direct compression tablet

8/12/2019 Direct Compression Tablet

1/61

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 anactive 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


2/61

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


3/61

1.1.1 Introduction to Directl" Copressible #djuvants

The International Pharmaceutical %cipients 5ouncil (IP%5) defines ecipient as

3ubstances, 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 process 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


4/61

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


5/61

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.

. Inertness

@iller&binders should not accelerate the chemical and


6/61

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 API5ontrolled 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 reducedproduction 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


7/61

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


8/61

-. 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 3cipients

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

adjuvants63TOD #D7#T#839GI;ITATIO6 3;#6)43


9/61

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 =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 &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

functionalityed 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


10/61

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 anded

detrose&maltose (%mde) and compressible sugar are co&processed products, they are

commonly considered as single components and are official in 0P


11/61

tarlac Gactose, ;ai>estarch ?o#uette, @rance.

Pharmatose 8G5 + Anhydrous lactose, lactitol 8;F, 6etherlands.

Avicel 5% ! ;55, 9uar 9um @;5, 0A.

5elocol ;55, 5alcium phosphate @;5, 0A.

Prosolv ;55, 5oloidial ilica Penwest.

8i&pac ucrose, 8etrin American sugur, 0A.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

IP. 0A.

5arbofarma 9!+ 5alcium 5arbonate ?esins industries, Argentina.

5arbofarma 9!! ;altodetrin ?esins industries, Argentina.

1.$ INTRODUCTION O& 3;CI)I3NT U3D

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., 0P


12/61

#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., 0Penges, for effervescent tablets and as bul$ing agent for modified release

formulations.


13/61

1.( INTRODUCTION TO DRU8 U3D

1.(.1 Introduction to #ceta0olamide

1. Description


14/61

(. )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 DC and 5O'& Thus DC ion secretion ta$e place and DC

echanges with luminal 6aCthrough 6aC&DCantiporter. This distal 6aCechange ta$e

place only with LC 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


15/61

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


16/61

econdary, acute (closed&angle)B I.F.B "+&++ mg, may repeat in "& hours to a

maimum of ! gation (unlabeled use)B OralB mg


17/61

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 ecretion lithium serum levels may be

decreased.

;ethenamineB 0rinary antiseptic effect may be prevented by Aceta>olamide.

PhenytoinB erum concentrations of Phenytoin may be increased 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


18/61

$. )harmaco,inetics:

#bsorption: well absorbed orally

Onset of action:'& hour.

Distribution:%rythrocyte mass may be compartment of distribution.

3limination plasma half life: appro. ."hr.

3cretion: *+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


19/61

& 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.


20/61

$. R37I3= O& =OR@ DON3

$.1 Revie' of =or, Done On Co+)rocessed 3cipients.

8onnissen et al.2/A$BBdeveloped 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 druged 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

druged 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.

ohn et al.2 A$BB/ 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.


21/61

Uhum'anho et al.2> A$BB* investigated the effect of varying the compression

pressure on the brittle fracture tendency of & cellulose and lactose. Tablet tensile

strength (T), Pac$ing fraction(Pf), and brittle fracture inde(E;I) were determined at

different compression pressure (+./", !."" and !.' ; Pa). in another aspect of study,

& 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.2EA$BBBmodifed 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


22/61

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.21$ A$BB( 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.

oani et al.21( A$BB- 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

(


23/61

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.21- A$BB 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 materials 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 0P 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.21/ A$BB/ 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 druge,

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


24/61

5ompritol/// ATO or Lollidon? were designed successfully and maintained drug

release for " h with >ero order and Diguchi $inetics, respectively.

Cavallari Cet al.21 A$BB-preparedphysical 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 state 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 lactose 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 compaction while no difference could be evidenced among the

three ecipients that, however, appear all suitable for this ultrasound&aided direct

compression process.

oani et al.21>

A$BB-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.21E A$BB- 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 wereused 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
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cavallari%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cavallari%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


25/61

was done in "+ ml distilled water in a thermal sha$er (;emmert) with a sha$ing

speed of + rpm at '2+5 +.+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* 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 0P

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 0P MMFII criteria, were evaluated by mathematical models

(>ero order, first order, Diguchi, Dison&5rowell, Lorsmeyer&Peppas), difference

factor (f!) and similarity factor.


