Article

Tablet Formulation Design And Manufacture:

Oral Immediate Release Application
Jayesh Parmar & Manish Rane
Colorcon Asia Pvt. Limited

Q Abstract
Tablet is the most preferred oral dosage form, due to many advantages it offers to formulators as well as physicians and patients.
However, the process of manufacturing tablets is complex. Hence, careful consideration has to be given to select right process,
and right excipients to ultimately give a robust, high productivity and regulatory compliant product of good quality.

Q Introduction Q Tablet Manufacturing Direct compression avoids many of the

problems associated with wet and dry
Tablets are solid dosage forms Tablets are compressed powders and granulations. However, the inherent physical
containing medicinal substances with or their manufacturing is a complex, multistep properties of the individual filler materials are
without suitable diluents. They are the most process. The ultimate aim of these highly critical, and minor variations can alter
widely preferred form of medication both by compressed solids is to easily disperse in flow and compression characteristics, so as
pharmaceutical manufacturer as well as gastrointestinal fluid, aid in complete to make them unsuitable for direct
physicians and patients. They offer safe and absorption of API and, at the same time, offer compression. Excipients are now available
convenient ways of active pharmaceutical stability to the formulation. that allow production of tablets at high
ingredients (API) administration with speeds without prior granulation steps.
excellent physicochemical stability in The tablet manufacturing process can These directly compressible excipients
comparison to some other dosage forms, and be broadly classified as granulation (wet consist of special physical forms of
also provide means of accurate dosing. They granulation or dry granulation) and direct substances, such as lactose, sucrose,
can be mass produced with robust quality compression. Granulation is an dextrose, or cellulose, which possess the
controls and offer different branding agglomeration process to improve the flow, desirable properties of fluidity and
possibilities by means of colored film coating, density and compressibility of particulate compressibility.
different shapes, sizes or logos. material by size enlargement and
densification. Granulation can be achieved Some of the most widely used direct
The objective of this review article is to
by the use of binder solution (wet granulation) compression fillers are cellulose derivatives
provide a comprehensive overview of the
or dry binder (dry granulation). Wet (e.g. microcrystalline cellulose), saccharides
tablet core manufacturing process with
granulation is often chosen over dry (e.g. lactose and mannitol), mineral salts
emphasis on oral immediate release
granulation because of dust elimination, (e.g. dicalcium phosphate, calcium
formulations, along with common excipients
used. single pot processing, uniformity of API carbonate), and partially pregelatinzed starch
content (low dose API) and obtaining (Starch 1500®). Table 1 provides the
predictable granulation end point advantages and limitations of different table
Q Types of Tablet determination. Examples of wet granulation manufacturing methods.
methods include fluid bed, high shear,
The tablet dosage form is a versatile
drug delivery system. Different types of
pelletization techniques, such as extrusion-
spheronization, spray drying, etc. The quality
Q Tablet Components
tablet formulations are available, which could
of this solid oral dosage form is, as a general Tablet dosage form is composed of two
be broadly classified based on: (1) route of
rule, primarily governed by the main ingredients: (1) API and, (2) inactive
administration such as tablets for oral
delivery, sublingual delivery, buccal delivery, physicochemical properties of the powder/ ingredients also termed as excipients. The
rectal delivery or vaginal delivery, and (2) granulation from which the tablets are different physicochemical properties of API
formulation characteristics such as composed. Dry granulation (roll compaction and manufacturing process selected dictates
immediate release tablets, effervescent or slugging) involves the compaction of addition of different types of excipients,
tablets, melt-in-mouth or fast dissolving powders at high pressures into large, often depending on the specific function they
tablets, delayed release or extended release poorly formed tablets or compacts. These provide to aid in manufacture of tablets,
tablets. In all the cases, the general compacts are then milled and screened to efficacy and stability of the product.
manufacturing process, machinery used for form a granulation of the desired particle size.
The advantage of dry granulation is the Active Pharmaceutical Ingredients
preparation of tablets and materials used are
similar. The process of manufacturing a elimination of heat and moisture in the API play a very important role in
robust tablet dosage form and consistently processing. Dry granulations can be selecting the excipients, method of
maintain its quality is a key challenge to all produced by extruding powders between manufacture, size of tablet, etc. Some of the
formulators. Hence the manufacturing hydraulically-operated rollers to produce thin important characteristics of API, which
process and formulation components take cakes that are subsequently screened or influence the tablet performance are listed
pivotal importance. milled to give the desired granule size. in Table 2.
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Pharma Times - Vol 41 - No. 4 - April 2009 21

