1.

INTRODUCTION
1.1 Introduction to Direct Compression
Over the past hundred years tablet manufacturers have developed materials and
processes that can produce compressed tablets containing a precise amount of an
active pharmaceutical ingredient (API) at high speed and at relatively low cost. The
development in the field of APIs, ecipients and tableting machines during the past
decades has made tablet manufacturing a science and the tablets the most commonly
used dosage form
!,"
The ease of manufacturing, convenience in administration,
accurate dosing, and stability compared to oral li#uids, tamperproofness compared to
capsules, safe compared to parental dosage forms ma$es it a popular and versatile
dosage form. %perts in the art of tableting are aware with the basic art of tableting by
the three well&$nown methods, i.e. wet granulation, roller compaction and direct
compression
!,",'
. The pros and cons of wet granulation and roller compaction are well
documented in the literature
',(,)
Prior to the late !*)+s, the literature contained few
references on the direct compression of pharmaceuticals. A great deal of attention has
been given to both product and process development in the recent years. The
availability of new materials, new forms of old materials and the invention of new
machinery has allowed the production of tablets by simplified and reliable methods
!
.
In early !*,+-s, the introduction of spray dried lactose (!*,+) and Avicel (!*,() had
changed the tablet manufacturing process and opened avenues of direct compression
tableting. .hangraw
(
conducted a survey of )/ products in 0nited .tates of America
for the preference for the granulation process. The results were in favour of direct
compression. Of the five processes listed in the survey, the average score (!.+ being
the perfect score) for direct compression was !.) compared to wet massing and fluid
bed drying (".+), wet massing and tray drying (".)), all&in&one ('.') and roller
compaction ('.,). About (!1 of the companies indicated that direct compression was
the method of choice, and (!.!1 indicated that they used both direct compression and
wet granulation. Only !.21 of the respondents indicated that they never used direct
compression and !).)1 indicated that the process was not recommended. Previously,
the word 3direct compression4 was used to identify the compression of a single
crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide,
etc.) into a compact form without the addition of other substances. 5urrent usage of
the term 3direct compression4 is used to define the process by which tablets are
!
compressed directly from the powder blends of active ingredients and suitable
ecipients. 6o pre&treatment of the powder blends by wet or dry granulation is
involved ()). The simplicity of the direct compression process is apparent from a
comparison of the steps involved in the manufacture of tablets by wet granulation,
roller compaction and direct compression techni#ues (() (.ee Table !). It has been
estimated that less than "+ percent of pharmaceutical materials can be compressed
directly into tablets ((). The rest of the materials lac$ flow, cohesion or lubricating
properties necessary for the production of tablets by direct compression. The use of
directly compressible ad7uvants may yield satisfactory tablets for such materials.
Table 1: Comparison of major steps involved in the ranulation methods.
.tep 8irect 5ompression 8ry 9ranulation :et 9ranulation
! ;iing<blending of API
= Ad7uvants
!
;iing<blending of API
= Ad7uvants
!
;iing<blending of API =
Ad7uvants
!
" 5ompression 5ompression in to slug
!
Preparation of binder
solution
!
' .i>e reduction of slug =
sieving
!
;assing of binder solution
of step " with powder
miture of step !
!
( ;iing of granules with
pharmaceutical aid<s
!
:et screening of step !
!
) 5ompression 8rying of wet granulation
!
, ?esifting of dry granules
= blending with the
pharmaceutical aid<s
!
2 5ompression
"
1.1.1 Introduction to Directl" Copressible #djuvants
The International Pharmaceutical %cipients 5ouncil (IP%5) defines ecipient as
3.ubstances, other than the API in finished dosage form, which have been
appropriately evaluated for safety and are included in a drug delivery system to either
aid the processing or to aid manufacture, protect, support, enhance stability,
bioavailability or patient acceptability, assist in product identification, or enhance any
other attributes of the overall safety and effectiveness of the drug delivery system
during storage or use4
)
. .olvents used for the production of a dosage form but not
contained in the final product are considered to be ecipients, i.e. the granulation
fluids, which might be dried off later, should comply with relevant re#uirements of
pharmacopoeia unless ade#uately 7ustified. %cipients no longer maintain the initial
concept of 3inactive support4 because of the influence they have both over
biopharmaceutical aspects and technological factors. The desired activity, the
ecipients e#uivalent of the active ingredient-s efficacy, is called its @unctionality. The
inherent property of an ecipient is its functionality in the dosage form. 8etermination
of an ecipient-s functionality is important to the ecipient manufacturer in its
assessment of the proper level of 9;P, and yet the drug manufacturer may withhold
this information until well into the development process.
In order to deliver a stable, uniform and effective drug product, it is essential to $now
the properties of the active ingredient alone and in combination with all other
ingredients based on the re#uirements of the dosage form and processes applied.
%cipients are usually produced by batch processA hence, there is a possibility of
batch&to&batch variation from the same manufacturer. %cipients obtained from the
different sources may not have identical properties with respect to use in a specific
formulation. To assure interchangeability in such circumstances, users may wish to
ascertain e#uivalency in final performance or determine such characteristics before
use. .uch tests are thus related to the functionality, that the ecipient impart to a
specific formulation.
In order to manufacture any finished product with consistent #uality, standardi>ation
of raw materials in the drug formulation is necessary for its acceptance by regulatory
authorities and pharmaceutical formulators. 0nfortunately, such performance
standards have not been included in pharmacopoeia primarily because their
specifications have always been based on chemical purity and because it is not
'
possible to standardi>e Performance criteria. Pharmacopoeial standards do not ta$e
into account particle characteristics or powder properties, which determine
functionality of ecipients. 5ontrol of functionality is important as a control of
identity and purity. The following reasons can be citedB
!. ;any ecipients have multiple functions (e.g. microcrystalline cellulose,
starch).
". There is lac$ of awareness that the ecipients behave differently, depending
upon the vendor (i.e. microcrystalline cellulose).
As a conse#uence, ecipients with optimal functionality are needed to ensure smooth
tablet production on modern machines. The introduction of special force feeder to
improve flow of granules from hopper mar$ed a significant advancement in direct
compression technology
1.1.$ Ideal Re%uirements of Directl" Compressible #djuvants
1. &lo'abilit"
The directly compressible ad7uvant should be free flowing. @lowability is re#uired in
case of high&speed rotary tablet machines, in order to ensure homogenous and rapid
flow of powder for uniform die filling. 8uring the short dwell&time (milliseconds), the
re#uired amount of powder blend should be transferred into the die cavities with
reproducibility of C )1. ;any common manufacturing problems are attributed to
incorrect powder flow, including non&uniformity in blending, under or over dosage
and inaccurate filling.
$. Compressibili"
5ompressibility is re#uired for satisfactory tableting, i.e., the mass must remain in the
compact form once the compression force is removed. @ew ecipients can be
compressed directly without elastic recovery. Dence, the directly compressible diluent
should have good compressibility, i.e. relation between compaction pressure and
volume.
(. Dilution )otential
(
8ilution potential can be defined as the amount of an active ingredient that can be
satisfactorily compressed in to tablets with the given directly compressible ecipient.
A directly compressible ad7uvant should have high dilution potential so that the final
dosage form has a minimum possible weight. The dilution potential is influenced by
the compressibility of the active pharmaceutical ingredient.
*. Re+'or,abilit"
A directly compressible ad7uvant should be capable of being rewor$ed without loss of
flow or compressibility. On recompression, the ad7uvant should ehibit satisfactory
tableting characteristics.
-. .tabilit"
It is the ability of ad7uvant to remain unchanged chemically and physically. The
directly compressible ad7uvant should not ehibit any physical or chemical change on
ageing and should be stable to air, moisture and heat.
/. Control )article .i0e
A directly compressible ad7uvant should have a particle si>e e#uivalent to the active
ingredients present in the formulation. The particle si>e distribution should be
consistent from batch to batch. ?eproducible particle si>e distribution is necessary to
achieve uniform blending with the active ingredient(s) in order to avoid segregation.
1. Inertness
@iller&binders should not accelerate the chemical and<or physical degradation of the
API(s) or ecipients. It should not interfere with the biological availability of active
ingredient<s. It should be compatible with all the ad7uvants present in the formulation.
It should be physiologically inert
)
. It should not interfere with the disintegration or
dissolution of the active ingredient. It should be colourless and tasteless. It should be
relatively cost effective and available in desired time. It should accept colorants
uniformly. It should show low lubricant sensitivity. It should show batch&to&batch
reproducibility of physical and physicomechanical properties. It should possess proper
mouth fill, which is defined as the feel or the sensation in the mouth, produced when
the ecipient is used in chewable tablets
Table $: Ideal re%uirements2 advantaes and limitations of direct compression
)
ID3#4 R35UIR363NT. #D7#NT#83 4I6IT#TION
@lowability 5ost effective production .egregation
5ompressibility Eetter solubility of API Fariation on functionality
8ilution potential @aster dissolution Gow dissolution potential
?ewor$ability Gess wear = tear punches ?ewor$ability
.tability .implified validation Poor compressibility of API
5ontrolled particle si>e Gower microbial
contamination
Gubrication sensitivity
1.1.( #dvantaes of Direct Compression
1. Cost 3ffectiveness
The prime advantage of direct compression over wet granulation is economic since
the direct compression re#uires fewer unit operations. This means less e#uipment,
lower power consumption, less space, less time and less labor leading to reduced
production cost of tablets.
$. .tabilit"
8irect compression is more suitable for moisture and heat sensitive APIs, since it
eliminates wetting and drying steps and increases the stability of active ingredients by
reducing detrimental effects. 5hanges indissolution profiles are less li$ely to occur in
tablets made by direct compression on storage than in those made from granulations.
This is etremely important because the official compendium now re#uires
dissolution specifications in most solid dosage forms.
(. &aster Dissolution
8isintegration or dissolution is the rate limiting step in absorption in the case of
tablets of poorly soluble API prepared by wet granulation. The tablets prepared by
direct compression disintegrate into API particles instead of granules that directly
come into contact with dissolution fluid and ehibits comparatively faster dissolution.
*. 4ess 'ear 9 tear of punches
,
The high compaction pressure involved in the production of tablets by slugging or
roller compaction can be avoided by adopting direct compression. The chances of
wear and tear of punches and dies are less.
-. .implified 7alidation
;aterials are Hin processH for a shorter period of time, resulting in less chance for
contamination or cross contamination, and ma$ing it easier to meet the re#uirement of
current good manufacturing practices. 8ue to fewer unit operations, the validation and
documentation re#uirements are reduced. 8ue to the absence of water in granulation,
chance of microbial growth is minimal in tablets prepared by direct compression.
1.1.* 4imitations of Direct Compression
1. .ereation
8irect compression is more prone to segregation due to the difference in density of
the API and ecipients. The dry state of the material during miing may induce static
charge and lead to segregation. This may lead to the problems li$e weight variation
and content uniformity.
$. Cost
8irectly compressible ecipients are the speciality products produced by patented
spray drying, fluid bed drying, roller drying or co&crystalli>ation. Dence, the products
are relatively costly than the respective raw materials.
(. 4o' dilution potential
;ost of the directly compressible materials can accommodate only '+&(+ 1 of the
poorly compressible active ingredients li$e acetaminophen that means the weight of
the final tablet to deliver the )++ mg of acetaminophen would be more than !'++ mg.
The large tablets may create difficulty in swallowing.
*. Re+'or,abilit"
All the spray&dried directly compressible ad7uvants show poor rewor$ability since on
preparation of tablets the original spherical nature of the ecipient particles is lost.
API that has poor flow properties and<or low bul$ density is difficult to process by
direct compression.
2
-. 4ubricant sensitivit"
Gubricants have a more adverse effect on the filler, which ehibit almost no fracture
or shear on compression (e.g. starch !)++). The softening effects as well as the
hydrophobic effect of al$aline stearates can be controlled by optimising the length of
blending time to as little as "&) min.
/. 7ariation in functionalit"
There is a lac$ of awareness in some situations that the ecipient behave differently,
depending upon the vendor so much so that substitution from one source to that of
another is not possible. Dence, there is a need for greater #uality control in purchasing
of raw material to assure batch uniformity.
1.1.- 6ethods of )reparin Directl" Compressible 3:cipients
8irectly compressible ad7uvant can be prepared by various methods. The outline and
main features of the methods are depicted in Table '. 5o&processing is the one of the
most widely eplored and commercially utili>ed method for the preparation of
directly compressible ad7uvants. Dence, co&processing is discussed in more depth in
the present review.
Table (: .ummar" of various methods used to prepare directl" compressible
adjuvants
63TOD #D7#T#83.9GI;ITATIO6. 3;#6)43
/
5hemicalmodification ?elative epensive,
Time consuming,
?e#uire toicological data
%thyl cellulose, ;ethyl
cellulose,
Dydroy propyl methyl
cellulose,
6a&5;5, 5yclodetrin.
Physical modifiction ?elatively simple = economical 8etrates or compressible
sugurs, sorbitol.
9rinding =<or .ieving 5ompressibility may alter because
of 5hange in partical properties
such as .urface area.
I&lactosemonohydrate(!++J),
8ibasiccalciumphosphate.
5rystli>ation Ipart flowability to ecipients but
not necessarily self&binding
properties.
K&lactose, 8ipac.
.pray 8rying spherical shape = uniform si>e
gives spray dried matirials, good
fowability = poor wor$ability.
.pray dried lactose, %mde, fast
flow lactose, Avicle PD, Larion
instant, T?I&5A@O. .,
Advantose !++.
9ranulation Transformation of small,cohesive
= poorly flowable powders.
9ranulated lacitol Tabletose.
8ehydration Increased binding properties by
thermal = chemical dehydration.
Anhyrous I&lactose
1.1./ Co+)rocessin
5o&processing is another way that new ecipients are coming to mar$et without
undergoing the rigorous safety testing of a completely new chemical. It can be defined
as combining two or more established ecipients by an appropriate process. 5o&
processing of ecipients could lead to the formation of ecipients with superior
properties compared to the simple physical mitures of their components. The main
aim of co&processing is to obtain a product with added value related to the ratio of its
functionality<price. 8evelopment of co&processed directly compressible ad7uvant
starts with the selection of the ecipients to be combined, their targeted proportion,
selection of preparation method to get optimi>ed product with desired physico&
chemical parameters and it ends with minimi>ing avoidance with batch&to&batch
variations. An ecipient of reasonable price has to be combined with the optimal
amount of a functional material in order to obtain integrated product, with superior
functionality than the simple miture of components. 5o&processing is interesting
because the products are physically modified in a special way without altering the
*
chemical structure. A fied and homogenous distribution for the components is
achieved by embedding them within minigranules. .egregation is diminished by
adhesion of the actives on the porous particles ma$ing process validation and in
process control easy and reliable. The randomi>ed embedding of the components in
special minigranules minimi>es their anisotropic behaviour. .o, deformation can
occur along any plane and multiple clean surfaces are formed during the compaction
process. Thus, the use of the co&processed ecipient combines the advantages of wet
granulation with direct compression. The use of one&body components is 7ustified if it
results in a potentiation of the functionalities over that of the mere dry blend of the
components prepared by gravity miture. This synergistic effect should improve the
#uality of the tablet e#ually in all aspects ranging from hardness to dissolution and<or
stability. %cipient mitures in co&processing are produced to ma$e use of the
advantages of each component and to overcome specific disadvantages, if any. ;ost
important characteristics are the binding and blending properties of the co&processed
ecipients, which must be better than those of a physical miture of the starting
materials. 5ost is another factor to be considered in the selection of co&processed
product. ;a7or limitation of co&processed ecipient miture is that the ratio of the
ecipients in a miture is fied and in developing a new formulation, a fied ratio of
the ecipients may not be an optimum choice for the API and the dose per tablet under
development. 5oprocessed ad7uvant lac$s the official acceptance in pharmacopoeia.
@or this reason, a combination fillerbinder will not be accepted by the pharmaceutical
industry until it ehibits significant advantages in the tablet compaction when
compared to the physical mitures of the ecipients. Although the spray&crystalli>ed
detrose&maltose (%mde) and compressible sugar are co&processed products, they are
commonly considered as single components and are official in 0.P<6@.
Table *: Co+processed directl" compressible e:cipients
<rand Name #djuvants 6anufacurer2 Countr"
5ellactose ;55, Gactose ;eggle, 9ermany.
Mylitab Mylitol, 6a 5;5 ;eggle, 9ermany.
Gudipress Gactose, PFP, 5rosspovidone EA.@, 9ermany.
!+
.tarlac Gactose, ;ai>estarch ?o#uette, @rance.
Pharmatose 8G5 (+ Anhydrous lactose, lactitol 8;F, 6etherlands.
Avicel 5% !) ;55, 9uar 9um @;5, 0.A.
5elocol ;55, 5alcium phosphate @;5, 0.A.
Prosolv ;55, 5oloidial .ilica Penwest.
8i&pac .ucrose, 8etrin American sugur, 0.A.
Advantose @. *) @ructose, starch .PI polysol, @rance.
Advantose !++ ;altoe .PI polysol, @rance.
Earcoft 5. *+ 5acium carbonate,.tarch .PI polysol, @rance.
Earcoft premi .t. Al&hydroide,;g&hydroide,
.orbitol
.PI polysol, @rance.
Plasdone .&,'+ Finyl acetate, vinyl
pyrrolidone
I.P. 0.A.
5arbofarma 9!+ 5alcium 5arbonate ?esins industries, Argentina.
5arbofarma 9!! ;altodetrin ?esins industries, Argentina.
1.$ INTRODUCTION O& 3;CI)I3NT. U.3D
1.$.1 Introduction to 4udipress.
Chemical Name: Gactose, povidone, crospovidone
C#. No: )*/*&/!&! C *++'&'*&/
5ualit" .tandard: The formulated ingredients lactose monohydrate, Lollidon '+ and
Lollidon 5G correspond to the current monographs in Ph.%ur., 0.P<6@ and NP.
!!
#pplications: The main application is for direct compression, but is also suitable as a
filler for hard gelatin capsules.
1.$.$ Introduction to 4udipress 4C3.
Chemical Name: Gactose and Povidone.
C#. NO: )*/*&/!&!C*++'&'*
5ualit" .tandard: The formulated ingredients lactose monohydrate and Lollidon '+
correspond to the current monographs in Ph.%ur., 0.P<6@ and N.P.
#pplications: The main application is for direct compression for use in chewable
tablets and lo>enges, for effervescent tablets and as bul$ing agent for modified release
formulations.
!"
1.( INTRODUCTION TO DRU8. U.3D
1.(.1 Introduction to #ceta0olamide
1. Description
<rand Name: Acetameb tablet, Acetamine tablet, 8iamo Tablet, etc.
Cateor"B 8iuretic, anti glaucoma, anti epilepsy
3mpirical &ormulaB5
(
D
,
6
(
O
'
.
"
.tructureB