26/61

6d. elim Re0a et al.2$1 A$BB( 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 0P 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 (21) 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.


27/61

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, 85), 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$(A$BBB 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 Ret al.2

$*

A$BBB using Gudipress greatly simplifies formulation developmentand 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
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heinz%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heinz%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


28/61


29/61

hardnesses of the tablets made on an eccentric press is suggested as an alternative

method to determine the comparative consolidation mechanisms of different

substances.


30/61


31/61

*. 6#T3RI#4 #ND 35UI)63NT U3D

The following materials that were either A?olamide E.P. Xydus 5adila pharmaceutical Gtd., Ahmedabad.

". ;etformin D5G E.P. Xydus 5adila pharmaceutical Gtd., Ahmedabad.

'. Gudipress 0P EA@, 9ermany.

. Gudipress G5% 0P 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" 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,0P MMIII


32/61

-. 63T?ODO4O8H

-.1 )R3)#R#TION O& C#4Iolamide was dissolved in !++ ml of

+.!6 D5I (PD !.") to get ! mg


33/61


34/61

&iure 1: tandard Calibration Curve for #ceta0olamide

-.1.$ )R3)#R#TION O& T#ND#RD CUR73 O& 63T&OR6IN ?C4 IN

)?O)?#T3 $

!. An accurately weighted !++ mg of ;etfrminD5G was dissolved in !++ ml of

phosphate buffer (PD ./ ) to get ! mg


35/61

&iure $: tandard Calibration Curve of 6etformin ?Cl

Table /. tandard calibration curve for 6etformin ?Cl

ConcentrationAJml #bsorbence at $(* nm.+ +.+++

" +."+/

+.'

+.!/

/ +./+

!+ +./+!

!" +.**


36/61

-.$)?HIC#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. '+


37/61


38/61

?espectively, where a and b Z constant nZ Tap number and Fo, Fnand FinfZpowder

bed volumes at initial, after nth tapping and at e#uilibrium state, respectively.

In this method, agglomerates


39/61

-.()R3)#R#TION O& T#

5onventional tablets were prepared by direct compression method. Other ecipients

were Gudipress =


40/61

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)

the tensile strength (;Pa) of the tablets was calculated by using %#uation as follows

T LLA-

-.*.* &riabilit"*B

@riability was evaluated as the percentage weight loss of "+ tablets in a friabilator

(model %@" %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/

: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.


41/61

-.*./ 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)RatioySensitivitLubricant

= LLL A

:here, T(u) and T(l) is a tensile strength of unlubricated and lubricated tablets

respectively.

-.*. 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


42/61

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) '++! '++!" '++!! '++! '+++* '++!

)arameters

Tensile trength (;Pa) !.! !.!/ !.!+" +.** +.+/ +./!

@riability (1) +.!' +.+" +.2" +./+' .++/ ".!'

8isintegration Time (min) 2. 2 . ." ./

Table 11. Composition and results for dilution potential stud".

IngredientEatch 5ode

43# 43< 43C 43D 433 43&

Gudipress G5% "! "'! "+! !2! !! &

Gactose (Physical miture) & & & & & "!

Aceta>olamide '+ + *+ !"+ !+ '+

Talc

;g. tearate ' ' ' ' ' '

Total :eight (mg) '++! '++!+ '++!" '++! '+++/ '++!'

)arametersTensile 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" %lectrolab, ;umbai), was measured at '2C!o5 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 0P. amples were withdrawn at +, !+, "+, = '+ min. After each

withdrawal, !+ ml of fresh dissolution medium was replaced at the same time. The


43/61

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 +. o5 '2 +. o5

R)6 !++ !++

ma " nm "' nm


44/61

/. R3U4T #ND DICUION

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 3cipients.

/.$.1 #nle of repose2 ?ausner 2s ratio2 Carr 2s Inde2 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 !.!)


45/61

Table 11. Results of ph"sical parameters

6aterial 4udipress 4udipress 4C3

#nle of Repose Ao '+.2 '!."


46/61

&iuer (: )article si0e distribution of 4udipress and 4udipress 4C3

Aa


47/61

Ab

&iure *: 36 photoraph of Aa 4udipress alomerates and Ab 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 &lactose monohydrate, '." 1 polyvinyl pyrrolidone (Lollidon '+) and '.