 Table 1 : Tablet manufacturing methods - advantages and limitations
Q Excipients
Method Advantages Limitations
Pharmaceutical excipients can be
Direct compression z Simple, economical process. z Not suitable for all API, defined as any substance other than the
z No heat or moisture, so good generally limited to lower active API or pro-API that has been
for unstable compounds. dose compounds. appropriately evaluated for safety and is
z Segregation potential. included in API delivery system to either;
z Expensive excipients. 1. Aid processing of the system during
manufacture or
Wet granulation z Robust process suitable for z Expensive: time and energy 2. Protect, support or enhance stability,
most compounds. consuming process. bioavailability or patient acceptability or
z Imparts flowability to z Specialized equipment 3. Assist in product identification or
a formulation. required. 4. Enhance any other attribute of the
z Can reduce elasticity problems. z Stability issues for moisture overall safety and effectiveness of the
z Coating surface with hydrophilic sensitive and thermolabile API product during storage or use
polymer can improve wettability. API with aqueous (Blecher, L., 1995).
z Binds API with excipient, thus granulation. Ideally all the excipients must be
reducing segregation potential. chemically inert, non-hygroscopic,
compatible with API, regulatory compliant,
Wet granulation z Suitable for moisture sensitive z Expensive equipment. non-toxic, have acceptable taste and be
(non-aqueous) API. z Needs organic facility. inexpensive. The pharmaceutical industry
z Vacuum drying techniques can z Solvent recovery issues. uses many different types of excipients,
remove/reduce need for heat. z Health and environment which can be classified as primary excipients
issues. based on their functionality or as secondary
excipients based on the way they are used.
Dry granulation z Eliminates exposure to moisture z Dusty procedure.
Primary excipients - This includes;
(slugging or roll and drying. z Not suitable for all
fillers (diluents), binders, disintegrants,
compaction) compounds.
lubricants, glidants. They comprise the major
z Slow process. part of a formulation and hold the key to its
success.

Table 2: Effect of different physicochemical properties of API on the formulation

Property of API Effects on tablet formulation Examples of API

Dose Low dose may have content uniformity effects. Misoprostol, ramipril - low dose.
High dose may result in direct physical impact of the API on tablet Metformin, paracetamol - high dose.
roperties.

Solubility Low solubility of API may dictate the choice of manufacturing process Nifedipine, gliclazide have low solubility.
from dissolution point of view. A wet granulation is the preferred method
with such API.

Melting point Low melting point of API may result in sticking problems or Ibuprofen (M.P. ~ 560 C) is known to
soft tablets during compression. cause tablet punch sticking.

Particle size Lower particle size of API may be important for higher solubility and Celecoxib, Albendazole.
dissolution. However, this may give rise to capping problem in tablets.

pKa It dictates the pH level at which ionization takes place and subsequent Aspirin, meloxicam exhibit better
solubilization. Acidic API having pKa (3-5) will solubilize at higher pH. solubility in basic pH.

Flow properties Poor flow of API may lead to loss of tablet hardness and weight variation Paracetamol bulk powder has poor flow.
issues. This may restrict the formulator to use granulation techniques or Hence needs to be granulated for tablet
higher levels of lubricants/glidants to impart the flow, which may preparation.
adversely affect dissolution and compaction.

Bulk density Density plays a significant role in the blend uniformity of API along Glucosamine sulphate has high bulk
with other excipients. In general, for a high density API, the diluent density, whereas Chondroitin sulphate
selected should have high density and vice-versa in order to avoid has low bulk density.
segregation issues in a directly compressible formulation.

Moisture content High moisture content of API may result in sticking issues during Ampicillin trihydrate formulation often
compression of tablets. cause tablet punch sticking problem.

22 Pharma Times - Vol 41 - No. 4 - April 2009

 Property of API Effects on tablet formulation Examples of API

Hygroscopicity Highly hygroscopic API may result in problems such as tablet punch Divalproex sodium and L-Carnitine.
sticking. Careful selection of manufacturing process, low humidity
conditions in processing area become critical for such API.

Polymorphism Certain API exhibit polymorphic forms, which may have differences Desloratadine, Clopidogrel
in solubility, chemical stability or bioavailability. The polymorphic
trans formation may occur during manufacturing process due
to application or generation of heat or presence of moisture.