Nomenclature: N&()&(aminosulfonyl)&!,',(&thiadia>ol&"&yl)&acetamide
6olecular =eiht: """."(/gm<mol
#ppearanceB Gightish yellow to white crystalline powder
.olubilit": Fery slightly soluble in water, slightly soluble in alcohol
.torae: .tore in a well closed container
$. )harmaco,inetics:
#bsorption: well absorbed orally
Onset of action: " hoursA I.F.B " minutes
)ea, effect: 5apsule, etended releaseB /&!" hoursA I.F.B !) minutesA TabletB "&(
hours
Duration: Inhibition of a#ueous humor secretionB 5apsule, etended releaseB !/&"(
hoursA I.F.B (&) hoursA TabletB /&!" hours
Distribution: %rythrocytes, $idneysA blood&brain barrier and placentaA distributes into
mil$ (O'+1 of plasma concentrations)
3:cretion: 0rine (2+1 to !++1 as unchanged drug)
!'
(. )harmacoloical #ctions:
Aceta>olamide is carbonic anhydrase en>yme inhibitor, present in renal tubular cell of
gastric mucosa, eocrine pancreas, cilliary body of eye, brain.5arbonic anhydrase is
an en>yme which catalyse the reversible reaction D
"
OC5O
"
to D
"
5O
'
,carbonic acid
spontaneously ioni>es into D
C
and 5O
'
&
Thus D
C
ion secretion ta$e place and DC
echanges with luminal 6a
C
through 6a
C
&D
C
antiporter. This distal 6a
C
echange ta$e
place only with L
C
which is lost in ecess.
*. Uses:
Aceta>olamide is often used in the treatment of various diseases.
@or glaucoma sufferers, the drug decreases fluid formation in the eye resulting in
lower intraocular pressure.
In epilepsy, its main use is in absence sei>ures, with some benefit in other sei>ure
syndromes. It is also used to decrease generation of cerebrospinal fluid in benign
intracranial hypertension and has shown efficacy in autosomal dominant
hyper$alemic periodic paralysis.
#cute mountain sic,ness:Aceta>olamide is sometimes ta$en prophylactically,
anywhere between !") milligrams (mg) to )++ mg per day, starting a few days
before going to the higher altitude. .uch use is recommended for those
ascending from sea level to '+++ meters (*/++ feet) in one day, or for those
ascending more than ,++ meters ("+++ feet) per day once above an altitude of
")++ meters (/"++ feet).
The drug forces the $idneys to ecrete bicarbonate, the con7ugate base of carbonic
acid. Ey increasing the amount of bicarbonate ecreted in the urine, the blood
becomes more acidic. Acidifying the blood stimulates ventilation, which is beneficial
during acclimati>atio.
-. #dverse effects:
5ardiovascularB @lushing
5entral nervous systemB Ataia, confusion, convulsions, depression, di>>iness,
drowsiness, ecitement, fatigue, headache, malaise
!(
8ermatologicB Allergic s$in reactions, photosensitivity, .tevens&Nohnson syndrome,
urticaria
%ndocrine = metabolicB %lectrolyte imbalance, growth retardation (children),
hyperglycemia, hypoglycemia, hypo$alemia, hyponatremia, metabolic acidosis
9astrointestinalB Appetite decreased, diarrhea, nausea, taste alternation, vomiting
9enitourinaryB 5rystalluria, glycosuria, hematuria, renal failure
DematologicalB Agranulocytosis, aplastic anemia, leu$openia, thrombocytopenia,
thrombocytopenic purpura
DepaticB 5holestatic 7aundice, hepatic insufficiency, liver function tests abnormal
6euromuscular = s$eletalB @laccid paralysis, paresthesia
OcularB ;yopia
OticB Dearing disturbance, tinnitus
;iscellaneousB Anaphylais.
/. Dose and dose schedule:
6oteB I.;. administration is not recommended because of pain secondary to the
al$aline pD.
ChildrenB
9laucomaB
OralB /&'+ mg<$g<day or '++&*++ mg<m
"
<day divided every / hours
I.F.B "+&(+ mg<$g<"( hours divided every , hours, not to eceed ! g<day
%demaB Oral, I.F.B ) mg<$g or !)+ mg<m
"
once every day
%pilepsyB OralB /&'+ mg<$g<day in !&( divided doses, not to eceed ! g<dayA sustained
release capsule is not recommended for treatment of epilepsy
#dults:
9laucomaB
5hronic simple (open&angle)B OralB ")+ mg !&( times<day or )++ mg sustained release
capsule twice daily
!)
.econdary, acute (closed&angle)B I.F.B ")+&)++ mg, may repeat in "&( hours to a
maimum of ! g<day
%demaB Oral, I.F.B ")+&'2) mg once daily
%pilepsyB OralB /&'+ mg<$g<day in !&( divided dosesA sustained release capsule is not
recommended for treatment of epilepsy
;ountain sic$nessB OralB ")+ mg every /&!" hours (or )++ mg etended release
capsules every !"&"( hours)
Therapy should begin "(&(/ hours before and continue during ascent and for at least
(/ hours after arrival at the high altitude
0rine al$alini>ation (unlabeled use)B OralB ) mg<$g<dose repeated "&' times over "(
hours
?espiratory stimulant in 5OP8 (unlabeled use)B Oral, I.F.B ")+ mg twice daily
3lderl":
OralB InitialB ")+ mg twice dailyA use lowest effective dose
1. Contraindication:
Aceta>olamide should not be ta$en by individuals if they have
sic$le cell anemia
allergic to sulfa medications
allergic to any carbonic anhydrase inhibitor
liver or $idney disease
adrenal gland failure (i.e. AddisonPs disease)
diabetes
pregnant or nursing mothers
>. Dru Interactions:
Inhibits 5QP'A( (wea$)
AmphetaminesB 0rinary ecretion of amphetamine may be decreasedA magnitude and
duration of effects may be enhanced.
!,
5yclosporine trough concentrations may be increased resulting in possible
nephrotoicity and neurotoicity.
8igitalis toicity may occur if hypo$alemia is untreated.
GithiumB Aceta>olamide increases lithium ecretionA lithium serum levels may be
decreased.
;ethenamineB 0rinary antiseptic effect may be prevented by Aceta>olamide.
PhenytoinB .erum concentrations of Phenytoin may be increasedA incidence of
osteomalacia may be enhanced or increased in patients on chronic Phenytoin therapy.
Primidone serum concentrations may be decreased.
RuinidineB 0rinary ecretion of Ruinidine may be decreased and effects may be
enhanced.
.alicylate use may result in carbonic anhydrase inhibitor accumulation and toicity
including 56. depression and metabolic acidosis
1.(.$ Introduction to 6etformin ?Cl
1. Description
<rand Name: 9lucophage, 9lycomate etc.
Cateor"B Anti 8iabatic.
3mpirical &ormulaB5
(
D
!!
6
)
D5G
.tructureB