1 crospovidone (Lollidon 5G). The agglomerates of Gudipress showed good

compression property compared with other samples.


48/61

Table 1(. Results of pac,abilit" testin

ample @a'a,itaKs

Constant Qa

@a'a,itaKs

Constant Qb

@unoKs

Constant Q,

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


49/61

/.( 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


50/61


51/61

A& P 2 AT Amin.

4udi. 4C3 4udi. 4C3 4udi. 4C3

61 +."' +."'! +.** !.!+ .! 2.+/

6$ +." +."' +.*+ +.*/ ." 2.!

6( +." +."" +.2/ +.*! .! ."6* +."" +."2 +.2+ +./" .+" .+

6- +." +."" +.2 +.2* . ."/

6/ +."2" +."* +.+ +.2! .'! ."!

/.(. 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

InredientsCondition # < C D 3

Gudipress (1) !++ ** ** ** **

;agnesium stearate (1) & ! ! ! !

;iing time (min) & ! ! !+ !+

5ompression time (sec) ! ! '+ ! '+

Dardness ($g


52/61


53/61

&iure . Dilution potential stud" ofP #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


54/61

Amin.

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 ?ClTime

Amin.

#bsorbance P C)R

6ar,eted

tablets

)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.+' /.*" 2/.! 2/.!'+ +."! +.'! +.+2/ */.+2 *2. *"." *"."


55/61

&iure >. Dru released profile of #ceta0olamide.

&iure E. Dru released profile of 6etforemin?Cl


56/61

. CONC4UION

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.


57/61

They can also be a good substitute for inert


58/61

>. R3&3RNC3


59/61

! !. am, A.P., @o$$ens, N.9., 8rug 8elivery ystem, Adding Therapeutic and %conomic value to

Pharmacotherapy, Pharm. Tech. %ur.!**2 *B /&.

" ". ?asenac$ 6, ;uller E:. 5rystal Dabit and Tableting Eehaviour. Int.. N. Pharm."++" "B &

2.

'

'. Lhan LA, ?hodes 5T. The Production of Tablets by 8irect 5ompression, 5an. N. Pharm.ci.!*2' /B !&.

. hangraw ?@, 8emarets 8A. urvey of 5urrent Particles in the @ormulation and ;anufacture of

tablets and 5apsules. Pharm. Technol !**' !2B '"&.

. ?obertson ;I. ?egulatory Issue with %cipients. Int. N. Pharm.!*** !*2B "2'&"2.

. 9onnissea Q, ?emona NP, Fervaet 5. Pharmaceutical ecipient having improved

compressibility. %uropian N. Pharma. "++2 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

cellulose tablets. Int. N. Pharma."++ "/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. "+++ /2B !!2&!"".

!+ !+. 9ohel ;5, Nogani P8. 8evelopment of agglomerated directly compressible diluents

consisting of brittle and ductile materials. Pharma. development and technology "++' /B !'&!!.

!! !!. ?ao AE, ;isra A6. ;odification of lactose for direct compression II Ind. N. Pharm. ci. !***

!()B "'!&"'.

!" !". 9ohel ;5, Nogani P8, Eariya D. 8evelopment of agglomerated directly compressible

diluents consisting of brittle and ductile materials. Pharma. development and technology "++' /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.

"++/ ""()B "2&".

! !. %l&;aradny DA, ;odulation of Pursetile drug delivery system using different swelleble

materials, 0niversity of Aleandria, Aleandria. "++2 !(/)B "'*&".


60/61

! !. 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."++

"'(")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."++ !+"(!)B '*&2.

!/ !/. Nogani P8. 9ohel ;5 ?eview of coprocessed 85. %cipients. N. Pharm. ci."++ /(!)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. "++ (!)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."++ ''(')B!"&!'2.

"! "!. ;d. elim ?e>a, ;ohiuddin Abdul Ruadir, yed habbir Daider, university of 8ha$a.

"++'.

"" "". Eudavri X. @ormulation of tablets decreasing Plasma homocysteine levels. emmelweis

%gyetem, 9ygys>ers>eti Int>et, Eudapest, Dgyes %ndre u. 2.&!+*". Acta Pharm. Dung."++!

2!()B ''&+.