Degradation Certain API are unstable to heat or moisture or light. Formulating Nifedipine is photosensitive.
profile such API into tablets may be challenging. Rabeprazole is sensitive to heat and
moisture.

Excipient Certain API may be incompatible with specific excipients and may Aspirin is incompatible with
compatibility limit their selection. Excipient compatibility testing would help in magnesium stearate, Primary amine
selecting right excipient. based API's are incompatible with
Lactose (due to Malliard's reaction)

Compactability Good ability to compact renders ease in direct compression of Acetaminophen has poor ability to
tablets. Certain API's, however, have poor ability to compact and compact, whereas Aspirin is good.
hence granulation techniques may be required as a means
of formulation velopment.

Secondary excipients - This includes; film coating, colors, flavors, sweeteners, wetting agents. These excipients are responsible for
appearance and performance.

Q Diluents
Diluent is added to formulation to increase the bulk volume of the active and hence the size of the tablet suitable for handling. The
selection of the diluent will depend on the type of processing and plasticity of materials to be used. In general, a direct-compression formulation
will require a diluent with good flow and compaction properties. Table 3 lists some of the commonly used diluents.

Table 3: List of most commonly used tablet diluents

Diluent Advantages Limitations Comments

Lactose z Lactose deforms by brittle fracture. z Lactose intolerance. z Available as anhydrous and
z Less sensitive to Mg. stearate z Bovine derived. monohydrate; anhydrous material
over blending. z Abrasive - requires high levels used for direct compression due
z Less sensitive to press speed. of lubricant. to superior compressibility.
z Granulation does impart some z May brown on aging/Maillard
plastic nature to the end product. reaction.
z Good compressibility. z Slowest dissolving sugar -
z Soluble in water. formulations need adequate
z Many different grades available. disintegrant.
z Spray dried forms may contain
amorphous material.

Mannitol z Non-hygroscopic. z Very abrasive. Requires high levels z It is not a reducing sugar and can be
z Partly soluble in water. of lubricant. substituted for lactose (lactose not
z Non reactive. z Can cause punch filming/ picking. acceptable in certain markets).
z Negative heat of solution - z Potential laxative effect at high dose. z 10 - 90% usage level.
cooling mouth feel. z Expensive.
z Many grades available. z Has both plastic and brittle nature
depending on grade.

MCC z Highly compactable. z Insoluble. z Very popular.

z Has some disintegrant properties z The wet massing process and the z Used at concentrations of 20 - 90%.
due to wicking properties. drying of the granules can lead to z Plastically deforming.
z Non-abrasive. a considerable decrease in
z Inert. compaction properties.
z Can be used in roller compaction z Incompatible with strong oxidizing
and extrusion/ spheronization. agents.
z Variety of particle size, moisture z Disintegrant should be used in
content and bulk density is formulations.
available.

Pharma Times - Vol 41 - No. 4 - April 2009 23

 Diluent Advantages Limitations Comments

Sucrose z Sucrose serves as a dry binder z Powdered sucrose is a cohesive solid. Sucrose is also available as invert
(2-20% w/w) or as a bulking agent z Tablets that contain large amounts sugar, compressible sugar and
and sweetener in chewable tablets of sucrose may harden over time to as sugar spheres.
and lozenges. give poor disintegration.
z Crystalline sucrose is free flowing.

Partial z Has better compaction properties z For direct compression, it may be z Can be used up to 75% in
pregelatinized than native starch. advantageous to combine partial wet granulation.
starch z Partial gelatinization improves pregelatinized starch with MCC or z Can be used up to 50% in
binding yielding, improved granule lactose in a 1:1 ratio for enhancing direct compression.
strength and enhanced tablet tablet hardness. z Globally accepted.
hardness.
z Multifunctional - acts as binder and
disintegrants.
z Self lubricant and reduces
requirement of lubricants.

Dicalcium z Excellent flow properties. z Practically insoluble in water, soluble z Not used extensively in
phosphate z Ability to compact is good and in acid but not alkali. wet granulations.
independent of machine speed. z Not recommended for use with z Deforms by brittle fracture.
z Less susceptible to Mg. stearate poorly soluble API. z Used up to 50%.
over-blending. z Loses water of crystallization at z Available in milled and
z Non-hygroscopic. elevated temperatures. unmilled forms.
z Can "trap" API under a cone or heap
in a dissolution vessel.
z Abbrasive - can cause accelerated
tooling and machine wear.