6olecular =eiht: !,).,'gm<mol
#ppearanceB off &white crystalline compound.
.olubilit": @reely soluble in water = practically soluble in alcohol and aceton.
.torae: .tore in a well closed container.
!2
$. )harmaco,inetics:
#bsorption: well absorbed orally
Onset of action: '&( hour.
Distribution: %rythrocyte mass may be compartment of distribution.
3limination plasma half life: appro. ,."hr.
3:cretion: *+1 drug ecrited in urine with in "(hr.
(. Uses:
)ediatric Use
The safety and effectiveness of 9G05OPDA9% for the treatment of type " diabetes
have been established in pediatric patients ages !+ to !, years (studies have not been
conducted in pediatric patients below the age of !+ years). 0se of 9G05OPDA9% in
this age group is supported by evidence from ade#uate and well&controlled studies of
9G05OPDA9% in adults with additional data from a controlled clinical study in
pediatric patients ages !+ to !, years with type " diabetes, which demonstrated a
similar response in glycemic control to that seen in adults
8eriatric Use
5ontrolled clinical studies of 9G05OPDA9% and 9G05OPDA9% M? did not
include sufficient numbers of elderly patients to determine whether they respond
differently from younger patients, although other reported clinical eperience has not
identified differences in responses between the elderly and younger patients.
;etformin is $nown to be substantially ecreted by the $idney and because the ris$ of
serious adverse reactions to the drug is greater in patients with impaired renal
function, 9G05OPDA9% and 9G05OPDA9% M? should only be used in patients
with normal renal function
*.#dverse effects:
& 8iarrhea
& 6ausea = vomiting.
& Asthenia
& @letuiense
!/
& In7estion
-. Contraindication:
& ?enal dysfunction
+ Lnown hyper sensitive reactions.
&;etabolic acidosis.
/. Dru intractions:
8l"buride: In a single&dose interaction study in type " diabetes patients,
coadministration of metformin and glyburide did not result in any changes in either
metformin pharmaco$inetics or pharmacodynamics. 8ecreases in glyburide A05 and
5ma were observed, but were highly variable. The single&dose nature of this study
and the lac$ of correlation between glyburide blood levels and pharmacodynamic
effects, ma$es the clinical significance of this interaction uncertain.
&urosemide: A single&dose, metformin&furosemide dr ug interaction study in healthy
sub7ects demonstrated that pharmaco$inetic parameters of both compounds were
affected by coadministration.@urosemide increased the metformin plasma and blood
5ma by ""1 and blood A05 by !)1, without any significant change in metformin
renal clearance. :hen administered with metformin, the 5ma and A05 of
furosemide were '!1 and !"1 smaller, respectively, than when administered alone,
and the terminal half&life was decreased by '"1, without any significant change in
furosemide renal clearance. 6o information is available about the interaction of
metformin and furosemide when coadministered chronically.
!*
$. R37I3= O& =OR@ DON3
$.1 Revie' of =or, Done On Co+)rocessed 3:cipients.
8onnissen et al.2
/
A$BB1C developed a continuous production of directly compressible
powders by coprocessing acetaminophen and carbohydrates via spray drying. Einary
and ternary powder mitures containing drug substance and carbohydrates were
prepared by co&spray drying and evaluated on spray drying processibility, powder
hygroscopicity, flowability, and compactibility. The influence of process parameters
during spray drying on the compaction behaviour of drug<ecipient mitures was
investigated via Dec$el analysis. %rythritol, lactose, maltodetrin, and mannitol were
efficient in co&spray drying with acetaminophen. Dowever, lactose mitures showed
poor flowability. .pray dried mitures containing mannitol and erythritol were
characteri>ed as non&hygroscopic, highly dense, and good flowing powders. ;annitol
increased tablet tensile strength in contrast with the poor compactibility of erythritol.
;anltodetrin was selected for further eperiment because it provided ecellent tablet
tensile strength. The use of erythritol, maltodetrin and mannitol in binary
drug<%cipient mitures resulted in high process yields. 5ompacts of erythritol,
mannitol and maltodetrin were characteri>ed by higher tablet tensile strength at
higher spray drying temperature due to the increased particle fragmentation of
erythritol and mannitol mitures and increased plastic deformation of maltodetrin
formulations. A combination of erythritol, maltodetrin and mannitol was selected for
further formulation and process optimi>ation of co&spray dried powders for direct
compression.
Dohn et al.2
1
A$BB/ C evaluated a microcrystalline cellulose based ecipient having
improved compressibility, whether utili>ed in direct compression, dry granulation or
wet granulation formulations, is disclosed. The ecipient is an agglomerate of
microcrystalline cellulose particles and an effective amount of surfactant, which, in
preferred embodiments is an anionic surfactant present in amount ranging from about
+.!1 to about +.)1, by weight of the microcrystalline cellulose, where in the
microcrystalline cellulose and surfactant are in intimate association with each other.
One preferred anionic surfactant utili>ed in the novel ecipient is sodium lauryal
sulphate.
"+
Uhum'anho et al.2
>
A$BB*C investigated the effect of varying the compression
pressure on the brittle fracture tendency of I& cellulose and lactose. Tablet tensile
strength (T), Pac$ing fraction(P
f
), and brittle fracture inde(E;I) were determined at
different compression pressure (+./", !."" and !.,' ; Pa). in another aspect of study,
I& cellulose and tapioca powders were mied in various proportion to obtain powder
of varying plastoelasticity.their tableting characteristics T, P
f,
= E@I wre also
determined at the different compression pressure. The difference in the response of
tablets to the change in compression pressure relates to the difference in the
plastoelasticity of the material tested.
Tsuimin et al.2
E
A$BBBC modifed the physical properties of microcrystalline cellulose,
the slurry form of this material was co&dried with cyclodetrin. ;55 slurry was
blended with at concentration of !+1 & )+1 w<w as a dried mass relative to ;55.
The mitures were than granulated with water and co&dried at ,+
o
c for !"hr or until a
constant weight was reached. 5o&dried granules were pulveri>ed, and the fraction
between ,! and !)+m in si>e was received. The powder and tableting properties of the
co& dried product were compared to those of the various grades of the ;55 and
corresponding components and physical mitures. The results showed that the
products of ;55 co&dried with significantly improved flowability was due to more
rounded shape of the particles formed with this co&dried process. ;oreover, the
compactibility and disintegration properties of the tablets produced from the co&dried
products were even better than those using ;55 alone, or various grade of ;55. In
final conclusion , ;55 c+&dried provides a useful %cipient for direct compression.
Olaf et al.2
1B
A$BB(C compared tablet formulation of compound based lactose and
starch (/)B!)1 w<w) to pure substance and graded mitures. Pressure& time&profiles,
pressure&porosity&profiles and compactibility&plots help to evaluate tableting property.
They studied in detail the disintegration and drug release from starlac compared to
those of the physical miture and this especially at higher maimum.
Rao et al.2
11
A1EEEC developed cheaper, indigenous, directly compressible lactose by
spry drying slurry of lactose I.P. the modified lactose (spry dried lactose & .8G) was
characteri>ed by evaluating physicochemical property and flow behaviour and the
results obtained were compared with those of mar$eted directly compressible
"!
lactose(;8G). The directly compressible .8G = ;8G was also evaluated by
compression on a rotary tablet machine results indicated that .8G has the potential to
be used as directly compressible lactose which replace imported direct compressible
lactose.
8ohel et al.2
1$
A$BB(C developed co&processed ad7uvant consisting of ;55, dibasic
calcium phosphate di hydrate and croscarmellose sodium. The properties of each
components were evaluated and tablets of 6imesulide were prepared to evaluate the
functionalities of the co&processed diluents. It was determine that developed ad7uvant
ehibited satisfactory tablet charachteristics.
Doani et al.2
1(
A$BB-C formulated a novel multifunctional co&processed ad7uvant
consisting of three $nown diluents those shows different consolidation. The method of
wet granulation was adopted for the preparation of co&processed mechanism. ;55
and colloidal silicone dioide, lactose monohydrate and dibasic calcium phosphate
dehydrate were used as independent variable in a simple lattice design. 5ross
carmellose sodium was used (1 level intra granularly in all the batches the granules
(((<!"+J) were for angle of repose, bul$ density, tapped density = carr-s inde. The
tablet of compressed ad7uvants was characteri>ed for crushing strength, friability and
disintegration time. ;ultiple linear rgressions were adopted for evolved refined
mathematical model. A chec$ point method was prepared for evaluation of the particle
si>e distribution, moisture upta$e and dilution potential by using nimesulide as model
drug. The results shows that desiered product characters can be obtained by varying
the #uantity of ;55, lactose and 85P.
$.$ R37I3= =OR@ DON3 ON 4UDI)R3..
.enle et al.2
1*
A$BB>C developed microsphere&based once&daily modified release
tablet formulations of diltia>em hydrochloride (8D), a potent calcium channel bloc$er
used in angina pectoris. @or this purpose, 8D&loaded microspheres were prepared by
the solvent evaporation techni#ue using %udragit ?. !++. The effect of variation in
the drug<polymer ratio on the physical and release characteristics of the microspheres
was investigated. After the selection of the suitable microspheres, tablets were
""
compressed using 5ompritol /// ATO, Gudipress and 5ellactose /+ as different direct
tableting agents and ecipients. As a result, modified release tablet formulations of
8D&loaded microspheres were designed successfully for oral administration once
rather than two or three times a day in angina pectoris.
3l+6aradn" et al.2
1-
A$BB1C prepare cores containing the drug were prepared by
direct compression using microcrystalline cellulose and Gudipress as hydrophilic
ecipients with the ratio of !B!. 5ores were then coated se#uentially with an inner
swelling layer of different swellable materialsA either %plotab, 5roscarmellose
sodium, or .tarch ?M !)++, and an outer rupturable layer of different levels of
ethylcellulose. The effect of the nature of the swelling layer and the level of the
rupturable coating on the lag time and the water upta$e were investigated. 8rug
release rate studies were performed using 0.P paddle method. ?esults showed the
dependence of the lag time and water upta$e prior to tablet rupture on the nature of
the swelling layer and the coating levels. %plotab showed a significant decrease in
the lag time, followed by 5roscarmellose sodium and finally by .tarch ?M !)++.
Increasing the level of ethylcellulose coating retarded the diffusion of the release
medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.
?ascice, et al.2
1/
A$BB/C developed modified release tablet formulations containing
diltia>em hydrochloride&loaded microspheres to be ta$en once rather than two or three
times a day was attempted. @or this purpose, ethylcellulose microspheres were
prepared by emulsion&solvent evaporation techni#ue. The influence of emulsifier type
and drug<polymer ratio on production yield, encapsulation efficiency, particle si>e,
surface morphology and in&vitro release characteristics of the microspheres was
evaluated. .uitable microspheres were selected and tabletted using different tabletting
agents, Gudipress, 5ellactose/+, @low&Gac!++ and ecipients 5ompritol/// ATO,
Lollidon.?. Tablets were evaluated from the perspective of physical and in&vitro drug
release characteristics. It was seen that type and ratio of the ecipients played an
important role in the tabletting of the microspheres. As a result, two tablet
formulations containing !/+ mg diltia>em hydrochloride and using either
"'
5ompritol/// ATO or Lollidon.? were designed successfully and maintained drug
release for "( h with >ero order and Diguchi $inetics, respectively.
Cavallari C et al.2
11
A$BB-C prepared physical mitures containing indomethacin and
beta&lactose and alpha&lactose&based ecipients (Gudipress and 5ellactose). The
mitures were compacted with the aid of ultrasound, obtaining tablets, which were
milled and sieved. 9ranules thus obtained were eamined by optical microscopy and
differential scanning calorimetry. The intense yellow color of the granules and the
absence of indomethacin pea$ in thermograms suggest important modifications of
indomethacin physical stateA the drug thus modified appears to be spread on the
ecipient particle surface as a thin film, giving a lustrous appearance. 6o influence of
ultrasound was observed on phase transition concerning lactoseA only loss of water
was important under high energy ultrasound. 8issolution profiles suggest an increased
release of the drug from the systems treated with ultrasound at high energy, with
respect to a traditional compactionA while no difference could be evidenced among the
three ecipients that, however, appear all suitable for this ultrasound&aided direct
compression process.
Doani et al.2
1>
A$BB-C direct compression is the preferred method for the preparation
of tablets. The present review outlines the importance of the functionality of the
directly compressible ad7uvants in the formulation of tablets. The co&processing is the
most widely eplored method for the preparation of directly compressible ad7uvants
because it is cost effective and can be prepared in&house based on the functionality
re#uired. Dence, the present review focuses on the properties of the co&processed
directly compressible ad7uvants available in the mar$et.
.elim et al.2
1E
A$BB-C prepared capsules of different formulations by using a
hydrophilic polymer, anthan gum and a filler Gudipress. ;etformin hydrochloride,
which is an anti&diabetic agent, was used as a model drug here with the aim to
formulate sustained release capsules. In the first , formulations, metformin
hydrochloride and anthan gum were used in different ratio. Gater, Gudipress was
added to the formulations in a percentage of /1 to (!1. The total procedure was
carried out by physical miing of the ingredients and filling in capsule shells of si>e S
!S. As metformin hydrochloride is a highly water soluble drug, the dissolution test
"(
was done in ")+ ml distilled water in a thermal sha$er (;emmert) with a sha$ing
speed of )+ rpm at '2
+
5 T +.)
+
5 for , hours. After the dissolution, the data were
treated with different $inetic models. The results found from the graphs and data show
that the formulations follow the Diguchian release pattern as they showed correlation
coefficients greater than +.** and the sustaining effect of the formulations was very
high when the anthan gum was used in a very high ratio with the drug. It was also
investigated that the Gudipress etended the sustaining effect of the formulation to
some etent. Eut after a certain period, Gudipress did not show any significant effect
as the pores made by the anthan gum networ$ were already bloc$ed. It is found here
that when the metformin hydrochloride and the anthan gum ratio was !B!, showed a
high percentage of drug release, i.e. *!./+1 of drug was released after , hours. Eut
:ith a anthan gum and metformin hydrochloride ratio of ,B!, a very slow release of
the drug was obtained. Only ,,.,/1 of the drug was released after , hours. The
percent loading in this case was !(1. Again, when Gudipress was used in high ratio, it
was found to retard the release rate more prominently.
@apat et al.2
$B
A$BB*C this wor$ has focused on the effects of different
hydroypropylmethylcellulose (DP;5) types and DP;5 Bdirect tabletting agent
(85&agent) ratio on Ferapamil Dydrochloride (F?P D5l) release from monolayered
and three&layered matri tablets. Investigated polymers were ;ethocel L!++GF,
L!);, L!++; and 85&agent was GudipressU G5%. %ight formulations were
prepared as monolayered matri tablets while four formulations were prepared as
three&layered matri tablets by direct compression method. 8rug release studies were
carried out according to the method given for 8elayed ?elease Articles in 0.P
MMFII. DP;5 types and ratios were found to be effective on drug release. Increasing
amount and viscosity grade of DP;5 resulted in a decrease in release of drug from
the matrices. Tablets containing low viscosity grade DP;5 at inner and outer layers
presented release profiles close to or within the limits of pharmacopeia. ?elease data
of three&layered matri tablet (@!") and the reference product (IsoptinU &LLD) which
were in agreement with 0.P MMFII criteria, were evaluated by mathematical models
(>ero order, first order, Diguchi, Dison&5rowell, Lorsmeyer&Peppas), difference
factor (f!) and similarity factor.
")
6d. .elim Re0a et al.2
$1
A$BB(C underta$en to investigate the effect of plastic,
hydrophilic and hydrophobic types of polymers and their content level on the release
profile of drug from matri systems. As the physico&chemical nature of the active
ingredients influence the drug retarding ability of these polymers, three different
drugs were used to evaluate their comparative release characteristics in similar
matrices. ;atri tablets of theophylline, diclofenac sodium and diltia>em D5l using
Lollidon .?, 5arnauba wa and Dydroypropyl methylcellulose (DP;5&!)cps) were
prepared separately by direct compression process. The 0.P Eas$et method was
selected to perform the dissolution test carried out in ")+ ml +.!6 D5l for first two
hours and !+++ ml phosphate buffer of pD ,./ for ten hours. .tatistically significant
differences were found among the drug release profile from different classes of
polymeric matrices. The release $inetics was found to be governed by the type and
content of polymer in the matri system. Digher polymeric content (2)1) in the
matri decreased the release rate of drug because of increased tortuosity and
decreased porosity. At lower polymeric level (")1), the rate and etent of drug
release was elevated. 5arnauba wa was found to cause the strongest retardation of
drug. On the otherhand, highest drug release was from DP;5 matrices while
Lollidon .? gave an intermediate release profile between these two polymers.
?elease rate was also found to be the function of physico&chemical nature of drug
molecule. Theophylline and diltia>em D5l, being soluble in nature, released faster
than diclofenac sodium from all matri systems. The release mechanism was eplored
and eplained with bieponential e#uation. ?elease profile showed a tendency to
follow >ero&order $inetics from DP;5 matri systems whereas @ic$ian (5ase I)
transport was predominant mechanism of drug release from Lollidon .? matri
system. The mean dissolution time (;8T) was calculated for all the formulations and
the highest ;8T value was obtained with 5arnauba wa for all the drugs under
investigate. The results generated in this study showed that the profile and $inetics of
drug release were functions of polymer type, polymer level and physico&chemical
nature of drug. A controlled plasma level profile of drug can be obtained by 7udicious
combination of polymers and modulation of polymer content in the matri system.
<udavFri G et al.2
$$
A$BB1C clinical studies confirm that inta$e of folate, vitamin E,
and E!" above the current recommended dietary allowance is of great significance in
the primary prevention of coronary heart disease. In order to fulfill the ever increasing
",
re#uirements concerning the eternal appearance, reproducible production of
medicines and to decrease the time necessary for the preformulation and formulation
eperiments, I selected methods which enabled rational eperimental design and fast
ob7ective evaluation. The ob7ective of my thesis was to formulate tablets containing
folic acid, vitamin E, and E!" of optimal therapeutic concentration and of re#uired
stability in the presence of novel ecipients applied in direct compression. In the
course of my preformulation wor$ thermoanalytical (8T9, 8.5), chromatographic
(DPG5) and spectrometric (6I?) methods were applied. 8estabili>ing interactions
were evaluated with directly compressible ecipients, li$e Ac&8i&.ol, 5ellactose,
Tablettose, Avicel PD!+!, Gudipress. Interactions were detected in the ! C ! physical
mitures of vitamins and ecipients containing lactose (5ellactose, Gudipress,
Tablettose) and their destabili>ing effect was confirmed. The results of preformulation
studies enabled detection of drug&ecipients interactions and selection of compatible
ecipient system to the given drug composition to formulate dosage form of re#uired
stability, processability and effectiveness.
8onul N et al.2
$(
A$BBBC investigated the consolidation and compressibility properties
and also the dilution potentials of some novel directly compressible filler&binders. @or
this purpose, Gudipress and 5ellastose /+ (one&body compounds), Tablettose 2+ and
Tablettose /+ (alpha&mono agglomerated lactose) were selected. They were diluted at
predetermined percentages with .pherolac !++ which is a coarse sieved hydrous
crystalline lactose. The consolidation and compressibility properties of the prepared
powder mitures were determined. The eperimental data were evaluated by using a
computer programme (Easic /+).
?ein0 R et al.2
$*
A$BBBC using Gudipress greatly simplifies formulation development
and the manufacturing process because only the active ingredient Gudipress and a
lubricant need to be mied briefly before being compressed into tablets. The studies
described here were designed to investigate the scale&up of Gudipress&based
formulations from laboratory to production scale, and to predict changes in tablet
properties due to changes in format, compaction pressure, and the use of different
tablet presses. It was found that the tensile strength of tablets made of Gudipress
increased linearly with compaction pressures up to '++ ;Pa. It was also independent
of the geometry of the tablets (diameter, thic$ness, shape). It is therefore possible to
"2
give an e#uation with which the compaction pressure re#uired to achieve a given
hardness can be calculated for a given tablet form. The e#uation has to be modified
slightly to convert from a single&punch press to a rotary tableting machine. Tablets
produced in the rotary machine at the same pressure have a slightly higher tensile
strength. The rate of increase in pressure, and therefore the throughput, has no effect
on the tensile strength of Gudipress tablets. It is thought that a certain minimum dwell
time is responsible for this difference. The production of tablets based on Gudipress
can be scaled up from one rotary press to another without problem if the powder
mitures are prepared with the same miing energy. The tensile strength curve
determined for tablets made with Gudipress alone can also be applied to tablets with a
small #uantity (V !+1) of an active ingredient.
8oto @ et al.2
$-
A1EEE) developed a novel type of multipurpose ecipient (;P%) with
high binding characteristics and high fluidity. In this study, the capabilities of ;P%s
(Gudipress and ;icrocelac) were compared with those of ecipients in general use.
Also, the effects on powder and tableting characteristics of the physical properties and
contents of active ingredients were eamined in tablets prepared with these ;P%s by
the direct compression method. ;ultipurpose ecipients mied with ad7uvants such as
fillers, binders, lubricants, disintegrants, and the li$e show superior fluidity and
compressibility. Tablets containing very small amounts of highly active ingredients
with little dispersion were prepared. Dowever, with increases in active ingredient
content, each of the physical properties was affected strongly by the properties of the
active ingredient. Tablets with appropriate hardness and disintegration characteristics
could be prepared by miing of different types of ;P%s.
6onedero )erales 6D et al.2
$/
A1EE*C determined the consolidation mechanisms of
the lactose&based ecipients @ast @lo Gactose, Gudipress, 5ellactose and Tablettose.
The Geuenberger e#uation has been modified to obtain values of compressibility and
compactability by using a value of compactability obtained from a tablet at maimum
applied force and by substituting deformation resistance by relative deformation
resistance. Also, parameters obtained from plots of the Dec$el tablet&indie and
e7ected&tablet methods were calculated in order to establish the comparative
consolidation mechanisms in the lactose&based ecipients under study. The possibility
of using the absolute value of the difference between upper and lower surface
"/
hardnesses of the tablets made on an eccentric press is suggested as an alternative
method to determine the comparative consolidation mechanisms of different
substances.
"*
(. #I6 O& )R3.3NT .TUDH
;a7or challenge for tablet manufacture comes from the powder characteristics of the
materials to be compressed. This in turn poses a challenge in achieving greater
productivity and better #uality product especially on the new generation high&speed
machines. The conventional method of wet granulation has inherent drawbac$s in
terms of achieving batch&to&batch reproducibility and higher productivity, especially
in low particle si>e range. 5ompared t wet granulation, direct compression re#uires
fewer processing steps, offers simplified validation and results in product with better
stability. Advancement in direct compression technology has come in the form of
directly compressible co&processed ecipients as a problem solver. The present study
evaluates and characteri>es two different spray dried co&processed materials, one
comprising lactose, crospovidone, and povidone and the other composed of lactose
and povidone. In this study, the capabilities of multipurpose ecipients (;P%s) were
compared with lactose. Also, the effects on powder and tableting characteristics of the
physical properties and contents of active ingredients were eamined in tablets
prepared with these ;P%s by direct compression method. Prototype tablet
formulations were developed with these co&processed materials using aceta>olamise
as a poorly compressible drug and metformin D5l as a hygroscopic drug. Their
performance was compared vis&W&vis conventionally processed tablet formulations.
'+
*. 6#T3RI#4. #ND 35UI)63NT U.3D
The following materials that were either A?<G? grade or the best possible grade were
used as supplied by the manufacturer without further purification or investigation.
No. 6aterials Used 8rade .upplier
!. Aceta>olamide E.P. Xydus 5adila pharmaceutical Gtd., Ahmedabad.
". ;etformin D5G E.P. Xydus 5adila pharmaceutical Gtd., Ahmedabad.
'. Gudipress 0.P EA.@, 9ermany.
(. Gudipress G5% 0.P EA.@, 9ermany.
). Talc A.?. Adelphi Gabs. Gtd.
,. ;agnesium stearate A.?. Adelphi Gabs Gtd.

