.
[edit]

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.
[edit]

Key Phrases

• Binders are added in tablet formulation to have required flow


property and compressibility of powders.

• Wet Granulation, Dry Granulation/Slugging, Direct Compression are


major granule manufacturing methods.

• Direct Compression Binders are more efficient than conventional


binders.

• Pregelatinized Starch is used as multifunctional excipient: tablet


binder (wet granulating agent as well as direct compression binder),
diluent, disintegrant and flow aid.

• Polyethylene Glycol used as meltable binder.


• Granules are formed in three stages: Nucleation, Transition and Ball
Growth.

• NIR a tool for granulation end point measurement. However, it was


shown to work only for fluid-bed granulation. Torque impeller
method and power consumption are still the best methods for high-
shear and planetary mixer-granulators.

• Compatibility of binder with API and other excipients, characteristics


of binder, process variables, and apparatus variables affects the
quality of granules.

• Granules have to be evaluated in order to measure its suitability for


tableting.