Diluents form a major portion of most of the tablet formulations tablet press, key process and corresponding diluent knowledge has
due to newer high potency API's. The moisture content, more become important. Use of combination of diluents with synergistic
specifically water activity coefficient of such diluents, may influence properties or co-processed excipients, such as StarCap 1500®, co-
API stability since many API are prone to degradation by hydrolysis. processed starch excipient, are gaining significance in the
In general, moisture content may indicate hydrate form or tightly pharmaceutical industry. Figure 2 shows impact of tablet press
bound water molecule of crystallization, or surface-bound or surface- speed on the tablet breaking force (hardness) when compressed at
absorbed water on the excipient. The bound water may not cause increasing compression pressure. It can be seen that formulation
hydrolysis of sensitive API, but free- or surface- absorbed water may with combination of MCC + Starch 1500 gives low yet acceptable
be responsible for hydrolysis of sensitive API. This free water is hardness of tablets when compressed at higher speeds and at high
termed as water activity coefficient. Figure 1 gives loss on drying compression pressures. This also means that the disintegration time
(LOD) and water activity coefficient of some commonly used filler. is not affected for tablets compressed at higher compression pressure
Lactose, for instance, has low LOD, but very high water activity
coefficient. On the other hand, Starch 1500 has very high LOD, but
very low water activity coefficient. Hence, for API such as Aspirin or
Ranitidine that undergo hydrolysis, Starch 1500 provides stable
formulation, whereas lactose or plain microcrystalline cellulose leads
to higher impurity levels on stability (Cunnigham CR 2001).
Tablet Breading Force (kp)

Today pharmaceutical companies increasingly use high speed

tablet press for faster and higher productivity. For such high speed
Water activity aw

Mositure content

Compression Force (KN)

Figure 2: Effect of Press Speed on Hardness of tablets compressed
at different compression pressures.
Formula 3 contains: Dicalcium Phosphate Dihydrate
(Emcompress®, 49.75%) +Microcrystalline Cellulose (Avicel® PH
102, 50%) + Magnesium Stearate (0.25%)
Formula 4 contains: Partially Pre-gelatinized Starch (Starch 1500®,
Figure 1: Water activity Vs Moisture content of some commonly 49.75%) +Microcrystalline Cellulose (Avicel® PH 102, 50%) +
used fillers. Magnesium Stearate (0.25%)

24 Pharma Times - Vol 41 - No. 4 - April 2009

 required mechanical agent in normal equipment or using fluid bed
strength. During equipment. When the granulate dries, the
compaction, the binders crystallization of any solids that had dissolved
provide the cohesive in the liquid will form solid bonds between
binding and deformation the particles. Inclusion of granulating agents
Disintegration Time (min)

characteristics or binders to increase granule strength is

necessary for the necessary. Granulating agents are usually
formation of tablets. hydrophilic polymers that have cohesive
Table 4 lists some properties that both aid the granulation
commonly used binders process and impart strength to the dried
in the pharmaceutical granulate. The binder may vary the
industry with their disintegration and dissolution and final
typical concentrations, performance of the tablet. Binders form films
advantages and on the surface of the granules, which can
limitations. aid in the wetting of hydrophobic API.
Compression Force (KN) However, if added at too great a
Before tableting, concentration, the films can form viscous gels
the powder mixture is
Figure 3: Effect of Press Speed on disintegration time (min) of on the granule surface and may retard
granulated simply by dissolution. Dry addition of binder is also
tablets compressed at different compression pressures.
adding water, hydro- possible in direct compression.
as shown in Figure 3 (Colorcon technical alcoholic mixture or an organic solvent to
data sheet). This property is important for form liquid bridges followed by the drying Starch paste has been widely used as
direct compression based formulations that process. This granulation process results in a binder. Starch paste is formed when starch
need low friability, high hardness yet powders of larger particle size and that are grains are heated in water causing the
acceptable disintegration time at a more free-flowing for tablet production. The rupture of the grains and release of the water
reasonable compression force. most common method of adding binders is soluble components. The paste is prepared
as a solution in the granulating fluid. It is by suspending the starch in water and then
Q Binder also possible to add polymers, such as
partially pregelatinized starch (e.g. Starch
adding boiling water with stirring. Paste is
cooled before adding to the powder, which
Binder is added during granulation step 1500), polyvinyl pyrrolidone (PVP) and on standing increases in viscosity and
to an API-filler mixture to ensure that hydroxypropyl methylcellulose (HPMC), as becomes an important property to control.
granules and tablets can be formed with the powders and use water as the granulating Pregelatinized starch is an advanced, more

Table 4: List of some most commonly used binders

Binders Typical Advantages Limitations

concentration
used (%)

Native starch paste 5 - 25 z Good binding ability. z Time consuming process, high
variability in preparation of
starch paste.

