I.

Introduction
Compression is the process of applying pressure to a material. In pharmaceutical tableting an appropriate volume of granules in a die cavity is compressed between an upper and a lower punch to consolidate the material into a single solid matrix, which is subsequently ejected from the die cavity as an intact tablet. Compaction of powders is the general term used to describe the situation in which these materials are subjected to some level of mechanical force. In the pharmaceutical industry, the effects of such forces are particularly important in manufacture of tablets and granules, in the filling of hard-shell gelatin capsules, and in powder handling in general. The physics of compaction may be simply stated as the compression and consolidation of two phases (particulate solid and gas) systems due to the applied forces. Consolidation is an increase in mechanical strength of the material resulting from particleparticle interaction.

II. Derived Properties of Powdered Solids:

1. Solid Air Interface:
Atoms or ions are located at the surface of any solid particle are exposed a different distribution of intramolecular and intermolecular bonding forces than those within the particle. This condition gives rise to free surface energy of the solid which plays a major role in the interaction between particles, and between a particle and its environment. Because of these unsatisfied bonding forces at the surface of particles, those that approach each other closely enough are inherently attracted and tend to stick to one another. This attraction between like particles is called cohesion. In addition, when they approach other types of particles or solid surfaces, they are attracted to them, leading to adhesion.

Fig 1

2. Angle of Repose:
It is the maximum angle that can be obtained between freestanding surface of a powder heap and the horizontal plane.

Such measurements give at least a qualitative assessment of the internal cohesive and frictional effects under low levels of external loading, as might apply in powder mixing, or in tablet die or capsule shell filling operations. Angle of Repose <25 25-30 30-40 >40 Type of Flow Excellent Good Passable Very Poor

3. Flow Rates:
A simple indication of the ease with which a material can be induced to flow is given by application of a compressibility index (I) given by the equation: [ ]

Where, v is the volume occupied by a sample of the powder after being subjected to a standardized tapping procedure, and vo is the volume before tapping.

Compressibility Index (I) 5-15 12-16 18-21 23-35 33-38 >40

Flow Excellent Good Fair to passable Poor Very Poor Very very Poor

4. Mass-Volume Relationships: Volume:

Measurement of the powder volume is more complicated because of the presence of air spaces or voids. Air spaces or voids can be distinguished as follows: 1. Open Intraparticulate voids: those within the single particle but open to the external environment. 2. Closed Intraparticulate voids: those within a single particle but closed to the external environment. 3. Interparticulate voids : the air spaces between individual particles. Therefore, atleast three interpretations of powder volume may be proposed: 1. The true volume (vt): the total volume of the solid particles, which excludes all spaces greater than molecular dimensions, and which has a characteristic value for each material. 2. The granular volume (vg): the cumulative volume occupied by the particles, including all intraparticulate (but not interparticulate) voids. 3. The bulk volume (vb): the total volume occupied by the entire powder mass under the particular packing achieved during the measurement. Relative volume (vr) can be defined as:

The relative volume decreases and tends toward unity as all the air is eliminated from the mass. This phenomenon occurs in compressional processed such as tableting. Porosity is the another parameter which is often selected to monitor the progress of compression. [ Methods to measure the volume of powder Helium Pycometer Liquid displacement method (Specific gravity bottle method) ]

Density:
The ratio of mass to volume is known as the density of the material. Three different densities for powdered solids, based on the following ratios, may be defined. 1. 2. 3. Where M is the mass of the sample. Relative density is given as During compressional processes, relative density increases to a maximum of unity when all air spaces have been eliminated.

5. Effect of Applied Forces:

i. Deformation:
When any solid body is subjected to opposing forces, there is a finite change in geometry, depending upon the nature of the applied load. The relative amount of deformation produced by such forces is called strain. Three commonest kind of strains are shown in the figure below:

Fig 2: Diagram for three kinds of strain

ii.