The following e#uipments were used in the present wor$B
No. 3%uipments Compan" I .upplier
!. %lectric balance .himad>u, Napan.
". ?otap sieve sha$er Pritec.A.5. Induction motor 9urprit elc.5o.
'. 0.F..pectrophotometer 0.F.!"+! , .himad>u, Napan.
(. Tablet Punchig machine ?oyal artist, ;umbai.
). 8ial caliper ;ituoya, Napan.
,. Dardness tester ;onsento.
2. @riabilator ?oche.
/. 8isintigration Apparatus %lectrolab, model %8 ", India.
*. 8issolution Apparatus %lectrolab,dissolution apparatus,0.P MMIII
'!
-. 63T?ODO4O8H
-.1 )R3)#R#TION O& C#4I<R#TION CUR73
-.1.1 )R3)#R#TION O& .T#ND#RD CUR73 O& #C3T#GO4#6ID3 IN
B.1N
?C4 A)?+1.$C
!. An accurately weighted !++ mg of aceta>olamide was dissolved in !++ ml of
+.!6 D5I (PD !.") to get ! mg<ml solution.
". @rom this solution, pipette out !+ ml of solution in !++ ml volumetric flas$ =
volume is ad7usted to !++ ml to get !++ Yg<ml.
'. @rom this stoc$ solution, ali#uot of +.!, +.", +.(, +.,, +./, !, !.", !.(l, !.,, !./,
"l ml were pipette out in different !+ ml volumetric flas$ = volume is ad7usted
to !+ ml.
(. The absorbance of different solution was measured at ",, nm using 0.F.
spectrophotometer against respective parent solvent as a blan$.
). The standard curve was obtained by plotting absorbance vs. concentration in
Yg<ml.