Pregelatinized starch 5 - 10 z Cold water soluble, so easier to prepare z Only functions as a binder.
than starch. The formulations with pregelatinized
starch require separate
disintegrating agents.

Partially 5 - 15 z Acts as binder and also as disintegrant. z Different suppliers have different
pregelatinized z Acts as a multifunctional agent. gelatinization level.
starch

Polyvinylpyrrolidone 2-8 z Available in range of molecular z Gives harder tablets upon stability
weight/ viscosities. prolonging the disintegration time
z Soluble in water and ethanol. and dissolution of the active.

Hydroxypropyl 2-8 z It is soluble in different solvent systems z May give hard granules especially if
methylcellulose and suitable for both aqueous, binder concentration and kneading
non-aqueous or hydro-alcoholic solvents. time is increased, during high
z Can be used for modulation of shear granulation.
API release.
z Number of viscosity grades available for
granulation.

Methylcellulose 1-5 z Good binder. z May give hard granules, especially

z Small concentration required for if binder concentration and
effective binding. kneading time is increased,
z Number of viscosity grades available for during high shear granulation.
granulation.

Pharma Times - Vol 41 - No. 4 - April 2009 25

 user-friendly version than native starch Table 5 - List of some most commonly used disintegrants
paste, since this material may be
incorporated as a dry powder and granulated Typical
with water. It is also possible to prepare Disintegrant Concentation Comments
slurry and use it as a granulating agent. A used (%)
next generation product is partially
pregelatinized starch. This product offers Native Starch 5 - 10 Probably works by wicking; swelling minimal at
disintegrant property along with binding body temperature.
capacity. Level of gelatinization is a key to
product performance. Partially 5 - 10 Amylose part of partially pregelatinized
pregelatinized starch causes swelling and gives disintegrant
PVP is a versatile binder used as starch action.
solution in water, ethanol or hydro-alcoholic
mixture, or added dry to powder blends and MCC 10 - 25 Strong wicking action; loses disintegrant action
granulated with water. One disadvantage when highly compressed.
with PVP is that it tends to reduce the
viscosity of granulations and makes the Insoluble ion 2 - 10 Strong wicking tendencies with some
determination of the granulation end point exchange swelling action.
more difficult with certain type of resings
instrumentation. The tablet produced with
PVP as binder also increases disintegration Sodium starch 2-8 Free flowing powder that swells rapidly on contact
time and retards the API release over time. glycolate with water.
HPMC is soluble in both water and ethanol,
and it is versatile and inert material. Croscarmellose 1-5 Swells on contact with water.
Generally, lower viscosity grades are sodium
preferred for wet granulation.
Gums such as <5 Swells on contact with water; forms viscous gels
agar, guar gum, that can retard dissolution, thus limiting
Q Disintegrant xanthan gum, etc concentration that can be used.

Disintegrant is included in the Alginic acid, 4-6 Swells like gums, but forms less viscous gels than
formulation to ensure that the tablet breaks sodium alginate guar gum, xanthan, etc.
up into small fragments in contact with liquid.
Figure 4 shows influence of disintegrating Crospovidone 1-5 High wicking activity.
agent on disintegration time of tablets.