Compression:

When external mechanical forces are applied to a powder mass, there is normally a reduction in its bulk volume as a result of one or more of the following effects. a. Repacking: the onset of loading is usually accompanied by closer repacking of the powder particles. It is the main mechanism of initial volume reduction as shown in the figure below. b. Particle Deformation: As the load increases, rearrangement becomes more difficult and further compression involves particle deformation. Elastic Deformation: if on removal of the load, the deformation is to a large extent spontaneously reversible then the deformation is said to be elastic. For e,g, Acetylsalicylic acid, MCC etc Plastic Deformation: if an elastic limit or yield point is reached and load above this level result in deformation not easily reversible on removal of applied force, then such deformation is said to be plastic. c. Brittle Fracture: when the shear strength is greater, particles may be preferentially fractured, and the smaller fragments then help to fill up any adjacent air space. This is known as Brittle fracture and it occurs in hard, brittle particles. For e.g Sucrose. d. Microsquashing: Irrespective of the behavior of large particles of the material, small particles may deform plastically. This process is known as Microsquashing. Hence the proportion of fine powder in a sample may be significant.
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Initial Repacking Deformation

Fig 3: Diagram of the effect of compressional force on a bed of powder

iii.

Consolidation:

When the surface of two particles approach each other closely enough (e.g at a separation of less than 50 nm , their free surface energies result in strong attractive force, which is known as Cold welding. This is supposed to be a reason for increasing the mechanical strength of a bed of powder when subjected to rising compressive forces. Fusion bonding is caused due to generation of considerable frictional heat when any applied load to the bed is transmitted through the particle contacts. This fusion bonding also increases the mechanical strength of the mass. In both cold and fusion welding, the process is influenced by several factors, including, The chemical nature of the materials The extent of the available surface The presence of surface contaminants The intersurface distances
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Fig 4: The effect of increasing compressional force on specific surface area of powder. When a powder mass is subjected to increasing compressional force there is initial particle fracture, which gives rise to increase in surface area (from O to A). At point A, particle rebonding occurs, causing decrease in surface area

iv.

Role of Moisture:

Moisture concentration well below the 1% level can dramatically affect the behavior of the feed materials and that of the finished products. As little as 0.02% moisture can affect the proportion of the applied force transmitted to the lower punch, and at 0.55% moisture, the behavior is actually the reverse of that for totally dry material.

III. Decompression:
As the applied force is removed, a new set of stresses within the tablet gets generated as a result of elastic recovery. The tablet must be mechanically strong enough to accommodate these stress, otherwise the structure failures occur. The degree and rate of relaxation within the tablet is the characteristic of a particular blend. Recording of this phase provides insights into tableting problems. For example, if the degree and rate of elastic recovery are high, the tablet may cap or laminate. If the tablet undergoes brittle fracture during decompression, the compact may form failure planes as a result of fracturing of surfaces. Tablets that do not cap or laminate are able to
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relieve the stresses by plastic deformation. Since the plastic deformation is time dependant,stress relaxation is also time dependant. The tablet failure is affected by rate of decompression (machine speed). Addition of a plastically deforming agent (e.g., PVP, MCC) is advisable to reduce the risk of such structure failures.

IV. Ejection:
The last stage in compression cycle is ejection from die. Ejection phase also requires force to break the adhesion between die wall and compact surface and other forces needed to complete ejection of tablet. Radial die wall forces and die wall friction also affect the ease with which the compressed tablet can be removed from the die. The force necessary to eject a tablet involves the distinctive peak force required to initiate ejection, by breaking of die walltablet adhesion. The second stage involves the force required to push the tablet up the die wall, and the last force is required for ejection. Variation in this process are sometimes found when lubrication is inadequate and a slip-stick condition occurs between the tablets and die wall, with continuing formation and breakage of tablet diewall adhesion. Heat is generated during ejection as a result of friction from shear between the compact and the die wall, and absorption of this heat can aid in bond formation. The shear forces during ejection can produce additional plastic flow and afford consolidation not achieved during the compaction event. Lubrication usually assists in reducing the ejection forces, however it also has the negative effect on compact strength because of reduction in cohesion characteristics. The unequal stress exerted on the compact during ejection can cause stress planes that break bonds and result in compact capping or laminating.