Table -. .tandard calibration curve for #ceta0olamide
Concentration AJImlC #bsorbance at $// nm.
! +.+("
" +.!+"
( +."!2
, +.'!(
/ +.(""
!+ +.)(,
!" +.,!'
!( +.,,(
!, +.2/(
!/ +./2*
"+ +.*22
'"
''
&iure 1: .tandard Calibration Curve for #ceta0olamide
-.1.$ )R3)#R#TION O& .T#ND#RD CUR73 O& 63T&OR6IN ?C4 IN
)?O.)?#T3 <U&&3R A)?+/.>C
$1

!. An accurately weighted !++ mg of ;etfrminD5G was dissolved in !++ ml of
phosphate buffer (PD ,./ ) to get ! mg<ml solution.
". @rom this solution, pipette out !+ ml of solution in !++ ml volumetric flas$ =
volume is ad7usted to !++ ml to get !++ Yg<ml.
'. @rom this stoc$ solution, ali#uot of ", (, /l, !+, !" ml were pipette out in
different !++ml volumetric flas$ = volume is ad7usted to !++ ml.
(. The absorbence of different solution was measured at "'( nm using 0.F.
spectrophotometer against respective parent solvent as a blan$.
). The standard curve was obtained by plotting absorbence vs. concentration in
Yg<ml.

'(



&iure $: .tandard Calibration Curve of 6etformin ?Cl
Table /. .tandard calibration curve for 6etformin ?Cl
Concentration AJImlC #bsorbence at $(* nm.
+ +.+++
" +."+/
( +.'),
, +.)!/
/ +.,/+
!+ +./+!
!" +.*)*
')
-.$ )?H.IC#4 C?#R#CT3RIG#TION O& .#6)43.:
-.$.1 )article si0e distribution
$>
Particle si>e distribution :as performed on random samples of all the batching using
a nest of standard sieve such as '+, ((, ,+, /), !++,!"+, "++ meshes having )*+&,
')+&, ")+&, !22&, !(*&, !")&, and 2(&Ym openings, respectively. The sieves were
agitated on a rotap sieve sha$er (International 5ombustion ltd., Gondon) for )
minutes. @rom the percentage weight of agglomerates retained on each sieve, the
mean agglomerate diameter was calculated.
-.$.$ )ercentae fines
$E

It is defined as the percentage of the agglomerate passed through "++ ;esh. '+<"++
sieve fraction was used for further evaluation. The 1 yield, mean particle si>e and
percentage fines are recorded.
-.$.( #nle of repose.
%nar ?eposograph ,(+ (%nar @oundation ?esearch 5enter, India) was used for
determining angle of repose. ")gm sample was used for the test and the sample was
graded as ecellent, good, fair or poor if the value of angle of repose was found to be
'+&'"
o
, ''&')
o
, ',&'2
o
or '/&()
o
respectively.
-.$.* CarrKs inde:
(B2(1
A glass cylinder with !++ml capacity was filled with sample and tapped ()++ times)
from a height of " inches. The value of bul$ density and tapped density were
calculated. The percentage compressibility was calculated as !++ times the ratio of the
difference between tapped density and bul$ density to tapped density.


CarrKs inde:
',
-.$.- ?ausner Ratio
($
A glass cylinder with !++ml capacity was field with sample and tapped ()++ times)
from a height of "cms. The value of Dausner ratio was calculated as,
?ausner Ratio
-.$./ 7olume flo'abilit"
((
A 9lass funnel as described in the Eritish Pharmacopoeia-s flow ability test was fied
in a strictly vertical position. The bottom opening was bloc$ed by a plastic stic$ and
then '+gm of product was introduced carefully into the dry funnel in order to avoid
dusting and compaction. The funnel was unbloc$ed and the time the entire powder
needed to flow out of the funnel was measured (nZ'). @low ability was epressed in
seconds per !++gm of sample.
Table 1. .tandard indication of material
Indication #nle of repose Carr
2
s Inde: ?ausnerKs Ratio
%cellent ") & '+ ! [ !+ ! & !.!!
9ood '! & ') !! [ !) !.!" & !.!/
@air ', & (+ !, [ "+ !.!* & !.")
Passable (! & () "! & ") !.", & !.'(
Poor (, & )) ", [ '! !.') & !.()
Fery poor ), & ,) '" [ '2 !.(, & !.)*
Fery very poor \,) \'/ \!.,+
-.$.1 @a'a,itaKs and 4uddeKs e%uation.
(*
The pac$ability was evaluated by tapping the agglomerates in a measuring cylinder.
The data were analy>ed by using Lawa$ita-s and Gudde-s e#uation !, ", '.
'2
?espectively, where a and b Z constantA nZ Tap numberA and F
o
, F
n
and F
inf
Zpowder
bed volumes at initial, after nth tapping and at e#uilibrium state, respectively.
In this method, agglomerates<granules was filled in )+ml capacity measuring cylinder
was tapped from a height of " inches. The volume of the !++, "++, '++, (++ and )++
taps. The slope was obtained from the plot between ratios of number of taps. The
reciprocal of slope gave the value of Lawa$ita-s constant ]a- and from the value
intercept and ]a-, the value of ]b- was calculatedB
a
n
ab
!
5
n
+ =
LL A1C
o
inf o
F
F F
a

=
LL A$C
o
n o
F
F F
5

=
LL.. A(C
-.$.> @unoKs e%uation
(-
It is .imilar eperimental observation can be used to calculate Luno-s constant ]$- by
e#uation ( as followsB

M
f
N M
n
N AM
f
+ M
o
C e
A+,nC
.L..A*C
:here, M
f
2 M
n
2 M
o
N apparent densities at initial stateB after nth tapping (), !+, !), "+,
"), )+, 2), !++, "++, '++, (++)A and at e#uilibrium ()++
th
tap) respectively. $Z
constant.
-.$.E. 6oisture upta,e
A )&gm sample of Gudipress and Gudipress G5% were separately spread uniformly in
a ) cm diameter petridish, and the dish was stored at 2)1 relative humidity at ()^5 in
a dessicator. The percentage increase in weight was noted after "( hrs.
'/
-.( )R3)#R#TION O& T#<43T.
(/2(12(>
5onventional tablets were prepared by direct compression method. Other ecipients
were Gudipress =<or Guipress G5%, Talc = ;agnesium stearate. @or preparation of
tablet, drug was accuratelyA mi thoroughly with other ecipients by geometrical
miing method. The resultant miture was compressed into tablet using a single
punch machine (?oyal artist, ;umbai), !+ mm die and punches were ad7usted as a
weight of each tablet and hardness between '&) $g<cm
"
. The formula for various
formulations attempted has been given in table.