Tablets must have sufficient strength to immediate release preparations. To powerful disintegrating agents
withstand the stresses of subsequent overcome the cohesive strength produced (superdisintegrants), such as croscarmellose
manufacturing operations, such as the by the compression process, and to break sodium, sodium starch glycolate,
coating, packaging, and distribution process. down the tablet into the primary particles as crospovidone and certain ion exchange
However, once the tablet is taken by the rapidly as possible, disintegrants are added resins, which display excellent disintegration
patient, it must break up rapidly to ensure to the tablet formulations. The positioning activity at low concentrations than native
rapid dissolution of the active ingredient in of disintegrants within starches. Major limitations of these
the intra- and extra- superdisintegrants are relatively high cost
granular portions of and hygroscopic nature, which could
granulated formulations negatively affect the stability of moisture
can affect their water sensitive API (if the packaging does not
uptake and provide adequate protection from the
disintegration time. environment). Figure 5 depicts the moisture
Table 5 gives list of vapor sorption graph for different
some disintegrants disintegrants (Cunnigham CR, 1999).
commonly used in tablet Superdisintegrants, such as crospovidone,
formulations.
sodium starch glycollate and croscarmellose
Starch was the first sodium, in general, have high moisture
disintegrant used in sorption tendency., Therefore, sometimes
tablet manufacture. The unsuitable for formulations containing
compaction properties of moisture sensitive or hygroscopic API.
many disintegrants, Higher concentration of such
including native starch, superdisintegrants also causes problems
are not satisfactory and during aqueous film coating, often giving rise
use of high to orange peel effect to the coating.
Figure 4: Effect of different disintegrants on the physical properties concentration can also
of Hydrochlorthiazide tablets Most pharmacopeias include a disintegration
reduce tablet strength.
test which can be applied to tablets and the
(Tablet are composed of Hydrochlorthiazide, Dicalcium Recent trend in
Phosphate, Lactose spray dried, magnesium Stearate and pharmaceutical industry detailed monograph is given in the
disintegrants) is towards use of pharmacopeias.

26 Pharma Times - Vol 41 - No. 4 - April 2009

 adherent. The level of talc that can be added
to a formulation is restricted by its
Crospovidone hydrophobic nature; too high levels resulting
in decreased wetting of the tablet and a
subsequent reduction in the rate of
dissolution. Fumed silicon dioxides are
perhaps the most effective glidants. These
are materials with very small (10 nm)
Socium starch glycolate spherical particles that act as dividing
% Weight Change

cohesive particles to provide their glidant

properties. They are available in a number
Crosslinked CMC
of grades with a range of hydrophobic and
hydrophilic forms, and are commercially
available under diverse brand names. Starch
has also been used as a glidant. The use of
Starch 1500 large amounts of starch can also aid the
disintegration properties. Table 6 gives list
of some commonly used lubricants in the
tablet formulations.

Q Anti-adherent
% Relative Humidity at 25 deg. C
Anti-adherent causes reduction in
Figure 5: Moisture uptake isotherms for powders of different disintegrating agents. adhesion of powder to punch faces and thus

Table 6 - List of some commonly used lubricants in tablet formulations

Q Lubricant Typical
Disintegrant Concentation Comments
Lubricants are used in formulations to used (%)
aid in smooth ejection of tablet from die
cavity, prevent sticking of powder on punch Glidant
faces (anti-adherence), reduce interparticle
friction during compression and, to improve Talc 1-5 Fine, crystalline powder, widely used as lubricant
flow of powder blend on the machine and and diluent
into the die cavity. For a robust formulation,
Fumed silicon dioxide 0.1 - 0.5 Has small particle size and large surface area for
careful consideration has to be given in good flowability; used for adsorbent, anti-tacking
selecting right type, concentration, order and agent, disintegrant and glidant.
duration of mixing of lubricant in the
formulation. Lubricants can be further Native starch 1 - 10 Native starch powder is used as glidant and also
classified into three types based on their as disintegrant.
detailed functionality: (1) glidant, which
Sodium lauryl sulfate 0.2 - 2 Anionic surfactant, lubricant and wetting agent.
enhance flow property of powder blend by
overcoming powder cohesiveness, (2) anti- Boundary lubricants
adherent, which reduce the friction between
the tablet punch faces and tablet punches, Magnesium stearate 0.2 - 2 Hydrophobic, variable properties between suppliers.
and (3) die wall lubricant, which reduce the
friction between the tablet surface and the Calcium stearate 0.5 - 4 Hydrophobic.
die wall during and after compaction to
Sodium stearyl fumarate 0.5 - 2 Less hydrophobic than metallic stearates, partially
enable easy ejection of the tablet. Die-wall soluble.
lubricants can be divided into two classes:
fluid and boundary lubricants. Fluid lubricants Polyethylene glycol 2 - 20 Soluble, poorer lubricant activity than fatty
work by separating moving surfaces 4000 & 6000 acid ester salts.
completely with a layer of lubricant. These
are typically mineral oils or vegetable oils, Sodium lauryl sulfate 1-3 Soluble, also acts as wetting agent.
and they may be either added to the mix or
Magnesium lauryl sulfate 1 - 3 Acts as wetting agent.
applied directly to the die-wall by means of
wicked punches. The oily lubricants may Sodium benzoate 2-5 Soluble.
give a mottled tablet appearance due to
uneven distribution, poor powder flow due Fluid lubricants
to their tacky nature, and reduced tablet
strength. Boundary lubricants work by Light mineral oil 1-3 Hydrophobic, can be applied to either formulation
or tooling.
forming a thin solid film at the interface of
the die and the tablet. Metallic stearates are Hydrogenated 1-5 Hydrophobic, used at higher concentrations as
the most widely used boundary lubricants. vegetable oil controlled release agents.
Talc is traditionally one of the most Stearic acid 0.25 - 2 Hydrophobic.
commonly used glidants, having the
additional benefit of being an excellent anti- Glyceryl behenate 0.5 - 4 Hydrophobic, also used as controlled release agent.
Pharma Times - Vol 41 - No. 4 - April 2009 27
 agent and ultimately result in prolonging disintegration time.
Formulation containing high concentration of magnesium stearate
may result in tablets of reduced hardness, even if the compression
force is increased. Figure 6 gives the effect of different concentration
Tablet Breading Force (kp)

