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CHAPTER 1

INTRODUCTION

TO

DIRECT COMPRESSION

AND

OBJECTIVES

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Direct Comnression

CHAPTER 1

Introduction to Direct Compression and Objectives

Section j Content

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Introduction to Direct Compression1.1«

1

1.2 Objectives

References

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Direct Comvression

1I

List of Tables!-

Year of Introduction of Some DC Filler-Binders

Directly Compressible Adjuvants in the International

Market

Table 1.1

Table 1.2ii

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Direct Compression

List of Figures

Figure 1.1 Tablet Production by Wet Granulation and Direct ij

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<

Compression

Figure 1.2 Particle Rearrangement During Compression of Single

| Particle Excipients

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1—=t!

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|Figure 1.3 j Particle Rearrangement During Compression of»

Agglomerated Excipients<

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Direct Compression

1.1 INTRODUCTION TO DIRECT COMPRESSION

Tablets account for approximately 80% of all the dosage forms

administered to man. The principal reasons for the continued popularity

include their ease of manufacturing, convenience of dosing, stability

compared to liquid and semisolid dosage forms and low production cost

[1]. Tablets are conventionally prepared by wet granulation, dry

granulation and direct compression. The major disadvantages of wet

granulation are: more number of processing steps, high expenditure

equipments and materials, addition and removal of aqueous or hazardous

organic solvent, material handling hazards, stability problems for

moisture and heat sensitive drugs, etc. Dry granulation technique requires

the use of special equipment such as roll compactor. Hence, the current

trend in pharma industry is to use direct compression. Figure 1.1 shows

comparison between wet granulation and direct compression.

on

Direct compression is the process in which tablets are compressed

directly from the powder blends of the active ingredient and suitable

excipients including diluent, disintegrant, lubricant and other additives

[2], When a powder blend is compressed within a die, the various stages

of the compaction process can be separated as shown below [1]:

> Rearrangement - particles move within the die cavity to occupy

void spaces that exist between particles.

> Deformation -when particles can no longer rearrange within a die,

the material will start to deform.

> Compaction - when the elastic limit of the material is exceeded, the

material will deform either plastically or destructively

(fragmentation or brittle fracture). Either mechanism can occur and

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Direct Compression

is dependent upon the material characteristics, the compression

speed, compaction pressure and particle size. Plastic deformation

will aid bonding because it increases the contact between particles

and fragmentation produces newer surfaces that also favour

formation of strong bonding.

*I'’*-, ua..?

ation and directrablet production by wet granul

compression

Fig. 1.1:r-

Ii

Direct comoressionWet granulationDrug,

Diluent,Disintegrant,

Glidant,Lubricant,

Mixing /lixinii)

etc.

GranulationBinderI

I Drying

-LX[ Sieving

Disintegrant(Extragranular),

Glidant,Lubricant

i Mixmg

L om > ionI Compression res1 L

> Relaxation - once a compression force has been withdrawn (during

punch withdrawal and ejection from the die cavity), the compact

will undergo relaxation. If the elastic forces exceed the tensile

strength of the tablet then tablet integrity will fail. Successful tablet

production will depend upon achieving the right balance between

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Direct Compression

brittle fracture and plastic behavior within the compression mix,

which in turn is dependent upon the compressional characteristics

of the drug substance and the excipients. Microcrystalline cellulose

undergoes plastic deformation whereas dicalcium phosphate

undergoes brittle fracture. In practice, the diluents can be ranked in

following order in terms of their brittleness as: microcrystalline

cellulose > spray-dried lactose > (3-lactose > a-lactose > a-lactose

monohydrate > dicalcium phosphate dihydrate. The table 1.1 and

1.2 show commonly available diluents.

Table 1.1: Year of introduction of some DC filler-binders IYear Filler-binders

4 •

I

1963 Spray-dried lactose

Anhydrous lactose

Dicalcium phosphate dihydrate (EmcompressR)

Directly compressible starch (Sta-RXR)

Spray crystallized dextrose/maltose (EmdexR)

Calcium sulphate dihydrate (CompactrolR)

y-Sorbitol (NeosorbR)

Tricalcium phosphate (Tri-TabR)

Lactose + Cellulose (LudipressR)

Cellulose + Lactose (Cellactose R)

Modified rice starch (Era-Tab)

Pharmatose DCL 40%

Starch +Lactose (StarlacR)

Ciystalline Maltose (AdvantoseR)

chewin

1964

1967

1982

1983

1984

1988

1990

1991

1992

2000

2001

um )

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Direct Compression

The tensile strength of tablets with a given geometry and

composition depends on two factors: the bonding capacity and the tablet

porosity [3]. Bonding capacity generally depends on the material

properties, which cannot be easily altered. With a view to optimize tablet

formation, attention shall be paid to porosity. The final tablet porosity

depends on consolidation of particles during compression and relaxation

of compact after punch removal.

n

Table 1.2: Directly Compressible Adjuvants in the International

Market

Name of Ad juvant/s1 1 1 — > —— - . — ~— - - - -— - - — — — — — -

_— — —— — ~

f * "„ÿ . . — '