V. Energy involved in Compaction:

It requires high input of mechanical work which is converted to other form of energy. Any protection of applied energy stored in a product such as tablet retains a destructive property. The work involved in various phases of tablet or granule compaction operation includes i. ii. Work necessary to overcome friction between particles. Work necessary to overcome friction between particles and machine parts
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iii. iv. v.

Work that is required to induce elastic or plastic deformation Work required to cause brittle fracture within the material Work associated with mechanical operation of various machine parts.

Total work involved is

Then, Where,

(1)
.(2)

WF = workdone in overcoming the friction depends upon properties of tablet mass WN = Net mechanical energy actually required to form the tablet WD = Elastic deformation energy that is stored in the tablet.

Fig 5: Force Displacement Curve

VI. Commonly used equipments to compress tablets

1. Single-punch Tablet Machine:
Tabletting machines are commonly used in the pharmaceutical industry. They are high-speed machines that create thousands of tablets in a small period. The compounding pharmacist uses a variation of these machines. It is called a single-punch tablet press and makes one tablet at a time. A "punch" has two pieces of cast tubular metal. The bottom metal piece has a small cavity in one end of the tube; the top metal piece has one end that is tapered into a small rod that will just fit into the small cavity in the other piece. The rod does not go all the way to the bottom of the cavity, but leaves a small gap. The punch is fitted into a press so that when the handle is depressed and released, the rod goes into and then comes out of the bottom piece. To make a tablet, the powder material is placed into the bottom piece, and the handle is depressed and released. The powders are compressed and occupy the size of the gap designed in the punch. Punches come in many sizes, which allow the production of tablets of different sizes and compression strengths. But each punch is a matched set; it is not possible to interchange the top and bottom pieces of different punches. Chewable tablets, effervescent tablets, and compressed tablets can be made using a tablet press. Chewable tablets are generally made using mannitol because it has a sweet, cooling taste and is easy to manipulate. Other ingredients may include binders (e.g., acacia), lubricants (e.g., stearic acid), colors, and flavors. The powder mixture is prepared; the desired quantity of mixture is weighed, and then pressed with a single-punch tablet machine. Effervescent tablets generally contain ingredients such as tartaric acid, ci tric acid, and sodium bicarbonate. These powders would be appropriately mixed and pressed into tablets using the same procedure as chewable tablets. They will not require a disintegrant since they will effervesce when placed in water. Compressed tablet mixtures generally contain the active drug, a diluent (e.g., lactose), a disintegrant (e.g., starch), and a lubricant (e.g., 1% magnesium stearate).

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2. Rotary Tablet Press:

Fig 6: Multi station Tablet Press It is also called multi station tablet press. The steps involved are: Over fill Corrected Fill Compression Ejection

Multi station presses are termed rotary because the head of the machine that holds the upper punches, dies and lower punches in place rotates. As the head rotates the tablet granulation runs from the hopper through the feed frame into the dies. Feed frame promotes a uniform fill of the