of magnesium stearate on the breaking force of Hydrochlorthiazide

tablets (Cunnigham CR, 2000). As the concentration of magnesium
stearate increased from 0.25% to 1.0% the tablet breaking force
reduced. The effect increased as a function of the compression
force. However, when stearic acid was used, at even 1%
concentration, the tablets produced were increased with compression
pressure.

Also, higher concentration of magnesium stearate can retard

the dissolution of API due to its hydrophobic nature. Figure 7 gives
the effect of magnesium stearate on release profile of
Hydrochlorthiazide.
Compression Force (KN) Many pharmaceutical companies use combination of talc and
stearic acid or talc and hydrogenated vegetable oils as an alternative
Tablets contained Hydrochlorthiazide, Dicalcium Phosphate, Lactose, to magnesium stearate. However, the major limitation to such
Starch 1500®, MCC, lubricant. combinations is high concentration required to give good lubricant
Figure 6: Effect of different concentrations of lubricants on the tablet properties in comparison to magnesium stearate.
breaking force
The level of a lubricant required in a tablet is formulation
dependent and can be optimized using an instrumented tableting
machine. It should be remembered that the requirements for
lubrication and anti-adherent may be very different when tablet
presses are run at laboratory scale and at production scale. No
single lubricant provides all the balanced functionality of each
individual class of lubricant.

Q Other excipients
Certain excipients, like anti-oxidants and surfactants, are used
only in situations where they are expressly needed to ensure the
stability or performance of the product.

Q Excipient selection
The selection of excipients is influenced by range of interrelated
factors, both objective and subjective. All the factors, like properties

Properties of excipients
z Stablity (chemical & physical)
z Hygroscopic
z Compatible
Figure 7: Effect of Magnesium Stearate on Dissolution of z Particle size
Hydrochlorthiazide z Availability
z Cost
z Regulatory acceptance
helps in preventing sticking. These materials
do not influence ejection force or residual
force. Thus they are most often used in Properties of drug
Manufacturing process
combination with other lubricants to improve z Dose
overall performance during compaction. z Solubility/ pKa
Selection of requirement
z Direct compression
z Particle Size/ Shape excipients for z Wet granulation
Magnesium stearate, a boundary wall z Melting Point/ Thermal
lubricant, readily forms a thin film on the die- Stability
solid oral z Fluid bed granulation
z Spray drying
wall surface. This results in reduction in z Flow Properties dosage forms z Extrusion &
powder ability to form strong compacts. Also, z Densities
due to hydrophobic nature, it can hinder spheronization
disintegration and dissolution performance z Other novel process

of tablets. When formulation contains

Desired release characteristics
disintegrating agents, the addition of lubricant
z Immediate release
should be at the end of the mixing process. z Sustained release
If both lubricant and disintegrant are added z Modified release
together, then lubricant may form a
hydrophobic film around the disintegrating Figure 8: Factors affecting the selection of excipients.