AvicelR PH 101, 102 Microcrystalline Cellulose

Co-crystallized sucrose &

dextrin

Anhydrous tricalcium

phosphate

Lactose

MCC, Lactose

Xylitol, Na CMC

MCC, Cal. Phosphate

Lactose, PVP,

Crospovidone

Pharmatose* DCL 40 Anhydrous lactose

Sta-RxR 1500 Partially gelatinized starch

Granulated Lactitol

Silicified MCC

Brand Name Manufacturer

FMC corporation

Amstar

Corporation

Rhone-Poulenc

RDi-Pac

RTri-Tab

Spray dried Lactose

Cellactose

XyliTab

Celocal

Ludipress

DMV, Netherlands

Meggle, Germany

Meggle, Germany

Meggle, Germany

BASF, Spain

R

R

R

R

DMV, Netherlands

Colorcon, USA

Xyrofin, USAii

oration

Finlac DCRProsolve

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Direct Compression

Brittle materials break easily at relatively small pressures. Ductile

materials behave elastically up to the yield point and plastically beyond

that point. Plastic materials can be deformed to a larger extent without

fracture. From fracture mechanics, it is known that there is a critical size

above which a particle starts to behave in a brittle fashion [4]. For

example, microcrystalline cellulose, which is a known ductile material, is

brittle w hen the particle size is larger than 1949 pm. In contrast, a-lactose

monohydrate, which is widely accepted as a predominantly brittle

material, is ductile when the size of the particle is less than 45 pm. The

distinction between brittle and ductile behavior has great practical

relevance. For brittle materials consisting of single particles (that is,

powder particle is not an agglomerate of numerous smaller particles), a

distinction can be made between materials with a high or low

fragmentation propensity (Figure 1.2). Materials with a

fragmentation propensity break during the particle rearrangement phase,

which occurs at low punch pressure. The fragments of the original

particles can be distributed at random within the compact. In contrast,

materials with a low7 fragmentation propensity mainly break after the

rearrangement process. Although the original particle is broken into

fragments, these fragments stay together. The fragmentation propensity is

important in relation to the lubricant sensitivity of filler binders [5],

Mixing of a material with lubricants such as magnesium stearate will

cause 3 film to be formed around the filler-binder particles. If these, more

less coated particles are brittle, new and ‘clean’ surfaces will be

created during compression. Materials consisting of particles with a low

fragmentation propensity will initially rearrange during compression and

high

or

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Direct Compression

subsequently break. Fragments originating from one particle will not be

mixed with fragments from another particle (Figure 1.2).

Figure 1.2: Particle rearrangement during compression of single

particle excipients

J j

Brittle Ductile

iHigh fragmentation

propensityPlastic (viscoelastic)

deformationLow fragmentation

propensity

pc >•#Lubricant sensitivity

The inter-particle bonding between freshly formed clean surfaces

will be better than that of surfaces covered with a lubricant film. The lack

of fragment mixing will cause a more or less coherent lubricant matrix.

This matrix works as a network of weak bonds, resulting in a

significantly lower compact strength than the strength of a compact

compressed from non-lubricated material. Brittle materials with low

fragmentation propensity are generally lubricant sensitive. This is in

sharp contrast to brittle materials with high fragmentation propensity. The

coated particles will break in the rearrangement stage, so that the

fragments originating from different particles will mix together. The

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Direct Comvression

lubricant is distributed as isolated patches in the tablet. Although these

patches are weak, the complete tablet will be strong because these weak

patches do not form a network. Brittle materials with a high

fragmentation propensity (for example, dicalcium phosphate dihydrate)

are not lubricant sensitive. From a lubricant sensitivity point of view,

ductile materials behave as materials with an extremely low

fragmentation propensity, and are highly lubricant sensitive. A significant

group of pharmaceutical excipients, however, consists of agglomerates of

smaller particles (Figure 1.3).

Figure 1.3: Particle rearrangement during compression of

agglomerated excipients

Brittle a

DuctileBrittLe

ILaw fragmentation

propensityPlastic {viscoelastic)

deformationHigh fragmentation

propensity

Jr1?"•-> V

These agglomerates are generally broken at low punch pressures.

As a consequence, the lubricant sensitivity is relatively low because only

the outside of the agglomerates is covered with lubricant. The primary

particles can have a brittle or ductile behavior, but this has no further

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Direct Compression

consequences for lubricant sensitivity. The brittle materials are preferable

to ductile materials. For sufficient bonding, however, a certain contact

area between two adjacent particles is necessary. Consequently, for

creation of area of contact, a certain plasticity of the material is necessary.

It is possible to alter the balance between brittleness, ductility and

fragmentation propensity.

Advantages of direct compression [1, 6]:

Requires fewer operations compared to wet granulation.

Shorter processing time and lower energy consumption.

Fewer stability issues for actives those are sensitive to heat or

moisture.

Faster dissolution rate may be achieved, and

Fewer excipients are needed in direct compression formula.

1.

?

3.

4.