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die. Compression takes place as the upper and lower punches pass between a pair of rollers. The up and down movement of the punches are guided by fixed cam tracks. The portion of the head that holds the upper and lower punches are called upper and lower turrets and the portion holding the dies is called the die table. At the start of a compression cycle, granulation from the hopper empties into the feed frame (A), which has several interconnected compartments. These compartments spread the granulation over a large area to provide time for the dies (B). Pull down cam (C) guides the lower punches to bottom of their vertical travel, allowing the die to the cam (E), which reduces the fill in the dies to the desired amount. A wipe-off blade (D) at the end of the feed frame removes the excess granulation and backs it into the front of the feed frame. Next, the lower punch travels over the lower compression roll (F) and upper punches rides below the upper compression roll (G) The upper punch enters a fixed distance into the dies, while the lower punches are raised and hence compacts the granulation within the dies. To regulate the upward movement of the lower punches, the height of the pressure roll is changed. After compression, the upper punches are withdrawn by upper punch raising cam (H) and lower punch ride up by the cam (I), which brings the tablet above the surface of the dies. The tablets strike a sweep off blade attached at the front of the feed frame and slide down to the receiver. At the same time, the lower punch re-enters the pull down cam (C) and cycle is repeated.

VII. Common Processing Problems

1. Capping & Lamination:
Capping is the complete or partial loss of top and bottom crowns of a tablet from the main body; lamination is the separation of a tablet into two or more distinct layers. These problems generally occur immediately after compression; however they may occur after several hours or days. Lamination is often blamed on over compressing - too much compression force flattens out the granules, and they no longer lock together. Lamination can also occur when groups of fine and light particles do not lock together. These groups of fine and light particles simply will not

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compress well. Lamination could also occur due to defects in the machinery, such as deep concave punches, claw formation in the punch, ring formation in the die wall. These problems could be remedied by precompression, by slowing the tabletting rate, or by using flat punches. Adding a taper into the die will also help eliminate lamination. Punch head flat diameter is often overlooked. As punches wear, the punch head flat usually becomes smaller and smaller and worn. Dies (dies with a wear ring) will make the tablet split during ejection which gives the tablet the appearance that capping has occurred (replace the dies). Cams are made of Phosphor Bronze, Teflon and OHNS. This Phosphor Bronze is a special grade PB2 with excel lent lubricating characteristics, longer life and more acoustic absorbency, when compared with the normally available PB2 Grade bronze. Constant Amount Feeder has special paddles to take up greater volume with better powder traction ability.

2. Picking & Sticking:

Surface materials from a tablet that is sticking to the punch and being removed from the tablet surface is picking. Sticking refers to tablet materials adhering to the die wall. When sticking occurs, additional force is required to overcome the friction between the tablets and die wall during ejection. Picking occurs when punch tips are of engraving or embossing types e.g. small enclosed areas in letter A. The source of the problem may relate to the product, the tooling, the upstream processes, or the operation of the tablet press. It might also be a combination of these factors. During the compression, air entrapment occurs in the concave cup of the punch face. The deeper the cup, the more likely it is to trap air. This trapped air creates a soft area on the very top of the tablet. New punches are more likely to entrap air than used punches simply because of their tighter clearances. Tight clearances are good, but they can cause air to escape more slowly during

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compression. With the old tooling, air escapes more quickly so particle to- particle bonding is more likely. Sticking occurs when granules attach themselves to the faces of tablet press punches. Picking is a more specific term that describes product sticking only within the letters, logos, or designs on the punch faces. Regardless whether it's sticking or picking, the result is a defective tablet. Sticking and picking can be prevented by appropriate use of lubricants and binders.

3. Mottling:
It is an unequal distribution of colors on a tablet with light and dark areas on tablet surface. This could be due to use of a drug whose color differs from that of the tablet excipients, or use of a drug whose dehydration products are colored. Colorants or dry colour additives could be added to remedy the problem. Alternately, the solvent system could also be changed if necessary.

4. Hardness Variation:
Hardness depends on the weight of materials and space between upper and lower punch at the moment of compression. If the volume of materials and distance between the punches varies, hardness also alters.

5. Double Impression:
This involves only punches that have monogram or engraving. If the monogram is present in upper punch, slight rotation of punch after precompression produces double impression. If monogram present in lower punch after compression is over lowered punch moves slightly downward to free the tablet and produces double impression. This problem can be overcome by using non-rotating cam track.