Table >. )reparation of #ceta0olamide tablet AmC
<atch Code #
1
#
$
#
(
#
*
#
-
#
/

Dru '+ ,+ *+ !"+ !)+ !/+
4udipress "2+ "(+ "!+ !/+ !)+ !"+
Talc , , , , , ,
6+stearate ' ' ' ' ' '
Table 't.AmC '++ '++ '++ '++ '++ '++
All the batches contains Gudipress G5% in batch A
2
to A
!"

Table E. )reparation of 6etformin ?Cl tablet AmC
<atch Code 6
1
6
$
6
(
6
*
6
-
Dru '+ ,+ *+ !"+ !)+
3:cipients "2+ "(+ "!+ !/+ !)+
Talc , , , , ,
6+stearate ' ' ' ' '
Table 't.AmC '++ '++ '++ '++ '++
All the batches contains Gudipress G5% in batch ;
,
to ;
!+

-.* 37#4U#TION O& T#<43T
-.*.1 Tablet Dimension
Thic$ness and diameter was measured using a calibration dial caliper. ten tablet of
each batch is calculated.
-.*.$ ?ardness
;onsento hardness taster was used to evaluate hardness of tablet. The taster consists
of a barrel containing a compressible spring held between two plungers. The lower
plunger was placed in contact with the tablet, and a >ero reading was ta$en. The upper
plunger was then forced aginst a spring by turning a thread bold until the tablet
'*
fractures. As the force of fracture was recorded, and the >ero force was deducted from
it. Ten tablet of each batch were evaluated.
-.*.( Tensile strenth
(E
The dimensions of tablets were measured by using a micrometer. The hardness of the
tablets was determined after "( hrs of compression (time for stress relaations of
compression) by using ;onsanto hardness tester (.hital .cientific Industries,
;umbai). @rom the values of diameter 8 (cm), thic$ness G (cm) and hardness P ($g)A
the tensile strength (;Pa) of the tablets was calculated by using %#uation ) as follows

T LLA-C
-.*.* &riabilit"
*B
@riability was evaluated as the percentage weight loss of "+ tablets in a friabilator
(model %@"A %lectrolab, ;umbai) for ( minutes at ")rpm. The tablets were then
dedusted and the loss in weight caused by fracture or abrasion was recorded as
percentage friability.

& L..A/C

:here, @ is percentage friability, :o is initial weight of tablets and : is final weight
of tablet

-.*.- =eiht 7ariation.
Twenty tablets randomly used, witch were weighed individualy and average was
calculated. Then deviation of each tablet from average weight was calculated and
percent deviation was computed.standard deviation was compired with the 0...P.
limits.

Table E. U.) 4imits
#verae 'eiht of tablets )ercentae deviation
!'" mg or less !+
!'" mg to '"( mg 2.)
'"( mg or more ).+
(+
-.*./ 4ubricant .ensitivit" Ratio
*1
Gubricant .ensitivity ?atio (G.?) is used as a #uantitative measure to epress
sensitivity of tableting materials (strength reduction) for lubricant. Agglomerates of
Gudipress, Gudipress G5% and magnesium stearate were mied in **B! proportion and
compressed into tablets. The lubricant sensitivity ratio was evaluated as per following
%#uation 2.
TS(u)
TS(l) TS(u)
Ratio y Sensitivit Lubricant

=
LLL A1C
:here, T.(u) and T.(l) is a tensile strength of unlubricated and lubricated tablets
respectively.
-.*.1 Dilution )otential .tud"
8ilution potential or dilution capacity is a measure of the proportion of poorly
compactable drug, which can be incorporated into a vehicle to produce satisfactory
tablets. 8ilution potential is assessed by comparing the hardness versus compaction
force curves for various binary mitures of the filler and poorly compactable
substance. ;any active ingredients are poorly compressible in either their crystalline
or their amorphous forms. Thus in choosing a vehicle it is necessary to consider the
dilution potential of the ma7or filler binder. It is not possible to give specific values for
the each filler because the dilution potential depends upon the properties of the drug
itself.
Aceta>olamide and ;etformin D5l have been used as a model drug for the
measurement of dilution potential. The poor tableting property of Aceta>olamide is
very well $nown to those good at the art. It is very difficult to produce tablets with
high content of drug because of Aceta>olamide is a high dose, poorly compressible
drug
("
. ;etformin D5l is a high dose, poorly flowing and hygroscopic in nature
('
.
8irectly compressible diluents (Gudipress and Gudipress G5%) or the physical blend
of the ingredients was blended with drug for ) min. The powder was blended with the
tableting aids li$e mai>e starch, saccharin, talc, and magnesium stearate. The powder
miture was tableted using ?otary Tablet machine (5admech ;achinery Gtd.,
Ahmedabad), fitted with !+&mm flat&faced punches. The average weight of tablets
(!
was '++ mg. The tablets were evaluated for tensile strength, friability, and
disintegration time.
Table 1B. Composition and results for dilution potential stud".
Ingredient
Eatch 5ode
4# 4< 4C 4D 43 4&
Gudipress ",! "'! "+! !2! !(! &
Gactose (Physical miture) & & & & & ",!
Aceta>olamide '+ ,+ *+ !"+ !)+ '+
Talc , , , , , ,
;g. .tearate ' ' ' ' ' '
Total :eight (mg) '++T!, '++T!" '++T!! '++T!( '++T+* '++T!)
)arameters
Tensile .trength (;Pa) !.!,( !.!(/ !.!+" +.**( +.(+/ +./!(
@riability (1) +.!'( +.,+" +.2(" +./+' ).++/ ".!'
8isintegration Time (min) 2.( 2 ,.) )." (./ )
Table 11. Composition and results for dilution potential stud".
Ingredient
Eatch 5ode
43# 43< 43C 43D 433 43&
Gudipress G5% ",! "'! "+! !2! !(! &
Gactose (Physical miture)
& & & & & ",!
Aceta>olamide '+ ,+ *+ !"+ !)+ '+
Talc , , , , , ,
;g. .tearate ' ' ' ' ' '
Total :eight (mg) '++T!, '++T!+ '++T!" '++T!) '++T+/ '++T!'
)arameters
Tensile .trength (;Pa) !.!2/ !.!)' !.!'/ !.++" +.'+/ +.2'"
@riability (1) +.!!" +.)/! +.,() +.2/" (./*! ".)'
8isintegration Time (min) /.) /.' 2.) 2." 2 ,
-.*.> Disinteration time
**
The time re#uired for disintegration of si tablets placed in each tube of disintegration
test apparatus (model %8"A %lectrolab, ;umbai), was measured at '2C!
o
5 using
*++ml distilled water.
-.*.E In+vitro dru release stud"
The method .pecified in 0...P as drug release test was followed.
)rocedure:
Tablet was placed in round bottomed flas$ of apparatus containing *++ ml of
dissolution medium. Assembly was set up as per re#uirement = condition was
maintained as per 0.P. .amples were withdrawn at +, !+, "+, = '+ min. After each
withdrawal, !+ ml of fresh dissolution medium was replaced at the same time. The
("
absorbance of withdrawn samples, after suitable dilution was measured at appropriate
_ma against appropriate buffer blan$s.

Table 1$. Conditions for in+vitro dru release stud"
Tablet used #ceta0olamide 6etformin?C4
U...). #pparatus used 0...P.Appratus&II
(paddle type)
0...P.Appratus&II
(paddle type)
Dissolution medium +.!6 D5G (pD&!.") Phosphate buffer (pD&,./)
Temperature '2 T +.)
o
5 '2 T +.)
o
5
R)6 !++ !++
Oma: ",) nm "') nm
('
/. R3.U4T. #ND DI.CU..ION
All the formulations were sub7ected to evaluation parameters such as thic$ness,
diameter, friability, weight variation, and in&vitro dissolution study. The results of all
the formulation was satisfied with predetermined ob7ects and results were shown in
the tabulated as well as graphical manner.
/.1 .tandard Calibration curve of model dru.
Table no. ) = , shows the absorbance readings of Aceta>olamide = ;etformin D5G
respectively. .ame way @igure ! = " represents the standard calibration curve of
Aceta>olamide = ;etformin D5G. The e#uation = value of ?
"
is given bellow.

& #ceta0olamide:
y Z "+.,* [ +.'/'+
?
"
Z +.**)+
+ 6etformin ?C4:
y Z +.+2/' C +.+''
?
"
Z +.**,"
/.$ )h"sical Characteri0ation of 3:cipients.
/.$.1 #nle of repose2 ?ausner
2
s ratio2 Carr
2
s Inde:2 9 &lo'abilit".
Angle of respose of both the mar$eted product was less than '"^ indicated good flow
property. In case of compressibility inde the both the material were ehibited
ecellent compression characteristics (5I V !" 1). Dausener ratio of both the product
are less than !.!( indicating good and acceptable property (D? V !.!()