5.

Disadvantages of direct compression [1j:

Care shall be taken to avoid segregation. The issues with

segregation can be reduced by matching the particle size and

density of the active drug substance with excipients.

The drug content is limited to approximately 30%.

It may not be suitable for materials with a low bulk density because

after compression the tablets produced may be too thick.

It is not suited for poorly flowable drug compounds.

Static charges may develop on the dmg particles or excipients

during dry mixing, which may lead to agglomeration of particles

producing poor mixing.

1.

2.

j.

4.

5.

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Direct Compression

Properties of an ideal direct compression excipient [1]:

It should have good fluidity or flowability.

It should exhibit high compressibility.

It should be physiologically inert, colorless, tasteless and relatively

inexpensive.

It should be compatible with all active ingredients.

It should not show any physical or chemical change on ageing and

should be stable to air, moisture and heat.

It should have high dilution potential.

It should accept colorants uniformly.

It should possess proper mouth fill when used for chewable tablets.

It should have desired particle size distribution and shape.

It should have high reworking potential without loss in the

properties like flowability, compressibility or compactibility, and.

It should have better pressure-hardness profile.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Although the principles governing direct compression have been

well known for many years, the technique has only recently become more

established as a result of the introduction of excipients specifically

designed for direct compression [7]. These excipients are not only

directly compressible themselves, but can also be mixed with a large

proportion of drug substance with no significant deterioration in tablet

quality.

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Direct Compression

1.2 OBJECTIVES

The picture at domestic front with respect to the use of direct

compression is disappointing because of the two major reasons:

1) High cost of imported custom made directly compressible adjuvants.

The primary reason for high cost of imported direct compression

diluent is use of spray drying.

2) Price control.

One of the objectives of the present investigation was to develop an

economical adjuvant so that the domestic manufacturers can meet the

requirements of price control. The cost of starch is less as compared to

that of lactose or MCC. Hence, starch based directly compressible

adjuvants were developed in the present investigation. It is well-known

fact that starch possesses poor compressibility. Hence, efforts were made

in the present work to augment functionality of starch by using a novel

approach. Colloidal silica is generally used as a glidant in pharmaceutical

formulations. The aqueous gel of Cab-0-SilR has not been explored by

any scientist as a binder. Directly compressible adjuvants can be

manufactured by spray drying, freeze thaw crystallization, granulation

and agglomeration, physical and chemical modification of crystal, roller

compaction, etc. The use of wet granulation, an economical method

compared to spray drying, is demonstrated in this work for the

preparation of directly compressible diluent.

Another objective of the present work was to develop a dosage

form for geriatric patients, who experience swallowing difficulty. Starch

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Direct Compression

based tablets will show quicker disintegration because of its superior

wicking action. Blends of treated starch and lactose/MCC will also be

explored for preparing quickly disintegrating tablets. The diluents

developed in this work can be used for formulating dispersible tablets or

mouth dissolve tablets.

The technique of direct compression is unsuitable in selected cases

(see disadvantages mentioned earlier). If a poorly compressible drug is to

be formulated for geriatric patients, the obvious option is to use wet

granulation. Traditionally, scientists use organic solvents to cut down the

time of drying. The current trend in the industry is to avoid use of organic

solvents because of regulatory restrictions and safety to personnel. The

upper acceptable limits for various organic solvents are given in relevant

regulatory guidelines. If one intends to achieve the same goals without

facing associated problems, a novel granulation technique is to be

adopted. We have proposed the use of a eutectic blend (camphor, menthol

and/or thymol) as a binder/granulating agent. The use of novel liquid

blend as a binder offers the advantages of quicker drying and safety. It is

worthwhile to note that the components of the eutectic blends are used for

internal use in ayurvedic system of medicine. Mouth-dissolve tablets of9

nimesulide will be developed for geriatric patients. The eutectic blend can

serve as a truly herbal binder for ayurvedic formulations.

The experimental work is broadly classified under the following

three heads:

(1) Functionality testing of directly compressible adjuvant

starch and colloidal silica

containing

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Direct Compression

(2) A systematic evaluation of various blends of physically modified

starch and microcrystalline cellulose or lactose for direct

compression

(3) Preparation of mouth dissolve tablets of nimesulide by a novel

approach

1.3 REFERENCES

Jivraj M., Martini L. G. and Thomson C. M., Pharm Sci. Tech.

Today, 2000, 3(2), 58.

Reimerdes D., Manuf. Chemist, 1993, 7, 14.

Voort K. M. and Bolhuis G. K., Pharma. Tech. Eur., 1998, 10(9),

1.

2.

3.

30.

4. Roberts R. J. and Rowe R. C., Int. J. Pharm., 1987, 36, 205.

Voort K. M. and Bolhuis G. K., Pharm. Tech. Eur., 1998, 10(10),5.

28.

6. Katdare A.V. and Bavitz J. E., Drug Dev. Ind. Pharm., 1987, 13,

1047.

7. Riepma K. A., Vromans H. and Lerk C. F., Int. J. Pharm., 1993,

97, 195.

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