6. Weight Variation:
Variation of tablet weight also causes variation of active medicament which changes the bioavailability.

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Causes: (a) Granule size & size distribution: Variations in the ratio of small to large granules and difference in granule size determines how the void spaces between particles are filled. Since volume of die cavity remains same, different proportions of large and small particles may change the weight of fill in each die. (b) Poor Flow: The die fill process is based on a continuous and uniform flow of granules from the hopper through the feed frame. When the granulation does not flow uniformly some dies are incompletely filled. Dies are also not filled properly when machine speed is in excess of granulations flow capability. With poor flow the addition of a glidant such as talcum or colloidal silica may be helpful. Cams are made of Phosphor Bronze, Teflon and OHNS. This Material of Construction of various cams are carefully chosen to take into consideration the forces acting on the punch head.

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VIII. Recent Advances:

The market for tablet compression technology and demands placed on equipment manufacturers have changed quite significantly in recent years. Although the operating principle and fundamental design of the rotary tablet press have not changed for decades, multiple machine design improvements have been developed and implemented by various suppliers. Advancements are basically focused To reduce cost and lead time To increase productivity, flexibility and safety performance

1. Exchangeable Turret:
Initial emphasis of innovation was on reducing the amount of time for machine cleaning and product changeover. The first significant change was the exchangeable turret introduced to the market by Fette in the early 1990s. The entire turret, including punches and dies, can be easily removed from the machine and replaced with a duplicate turret. Benefits of Exchangeable turret: Offers great flexibility with regard to tooling types that can be used in the same machine

Limitations: The complex inside of the tablet press still needed to be cleaned.

Therefore, openness of structure and accessibility were further improved by Korsch in its XL ranges.

2. Centrifugal Die Filling:

IMA came up with a revolutionary design without exchangeable turret but with centrifugal die filling and Clean-In-Place capability. Main Features were Complete separation between Mechanical parts and processing areas. Accurate feeding of the dies through specially shaped radial channels. Maximum protection of product against any variation and maximum operator safety.
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3. Exchangeable Compression Module (ECM):

In early 2000, GEA Courtoy introduced the Exchangeable Compression Module (ECM), a concept that made extremely fast product changeover possible. Exchangeable Compression Module (ECM) concept is a tremendous improvement on the exchangeable turret concept It offers very high containment with incomparable productivity and flexibility for tablet compression.No machine cleaning is required, as all product contact parts and powder residues are encapsulated in and removed with ECM. A duplicate clean ECM can be installed in the machine in just 15 minutes.

Fig 7: Exchangeable Compression Module

4. Exchangeable Die Disc:

The middle part of the turret holding the dies are removed manually and quickly replaced by a duplicate die disc. It takes less than 30 minutes. This is a more economical alternative to the exchangeable turret. Only the die disc needs to be duplicated instead of Sthe entire turret.

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Fig 8: Exchageable Die Disc

5. Exchangeable Die Disc with Die Shells:

The die shells have extremely simple cylindrical design. The die shells are locked in the die disc with a simple conical clamping mechanism. A dedicated tool allows installing and dismantling of die shells. Benefits: Increased output up to 50% due to increased numbers of punch positions Increased yield Reduced damage to the tooling Reduced tooling investment and maintenance design of die shell

6. Compression to Equal Force Technology:

Compression to equal force (EF) is a new concept that allows tablets to be compressed at the same peak compression force, independent of tablet weight. This method relies on air compensator. The air compensator is installed at the precompression and main compression stations. Because the surface of the cylinder and the air pressure are constant, the force is also constant. Tablets compressed under equal force technology has the benefit of more consistent density, tensile strength and disintegration rate than tablets compressed to equal thickness.
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Fig 9: Compression to equal Thickness versus Equal Force

7. Multi Tip Tooling:

Multi tip tooling has the following benefits: Significantly increases tablet production Decreases press run time Decreases tool cleaning time Minimizes assembly time Reduces operating costs

Fig 10: Multi Tip Tooling

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8. Multi Layer Tablet Press:

Multi Layer Tablet press accurately measures low compression forces. It accurately samples layers and prevents layer contamination.