((

Table 11. Results of ph"sical parameters
6aterial 4udipress 4udipress 4C3
#nle of Repose A
o
C '+.2, '!."(
<ul, Densit" Am I mlC +.)" +.)!
Tapped Densit"Am ImlC +.)/ +.)/
Carr
2
s Inde: A P C !+.'( !".+,
?aussner
2
s Ratio !.!! !.!'
&lo' Time Asec.C ).!, ,.!
/.$.$ )article .i0e #nal"sis.
The agglomerates of Gudipress and Gudipress G5% were analy>ed by rotap sieve
sha$er, the results revealed that all the agglomerates of both the mar$eted product
were passed through sieve "" mesh (2!+ Ym), not \"+ 1 passed through !"+ mesh
(!") Ym), and almost all the agglomerates retained on "++ mesh (2( Ym). As per the
analysis the mean particle si>e of Gudipress agglomerates was found !2/.,) Ym and
Gudipress G5% was found !*).'" Ym (Table !"). The scanning electron photograph
of both the mar$eted product is depicted in @igure (a and (b.
Table 1$. Results of particle si0e anal"sis stud" AnN1C
.tandard
.ieve
.i0e
reduced
A<1+<$C
Jm.
#rithmatic
mean.
=t.retained
AdC m.
P retained
A3C
=t. .i0e
A&N C : 3C
4udi. 4C3 4udi. 4C3 4udi 4C3
""<'+ 2!+&)++ ,+) +.+,2 +.!2, +.",/ +.2+( !,".!( (").*"
'+<(( )++&')) ("2.) +.+/* +.!," +.'), +.,(/ !)".!* "22.+"
((<,+ '))&")+ '+".) ,.+/* ).,/+ "(.') "".2" 2',)./ ,/2"./
,+</+ ")+&!22 "!'.) ).+") ,."++ "+.!+ "(./+ ("*!.' )"*(./
/+<!++ !22&!)+ !,'.) '.)/' ).)(+ !(.'' "".!, "'(".* ',"'.!,
!++<!"+ !)+&!") !'2.) (.!(( (.!)+ !,.)2 !,.,+ ""2/.' ""/".)+
!"+<"++ !")&2( **.) '.!** !.*!2 !".2* 2.,++ !"2"., 2),."+
()
&iuer (: )article si0e distribution of 4udipress and 4udipress 4C3
AaC
(,
AbC
&iure *: .36 photoraph of AaC 4udipress alomerates and AbC 4udipress
4C3 alomerates
/.$.( )ac,abilit" testin
*-
The pac$ability of samples were ascertained by comparing the constants a, b, and $,
in Lawa$ita-s and Luno-s e#uations, respectively (Table !'). The constant 3a4
represents the proportion of consolidation as closest pac$ing is attained. The
reciprocal of 3b4 and 3$4 represent the pac$ing velocity. The constant 3a4 for the
Gudipress (+.!++) was smaller than for the Gudipress G5%. The result indicates that
the agglomerates of Gudipress show good pac$ing even without tapping. The larger
value of 3b4 for the agglomerates of Gudipress (+.+*"/) proved that the pac$ing
velocity of the Gudipress was faster than the Gudipress G5%. The 3$4 for Gudipress
was found +.++(*. The smaller value of $ in the Luno-s e#uation supports the above
findings. The slow pac$ing velocity corresponds with proportion of the consolidation
of the powder bed per tap. The $awa$ita plot of Gudipress G5% and Gudipress
represent in @igure ). Gudipress is the co&processed multifunctional product, consists
of *'.( 1 I&lactose monohydrate, '." 1 polyvinyl pyrrolidone (Lollidon '+) and '.(
1 crospovidone (Lollidon 5G). The agglomerates of Gudipress showed good
compression property compared with other samples.

(2
Table 1(. Results of pac,abilit" testin
.ample @a'a,itaKs
Constant QaR
@a'a,itaKs
Constant QbR
@unoKs
Constant Q,R
Gudipress +.!++ +.+*"/ +.++(*
Gudipress
U
G5% +.!!" +.+)+) +.++/!

&iure -. @a'a,ita plot of 4udipress 4C3 and 4udipress
/.$.* 6oisture Upta,e stud"
After "( hr storage at 2) 1 relative humidity and ()`5, agglomerates of Gudipress
and Gudipress G5% adsorbed !! 1 w<w and !( 1 w<w moisture. This may be due to
the adsorptive nature of the PFP
(,
. The results revealed that the material is slightly
sensitive to moisture so, should be preserved in tightly closed container.
(/
/.( 3valuation of Tablet
/.(.1 Tablet dimension and ?ardness:
Tablet dimensions include diameter and thic$ness which was ta$en !+mm = ' mm
respectively. Three tablets of each batch were evaluated and hardness values were
found in range of '.) to ,.) $g<cm
"
. The results were tabulated in table no.!(=!).
Table 1*. 3valuation of #ceta0olamide Tablet.
<atch
Code
6ean Diameter
ADC mm
6ean Thic,ness
A4C mm
6ean ?ardness
A)C ,Icm
$
4udi 4C3 4udi 4C3 4udi 4C3
#
1
!+.++ +.*/ '.!" '.!" ).+ ).+
#
$
!+.! +.** '.!+ '.!+ (.+ ,.)
#
(
!+.' !+.( '.+/ '.+/ (.) (.)
#
*
!+.+ !+." '.!+ '.+, '.) ).+
#
-
!+.+ !+.+ '.!+ '.+) '.) '.)

Table 1-. 3valuation of 6etformin?C4
<atch Code 6ean Diameter
ADC mm 2
6ean Thic,ness
A4C mm.
6ean ?ardness
A)C ,Icm
$

4udi. 4C3 4udi. 4C3 4udi. 4C3
6
1
!+.! !+.! '.*+ '.+/ ).+ ).)
6
$
!+.+ !+." '.*" '.+* (.) ).+
6
(
!+.' !+.+ '.// '.+/ (.+ (.)
6
*
!+.+ +.** '.*+ '.+2 '.) (.+
6
-
!+.( !+.! '.*" '.!+ '.) (.+
6
/
!+." +.*/ './+ '.!! '.+ '.)
(*
/.(.$ &riabilit":
@riability test was carried out as per standard method given in 0.P.. These values are
with in the acceptable limit (V !1), implies good compactness and strength of each
formulation. The results were tabulated in table no.!, = !2.
/.(.* Tensile .trenth:
Tensile .trength \+./) was selected as the selection criterion for the formulation.
Almost all batches ehibit satisfactory Tensile strength. The results were tabulated in
table no.!, = !2.
/.(.- Disinteration time:
The disintegration time depends on the tensile strength of tablet. The disintegration
time of each formulation is mentioned in table no.!, = !2. 8isintegration time of
Gudipress containing tablet is between +.(* to !.+* minute while Gudipress G5%
containing tablet having *.(/ to !".+! minute shows that the Gudipress containg tablet
disintegrate faster then the Gudipress G5% containing tablet because of presence of
super disintegrant.

Table 1/: 3valuation of #ceta0olamide Tablet.
<atch Code &riabilit" APC

Tensile strenth
A6paC
Disinteration time
AminC
4udi. 4C3 4udi. 4C3 4udi. 4C3
#
1
+."!+ +."+' !.++ !.+" +.(* *.*+
#
$
+.""( +.!*) +.2* !.'" +.)( *.(/
#
(
+."!/ +."!+ +.// +./2 +.)* *.),
#
*
+.""! +.")+ +.2+ +.** !.!' !+.)"
#
-
+.""+ +."!* +.2+ +.2! !.+* !".+!

Table 11: 3valuation of 6etformin?C4 Tablet.
<atch Code &riabilit" Tensile strenth Disinteration time
)+
A&C P 2 ATC Amin.C
4udi. 4C3 4udi. 4C3 4udi. 4C3
6
1
+."(' +."'! +.** !.!+ ).!( 2.+/
6
$
+."() +."', +.*+ +.*/ ).") 2.(!
6
(
+.")) +."(" +.2/ +.*! (.(! ,."(
6
*
+."," +."(2 +.2+ +./" ).+" ,.)+
6
-
+.",) +.")" +.,2 +.2* (.(, ,."/
6
/
+."2" +.")* +.,+ +.2! (.'! ,."!
/.(.1 4ubication .ensitivit" Test.
The addition of magnesium stearate decreases the tensile strength of tablets. It is well
$nown that prolonged miing of magnesium stearate produces film around the
agglomerates and prevents the agglomerates from binding. The effect is more
pronounced in the case of plastically deforming material than for material undergoing
brittle fracture. In light of these arguments and from the data shown in Table !/ and
!*, one can conclude that prolonged miing of magnesium stearate decreases the
tensile strength of tablets. Gubricant sensitivity ratio is a #uantitative measure to
epress with a lubricantB the greater the lubricant sensitivity ratio, the more the
susceptibility to mi with a lubricant. ;iing time ehibits a greater effect on tensile
strength as compared with the effect of compression time. Dence, one may conclude
that both the agglomerates (Gudipress and Gudipress G5%) are sensitive to lubricant.
Table 1>. 3ffect of manesium stearate on 4udipress alomerates
InredientsICondition # < C D 3
Gudipress (1) !++ ** ** ** **
;agnesium stearate (1) & ! ! ! !
;iing time (min) & ! ! !+ !+
5ompression time (sec) ! ! '+ ! '+
Dardness ($g<cm
"
) *.) /.( *." /.) *.)
Tensile .trength (;Pa) ".() ".!+ ".'/ !./" !.*/
Gubricant .ensitivity ?atio (1) & +.!(" +.+"/ +.")2 +.!*!
Table 1E. 3ffect of manesium stearate on 4udipress 4C3 alomerates
InredientsICondition & 8 ? I D
Gudipress G5% (1) !++ ** ** ** **
;agnesium stearate (1) & ! ! ! !
;iing time (min) & ! ! !+ !+
5ompression time (sec) ! ! '+ ! '+
Dardness ($g<cm
"
) /.2 / /.) / /./
Tensile .trength (;Pa) ".'( ".+! "."* !./( !.*)
Gubricant .ensitivity ?atio (1) & +.!(! +.+"! +."!' +.!,,
)!
/.(.>. Dilution )otential .tud"
Tablets were prepared using !+&)+1 aceta>olamide. The authors arbitrarily decided to
select a batch that showed a friability value V ! and tensile strength tensile strength \
+./) ;Pa. @rom the results shown in Table 'and (, it is #uite evident that (+1
aceta>olamide produces acceptable tablets with both the mar$eted ad7uvants
(Gudipress and Gudipress G5%). As the percentage of aceta>olamide was increased,
the tensile strength decreased (@igure , and 2). This result might be caused by the
poor compressibility and elastic recovery of aceta>olamide which also affects the
percent friability and disintegration time. Physical miture having same composition
did not yield satisfactory tablets with !+ 1 aceta>olamide. This results shows that
agglomerates of Gudipress and Gudipress G5% ehibited higher compressibility and
better binding property than the other batches. 8isintegration time of batch GA to G@
compared with the batch G%A to G%@, the results revealed that Gudipress
agglomerates also decreases the disintegration time of aceta>olamide tablet then the
Gudipress G5% tablets. @or the metformin D5l drug the dilution potential capacity of
both the mar$eted product was found )+ 1.
&iure /. Dilution potential stud" of P #ceta0olamide 'ith 4udipress
)"
&iure 1. Dilution potential stud" of P #ceta0olamide 'ith 4udipress 4C3
/.(.E In+vitro Dru release stud"
In the In vitro drug release study of Aceta>olamide and ;etformine D5l the results
obtained are mentioned in Table "! = "". The drug release of Aceta>olamide is */."'
1 with the Gudipress and *).22 1 with Gudipress G5%. The Gudipress containing
tablets shows faster drug release than the tablet containing Gudipress G5%, because
Gudipress contains the cross povidon as a super disintigrater which increase the
disintigration rate.
Table $B. Information of the mar,eted tablets.
Dur Name #ceta0olamide 6etformin?C4
<rand Name 8iamo. 9lycomate.
Dose ")+ mg. )++ mg.
<atch No. 8I;. !!2 ''++++'2
6f. Compan" ;edreich Gtd. 0.F. Gtd.
Table $1: In+vitro dru release stud" of #ceta0olamide Tablet.
Time #bsorbance )ercentae C)R
)'
Amin.C
6ar,etedTablets. )repared
tablets
'ith
4udipress
)repared
tablets
'ith
4udipress
4C3
6ar,eted
tablets
)repared
tablets
'ith
4udipress
)repared
tablets
'ith
4udipress
4C3
+ +.+++ +.+++ +.+++
+.+++ +.+++ +.+++
!+ +."/! +.'(+ +.'!2
/+.+( /".!2 2)."/
"+ +.'!) +.'(/ +.')!
*!.+2 *+.", /(.,!
'+ +.(!! +.(," +.(!*
**.++ */."' *).22