"' "'. 9onul 6. The 5onsolidation and compressibility Property of some novel directly compressible

Einders = fillers. An$ara 0niversity,Acta Pol Pharm."+++ 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."+++ "()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.!*** "(/)B /*&/2/.

" ". ;onedero Perales ;8, ;uo>&?ui> A, Felasco Ante#uera ;F, Nimne>&5astellanos

Eallesteros ;?. tudy of compaction mechanism of lactose based directly compressible

%cipients using indentation hardness = Dec$el plots.N. Pharm. Pharmacol.!** (')B !22&!/!.

"2 "2. Almon 5N, Eravo A, Gamas ;A. N. Pharma. ci ."++" B "!'.

"/ "/. Parot %G, Gachman G, Giberman DA, Lanig NG. %ds Gea and febiger. Theory and practice of

Industrial Pharmacy.!*/ 'B "!&.

"* "*. O>$ir A. Linetic evaluation mechanical strength of bri#uette granules. 8rug 8ev. Ind.

Pharm.!**2 "'()B /*&*.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cavallari%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cavallari%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Albertini%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rodriguez%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rabasco%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rabasco%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rabasco%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fini%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Budav%C3%A1ri%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heinz%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heinz%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wolf%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schuchmann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schuchmann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22End%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22End%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kolter%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kolter%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Goto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sunada%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sunada%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Danjo%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Yonezawa%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Yonezawa%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Monedero%20Perales%20MD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mu%C3%B1oz-Ruiz%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mu%C3%B1oz-Ruiz%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Velasco%20Antequera%20MV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Velasco%20Antequera%20MV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jim%C3%A9nez-Castellanos%20Ballesteros%20MR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jim%C3%A9nez-Castellanos%20Ballesteros%20MR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Cavallari%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Albertini%20B%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rodriguez%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rabasco%20AM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fini%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Budav%C3%A1ri%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heinz%20R%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wolf%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Schuchmann%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22End%20L%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Kolter%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Goto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sunada%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Danjo%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Yonezawa%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Monedero%20Perales%20MD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Mu%C3%B1oz-Ruiz%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Velasco%20Antequera%20MV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jim%C3%A9nez-Castellanos%20Ballesteros%20MR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlushttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jim%C3%A9nez-Castellanos%20Ballesteros%20MR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus


61/61

'+ '+. @iese %@, Dagen TA, Gachman G, Giberman DA, Laninig NG, %ds Gea and @ebiger.

Preformulation, Theary and Practise of Industrial Pharmacy.!*/ '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. "++ '2.

' '. Lawa$ita L, Gudde LD. ome consideration on powder compression e#uation. Powder

technol.!*2+ B !&/.

' '. Lawashima Q, O$umura ;, Ta$ena$a D, $o7ima A. N. Pharma .ci.!*/ 2'B !'&!'/.

' '. Easu ;urali, ;ohan 9F. Ind N.Pharma. ci."++" '2&'B /+2.

'2 '2. 0P. MMIF&6@ MIM "+++. Asian edition, 0P 5onention Inc.!*!.

'/ '/. hirwai$ar AA, rinathA7. N. Pharma. ci."+++ ()B ''.

'* '*. 9ohel ;5, Ngani P8. An investigation of the direct compression 5haracteristics of

5o&processed Gactose [miccrocrystalline. 5ellulose using statistical design. Pharma.

Technol.!*** "'(!!)B &"

+ +. @riability in 0P "&6@ !*, 0nited tate Pharmacopeial convention Inc. ?oc$ville."+++

"!/.

!. Eolhuis 9L., and Dol>er, A,:., Gubricant ensitivity in Pharmaceutical Powder 5ompaction

Technology, Fol&2. Alderborn, 9., and 6ystron, 5., %ds., ;arcel 8e$$er, 0A.!** !2&+." . 9ohel ;5., Nogani, P. 8., and Eariya, . D., 8evelopment of Agglomerated 8irectly

5ompressible 8iluent 5onsisting of Erittle and 8uctile ;aterials, Pharm. 8ev. Technol. "++'

/(")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., "++' /(")B!2&!/

. 8isintigration Time in 0P "&6@ !*, 0nited tate Pharmacopeial convention Inc.

?oc$ville. "+++ B"!/.

Aulton ;% 5ellulose Powdered in Dandboo$ of Pharmaceutical %cipients ?owe ?5 :eller

direct compression tablet

Documents