9. External Spray Lubrication:

Lubricants are applied to punch tips and die walls and at the tablet surfaces. Lubricants are sprayed into the press with compressed air or in a solution. 0.005% - 0.05% typically resolves picking/sticking problems and die wall friction. This technique has the benefit in reducing tooling wear and in rapid disintegration and formation of stronger tablets. But the process becomes less sensitive to changes in API.

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IX. Recommendations:
Pharmaceutical Industry can achieve increase in operational efficiency through higher speeds, faster cleaning and product changeover, and fully automatic unmanned operation. Flexibility should also be developed further as the complexity of tablets increases, with the emergence of special tablets, such as multiple-layer tablets and core-coated tablets. But most of all, future developments should focus on advanced process control to guarantee improved and constant tablet quality. This is one of the basic requirements to help realise two crucially important new concepts, which will shape the future of solid dosage production: continuous processing and real-time release. The implementation of new control strategies and the implementation of new types of sensors into tablet presses are vital means to this end. All the advancements in tablet compression machine should result in tablet of high quality, desired hardness, friability, weight, disintegration and finally dissolution. With the advent of promising new devices such as NIR sensors, progress is being made, but these are just the early stages of the new developments that are required.

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X. Summary:
Compaction is an integral step for the manufacture of tablets, and it is pertinent to understand the underlying physics of compaction. Complete understanding of compaction physics still eludes us, many variables such as inherent deformation behavior of drugs/excipients, solid-state properties, and process parameters are known to affect the final attributes of tablets. A due consideration to the variables of compaction process, can aid a pharmaceutical scientist to design optimum formulation devoid of problems such as capping, lamination, picking, and sticking. Availability of sophisticated tableting instrumentations has catalyzed the understanding of process, and the generation of compaction profiles such as force-time profile, force-displacement profile, and pressure porosity relationships can help in deciphering the dynamics of the process. The compactibility of the drugs, especially in case of high dose systems, is critical for successful manufacturing of tablets. An appreciation of the contribution of tableting excipients to the compaction behavior of the tablet-matrix can enable science-based selection of excipients. Similarly, optimization of process parameters such as granulation, moisture content, and rate and magnitude of force transfer, can help in achieving satisfactory tensile strength and desired biopharmaceutical properties in tablet drug products.

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XI.

References:
1. Lachman, L., Lieberman, H. A. The Theory & Practice of Industrial Pharmacy, Special Indian Edition 2009, 346 - 372. 2. Aulton, M. E., Pharmaceutics: The Science of Dosage Form Design. 3rd Edition. Churchhill Livingstone Elsevier, 2002, 500-513 3. Remington the science and practice of pharmacy , 20th edition, volume 1 , Indian edition, Lippincott William's & Wilkins 4. S. Patel et.al. Compression Physics in the formulation development, Critical Reviews in Therapeutic Drug Carrier Systems, 23(1):1-65, 2006 5. Mudbidri Ashish, Tablet Compression Principles, Pharma Time- Vol. 42- No.11, Nov. 2010 6. Natoli Dale, Progression in Tablet Compression, European Industrial Pharmacy, Issue 11, Dec. 2011 7. Allenspach Carl, Recent Advances in Tablet Compaction Technology, NJPhAST, April, 2011 8. Vogeleer Jan, Tablet Compression: Changing trends, more demands, Pharmaceutical Technology Europe, Jun 1, 2010 9. Evelghem. V. Johan, Improving Tablet Quality with Compression to Equal Force Technology, Pharmaceutical Technology, May 1, 2008 10. http://www.gea-ps.com/npsportal/cmsdoc.nsf/WebDoc/webb85zbwt

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