Table $$: In+vitro dru release stud" of 6etformin ?Cl
Time
Amin.C
#bsorbance P C)R
6ar,eted
tablets
)repared
tablets
'ith
4udipress
)repared
tablets
'ith
4udipress
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tablets
'ith
4udipress
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tablets 'ith
4udipress
4C3
+ +.+++ +.+++
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)(
&iure >. Dru released profile of #ceta0olamide.
&iure E. Dru released profile of 6etforemin?Cl
))
1. CONC4U.ION.
5ommercially available different grade of lactose has the re#uired directly
compressible characteristics but it fails to provide the desire disintegration and
dilution properties re#uired for tablets. Gudipress G5% (EA.@ Pharmaceuticals,
9ermany) is a commercially available spray dried co&processed product comprising of
*,.)1 lactose monohydrate and '.)1 povidone having better flow and
compressibility but lac$ing in disintegration ability and suspendibility. As compred to
it, the investigated co&processed ecipient additionally contain crospovidone ('.( 1)
which is proven superdisintegrant. Incorporation of this imparted property of
disintegrability and suspendibility to co&processed ecipent.
In summary, a co&processed ad7uvant containing built in superdisintegrant can be used
as a potential multipurpose ecipient. 5learly from the results of this study, physical
modification of lactose monohydrate resulted in considerable improvement in its
functionality as a directly compressible filler. These materials can be ideal choice for
ma$ing, tablets containing medium dose medicament having poor compression
characteristics and hygroscopic drug by direct compression techni#ue, as well as
dispersible tablet with low dispersion time at high tablet hardness and tensile strength.
),
They can also be a good substitute for inert<dummy granules, which are normally used
in tablet manufacturing.
)2
>. R3&3RNC3.
)/
!
!. .am, A.P., @o$$ens, N.9., 8rug 8elivery .ystem, Adding Therapeutic and %conomic value to
Pharmacotherapy, Pharm. Tech. %ur.!**2A *B )/&,,.
"
". ?asenac$ 6, ;uller E:. 5rystal Dabit and Tableting Eehaviour. Int.. N. Pharm."++"A "((B ()&
)2.
'
'. Lhan LA, ?hodes 5T. The Production of Tablets by 8irect 5ompression, 5an. N. Pharm.
.ci.!*2'A /B !&).
(
(. .hangraw ?@, 8emarets 8A. .urvey of 5urrent Particles in the @ormulation and ;anufacture of
tablets and 5apsules. Pharm. Technol !**'A !2B '"&((.
)
). ?obertson ;I. ?egulatory Issue with %cipients. Int. N. Pharm.!***A !*2B "2'&"2,.
,
,. 9onnissea Q, ?emona NP, Fervaet 5. Pharmaceutical ecipient having improved
compressibility. %uropian N. Pharma. "++2A ,2B ""+&"",.
2
2. Nohn 6., Eob %., %dward AD. Pharmaceutical ecipieants having improve compressibility. 0.
Patent no )2")//'.
/
/. 0humwangho ;0, O$or ?.. Anmolous effect of compression on the brittle fracture of I
cellulose tablets. Int. N. Pharma."++(A "/(B ,*&2(.
*
*. Tsuimin Tasi, Nen&sen :u, Dsiu&O Do, ;ing thau .heu. ;odification of physical characteristic
of microcrystalline cellulose by 5o& drying with cyclodetrins. N. Pharma. .ci. "+++A /2B !!2&!"".
!+
!+. 9ohel ;5, Nogani P8. 8evelopment of agglomerated directly compressible diluents
consisting of brittle and ductile materials. Pharma. development and technology "++'A /B !('&!)!.
!!
!!. ?ao AE, ;isra A6. ;odification of lactose for direct compression II Ind. N. Pharm. .ci. !***A
,!(()B "'!&"',.
!"
!". 9ohel ;5, Nogani P8, Eariya .D. 8evelopment of agglomerated directly compressible
diluents consisting of brittle and ductile materials. Pharma. development and technology "++'A /B
!('&!)!.
!'. Nogani P8. 9ohel ;5. Preparation and assessment of novel co&processed superdisintigrant
consisting of crosspovidone and sodium starch glycolate. AAP. Pharm. .ci. Tech. "++).
!'
!(
!(. .engel& Tur$ 5T, Dascice$, 9onul 6, ;icrosphere&based once&daily modified release matri
tablets for oral administration in angina pectoris, 0niversity of An$ara, Tandogan, An$ara, Tur$ey.
"++/A "")(()B ")2&",,.
!)
!). %l&;aradny DA, ;odulation of Pursetile drug delivery system using different swelleble
materials, 0niversity of Aleandria, Aleandria. "++2A !((/)B "'*&"(,.
!,
!,. Dascice$, 9onul 6, ;icrosphere&based once&daily modified release matri tablets for
oral administration in angina pectoris, 0niversity of An$ara, Tandogan, An$ara, Tur$ey."++,A
"'(")B !')&!)".
!2
!2. 5avallari 5, Albertini E, ?odrigue> G, ?abasco A;, @ini A. ?elease of Indomethacin from
ultra sound dry granules containing Gactose bsed %cipients. 8ipartimento di .cien>e
@armaceutiche, 0niversitW di Eologna, Italy.5otrolled release."++)A !+"(!)B '*&(2.
!/
!/. Nogani P8. 9ohel ;5 ?eview of coprocessed 85. %cipients. N. Pharm. .ci."++)A /(!)B 2,&
*'.
!*
!*. ;ash$ura Ashrafi, Na$ir Ahmed 5howdhury, ;d .elim ?e>a. 5ontrolled ?elease of ;etformin
Dydrochloride I. In vitro ?elease from Physical ;iture 5ontaining Manthan 9um as Dydrophilic
?ate ?etarding Polymer. 8ha$a 0niv. N. Pharm. .ci. "++)A ((!)B !")&!'2
"+
"+. Lapat. %ffects of polymer type, polymerBdirect tabletting agent ratio and tabletting
method on verapamil, An$ara %c>. @a$. 8erg N. @ac. Pharm. An$ara."++(A ''(')B!")&!'2.
"!
"!. ;d. .elim ?e>a, ;ohiuddin Abdul Ruadir, .yed .habbir Daider, university of 8ha$a.
"++'.
""
"". Eudavari X. @ormulation of tablets decreasing Plasma homocysteine levels. .emmelweis
%gyetem, 9ybgys>ercs>eti Intc>et, Eudapest, Dbgyes %ndre u. 2.&!+*". Acta Pharm. Dung."++!A
2!(()B (''&((+.
"'
"'. 9onul 6. The 5onsolidation and compressibility Property of some novel directly compressible
Einders = fillers. An$ara 0niversity, Acta Pol Pharm."+++A )2(()B '!!&'!2.
"(
"(. Dein> ?, :olf D, .chuchmann D, %nd G, Lolter L. @ormulation of tablet based on Gudipress
and scale up from Gab. .cale. 8rug 8ev Ind. Pharm."+++A ",())B )!'&)"!.
")
"). 9oto L, .unada D, 8an7o L, Qone>awa Q.%valuation of multifunctional %cipients for direct
compression. ;ei7o 0niversity, 6agoya, Napan. 8rug 8ev Ind. Pharm.!***A ")(/)B /,*&/2/.
",
",. ;onedero Perales ;8, ;udo>&?ui> A, Felasco Ante#uera ;F, Nimcne>&5astellanos
Eallesteros ;?. .tudy of compaction mechanism of lactose based directly compressible
%cipients using indentation hardness = Dec$el plots. N. Pharm. Pharmacol. !**(A (,(')B !22&!/!.
"2
"2. Almon 5N, Eravo .A, Gamas ;A. N. Pharma. .ci ."++"A )B "!'.
"/
"/. Parot %G, Gachman G, Giberman DA, Lanig NG. %ds Gea and febiger. Theory and practice of
Industrial Pharmacy.!*/,A 'B "!&(,.
"*
"*. O>$ir A. Linetic evaluation mechanical strength of bri#uette granules. 8rug 8ev. Ind.
Pharm.!**2A "'(,)B )/*&)*(.
'+
'+. @iese %@, Dagen TA, Gachman G, Giberman DA, Laninig NG, %ds Gea and @ebiger.
Preformulation, Theary and Practise of Industrial Pharmacy.!*/,A 'B !2!&!*(.
'!
'!. 5arr ?G. %valuating flow properties of solids.5hem %ng !*,)B !/.
'"
'". Dausner D. @riction conditions in a mass of metal powder. Int. N. Powder ;etal !*,2B
'.
''
''. The Eritish Pharmacopoeia IF. Pharmaceutical Technical Procedures, Appendi MFII&%,
@lowability. "++)A '2(.
'(
'(. Lawa$ita L, Gudde LD. .ome consideration on powder compression e#uation. Powder
technol.!*2+A (B ,!&,/.
')
'). Lawashima Q, O$umura ;, Ta$ena$a D, $o7ima A. N. Pharma ..ci.!*/(A 2'B !)')&!)'/.
',
',. Easu ;urali, ;ohan 9F. Ind N.Pharma. .ci."++"A '2&('B /+2.
'2
'2. 0.P. MMIF&6@ MIM "+++. Asian edition, 0.P 5onention Inc.!*(!.
'/
'/. .hirwai$ar AA, .rinathA7. N. Pharma. .ci."+++A ,,(()B (''.
'*
'*. 9ohel ;5, Ngani P8. An investigation of the direct compression 5haracteristics of
5o&processed Gactose [miccrocrystalline. 5ellulose using statistical design. Pharma.
Technol.!***A "'(!!)B )(&,"
(+
(+. @riability in 0.P "(&6@ !*, 0nited .tate Pharmacopeial convention Inc. ?oc$ville."+++A
"!(/.
(!
. Eolhuis 9L., and Dol>er, A,:., Gubricant .ensitivity in Pharmaceutical Powder 5ompaction
Technology, Fol&2. Alderborn, 9., and 6ystron, 5., %ds., ;arcel 8e$$er, 0.A.!**,A )!2&),+.
("
. 9ohel ;5., Nogani, P. 8., and Eariya, .. D., 8evelopment of Agglomerated 8irectly
5ompressible 8iluent 5onsisting of Erittle and 8uctile ;aterials, Pharm. 8ev. Technol. "++'A
/(")B!('&!)!.
('
. 9ohel ;5., and Nogani, P. 8., %ploration of ;elt 9ranulation Techni#ue for the 8evelopment
of 5o&processed 8irectly 5ompresible Ad7uvant 5ontaining Gactose and ;icrocrystalline
5ellulose, Pharm. 8ev. Technol., "++'A /(")B!2)&!/)
((
((. 8isintigration Time in 0.P "(&6@ !*, 0nited .tate Pharmacopeial convention Inc.
?oc$ville. "+++ B"!(/.
(). Aulton ;%., 5ellulose Powdered, in Dandboo$ of Pharmaceutical %cipients, ?owe ?5., :eller
PN., %ds., The Pharmaceutical Press, 0L., "++'A !!"&!!(.
()
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