28 Pharma Times - Vol 41 - No. 4 - April 2009

of API and excipients, desired release formulation containing a plastically Pharmaceutical Excipients.
characteristics and even manufacturing deforming excipient, AAPS, October Pharmaceutical Press and American
process, play an important role in making a 2000. Pharmacists Association, Fourth edition,
decision [Figure 8]. For example, the choice z Cunnigham C. R. and Scattergood L. K., 2005.
of manufacturing method depends on the Evaluation of partially pregelatinized z Kottke, M. K. and E. M. Rudnic, chapter
infrastructure available with the company, starch in comparison with 10 - Tablet dosage form in Modern
associated cost and may be personal superdisintegrants in a direct Pharmaceutics, Ed. Banker GS, Rhodes
preference or experience. It also depends compression hydrochlorthiazide C, Marcel Dekker Inc., 2002.
on the dose of API and its physicochemical formulation, AAPS, October 1999.
properties. And finally, suitability and z Cunnigham, C. R. and Scattergood, L.
z Colorcon Technical Data Sheet, Dibasic
availability of excipient also play an important K., Fluid bed granulation of
calcium phosphate replacement with
role. In the present scenario, even quality of Acetaminophen: Effect of key process
Starch 1500® in a direct compression
service offered by supplier, batch-to-batch variables on granule and tablet
formula.
uniformity of product, regulatory acceptance, characteristics, AAPS, October 1999.
are also important parameters to be z Cunnigham C. R. and Scattergood L. K.,
z Do N., Farrel T., Control of dissolution
considered. The effect of Starch 1500® on the
rate of immediate release tablets
stability of aspirin tablets stored under
containing Starch 1500® with a
Q Bibliography And accelerated conditions, AAPS, October
combination of different types and
References 2001.
grades of Methocel™, AAPS, Nov.
z Blecher, L., Excipients - The important z Cunnigham C. R. and Scattergood L. K., 2006.
components, Pharm. Process., 1995, 12 Use of Starch 1500® to improve the
z Kadtare A, Chaubal M, Excipient
(1), pg 6 - 7. uniformity of a low dose direct
Development for Pharmaceutical,
compression chlorpheniramine
z Cunnigham C. R. and Scattergood L. K., Biotechnology, and API Delivery
formulation, AAPS, October 2000.
Optimizating lubricant usage in a direct Systems, Informa Healthcare, USA,
compression hydrochlorthiazide z Rowe RC, Sheskey PJ, Owen SC (Ed.), 2006.

Real-time analysis of tablet surfaces

Phil Taylor

UK company Paraytec has introduced a drug to come to market, thereby offering used in a number of other applications in the
a new instrument designed to allow significant potential gains in earnings," pharmaceutical industry, including enzyme
formulation scientists to visualise - in real according to a Paraytec statement. assays and protein sizing. Paraytec has also
time - what is happening at a tablet surface been developing the technology for in-line
Tablet holder enables accurate analysis
when it dissolves. testing in bioprocessing, for example by
The instrument combines a specially quantifying protein aggregation.
The new device - called the ActiPix
designed tablet holder and Paraytec's ActiPix
Dissolution Imager - was introduced to the Paraytec spun of from University of York
D-100 UV area imager. The holder is placed
marketplace at Pittcon on March 9 and could Paraytec was spun out from the
inside the ActiPix D-100 which enables real
make it easier for drug developers to develop University of York to develop a series of
time recording and review of data. When
controlled-release medications. instruments based on miniaturised
liquid flows over the surface of the
formulation, release of the active ingredient ultraviolet-visible (UV-vis) absorbance
Paraytec says the instrument offers
can be quantitatively monitored directly at the detectors and capillary-based fluid handling
formulation scientists an alternative to "high-
tablet surface. technology.
cost, complex techniques such as terahertz
spectroscopic imaging and magnetic UV absorbance detection is a laboratory
"It is important ... to understand the
resonance imaging "as they investigate the technique widely employed to characterise
mechanism of drug release behaviour, as this
release of active compounds from dosage and determine the levels of substances which
regulates the performance of many solid
forms. dissolve in water and other liquids, with light
pharmaceutical dosage formulations," said
absorbed at different wavelengths in the
The ActiPix Dissolution Imager is "a Paraytec.
ultra-violet region indicating different
powerful tool that can reduce the time it takes
The ActiPix D-100 instrument has been compounds.

Pharma Times - Vol 41 - No. 4 - April 2009 29