Compaction and Compression of Powders

The Process of Compression: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. The subsequent events that occur in the process of compression are (a) transitional repacking, (b) deformation at points of contact, (c) fragmentation and/or deformation, (d) bonding, (e) deformation of the solid body, (f) decompression, and (g) ejection.

A. Transitional Repacking or Particle RearrangementIn the preparation of the granulation to be placed in the hopper of the tablet press,

formulation and processing are designed to ensure that the desired volume of the granulation is fed into each die cavity so that at a fast production rate the weight variation of the final tablets is minimal. The particle size distribution of the granulation and the shape of the granules determine the initial packing (bulk density) as the granulation is delivered into the die cavity. In the initial event the punch and particle movement occur at low pressure. The granules flow with respect to each other, with the finer particles entering the void between the larger par ticles, and the bulk density of the granulation is increased. Spherical particles undergo less particle rearrangement than irregular particles as the spherical particles tend to assume a close packing arrangement initially. To achieve a fast flow rate required for high-speed presses the granulation is generally processed to produce spherical or oval particles; thus, particle rearrangement and the energy expended in rearrangement are minor considerations in the total process of compression.

B. Deformation at Points of ContactWhen a stress (force) is applied to a material, deformation (change of form) occurs. If the

deformation disappears completely (returns to the original shape) upon release of the stress, it is an elastic deformation. A deformation that does not completely recover after release of the stress is known as a plastic deformation. The force required to initiate a plastic deformation is known as the yield stress. When the particles of a granulation are so closely packed that no further filling of the void can occur, a further increase of compressional force causes deformation at the points of contact. Both plastic and elastic deformation (Fig. 1) may occur although one type predominates for a given material. Deformation increases the area of true contact and the formation of potential bonding areas.

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Figure 1. Schematic illustration of particle deformation, elastic and plastic, during compression.

C. Fragmentation and DeformationAt higher pressure, fracture occurs when the stresses within the particles become

great enough to propagate cracks. Fragmentation furthers densification, with the infiltration of the smaller fragments into the void space. Fragmentation increases the number of particles and forms new, clean surfaces that are potential bonding areas. The influence of applied pressure on specific surface area (surface area of 1 g of material) is shown in Fig. 2.

Figure 2. The effect of applied pressure on the specific surface of sulfathiazole tablets.

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The specific surface of the starch and sulfathiazole granulation is 0.18 m2/ g; the tablet compressed at a pressure of 1600 kg/cm2 had a specific surface of 0.9 m2/g.

With some materials fragmentation does not occur because the stresses are relieved by plastic deformation. Plastic deformation may be thought of as a change in particle shape and as the sliding of groups of particles in an attempt to relieve stress (viscoelastic flow). Such deformation produces new, clean surfaces that are potential bonding areas.

D. BondingSeveral mechanisms of bonding in the compression process have been conceived. Three

theories are the mechanical theory, the intermolecular theory, and the liquid-surface film theory.

The mechanical theory proposes that under pressure the individual particles undergo elastic, plastic, or brittle deformation and that the edges of the particles intermesh, forming a mechanical bond. If only the mechanical bond exists, the total energy of compression is equal to the sum of the energy of deformation, heat, and energy adsorbed for each constituent. Mechanical interlocking is not a major mechanism of bonding in pharmaceutical tablets.

According to the intermolecular forces theory, under pressure the molecules at the points of true contact between new, clean surfaces of the granules are close enough so that van der Waals forces interact to consolidate the particles. A microcrystalline cellulose tablet has been described as cellulose fibrils in which the crystals are compressed close enough together so that hydrogen bonding between them occurs . It appears that very little deformation or fusion occurs in the compression of microcrystalline cellulose. Although aspirin crystals undergo slight deformation and fragmentation at low pressure, it appears that hydrogen bonding has strongly bonded the tablets, because the granules retain their integrity with further increases in pressure.

The liquid-surface film theory attributes bonding to the presence of a thin liquid film, which may be the consequence of fusion or solution, at the surface of the particle induced by the energy of compression. During compression an applied force is exerted on the granules; however, locally the force is applied to a small area of true contact so that a very high pressure exists at the true contact surface. The local effect of the high pressure on the melting point and solubility of a material is essential to bonding. The relation of pressure and melting point is expressed by the Clapeyron equation:

dT /dP = T (V1 – Vs)/ ΔH

in which dT/dP is the change in melting point with a change in pressure, T is the absolute temperature, ΔH is the molar latent heat of fusion, and V 1 and Vs are the molar volumes of the liquid melt and the solid, respectively.

The poor compressibility of most water-insoluble materials and the relative ease of compression of water-soluble materials suggest that pressure-induced solubility is important in

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tableting. The moisture may be present as that retained from the granulating solution after drying or that adsorbed from the atmosphere. Granulations that are absolutely dry have poor compressional characteristics. Water or saturated solutions of the material being compressed may form a film that acts as a lubricant, and if less force is lost to overcome friction, more force is utilized in compression and bonding, and the ejection force is reduced.

E. Deformation of the Solid BodyAs the applied pressure is further increased, the bonded solid is con solidated toward

a limiting density by plastic and/or elastic deformation of the tablet within the die as shown in Figure 3.

Figure 3. The effect of applied pressure on the apparent density of tablets of sulfathiazole.

F. DecompressionThe success or failure to produce an intact tablet depends on the stresses induced by

elastic rebound and the associated deformation processes during decompression and ejection. Often, if capping or lamination of the ejected tablet has occurred, the individual pieces are dense, hard, and strongly bonded indicating that sufficient areas of true contact existed during compression. In such cases, the mechanism of failure is different from that of a crumbly tablet. As the upper punch is withdrawn from the die cavity, the tablet is confined in the die by a radial pressure. Consequently, any dimensional change during decompression must occur in the axial direction.

Ideally, if only elastic deformation occurred, with the sudden removal of axial pressure the granules would return to their original form breaking any bonds that may have formed under pressure. Also the die wall pressure would be zero as the elastic material recovered

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axially and contracted radially. Actually under nonisostatic pressure, pharmaceutical materials undergo sufficient plastic deformation to produce a die wall pressure in excess of that that may be relieved by elastic recovery accompanying removal of the upper punch. As the movement of the tablet is restricted by the residual die wall pressure and the friction with the die wall, the stress from the axial elastic recovery and the radial contraction causes splitting (capping) of the tablet unless the shear stress is relieved by plastic deformation.

Thus, capping is due to uniaxial relaxation in the die cavity at the point where the upper punch pressure is released and some may also occur at ejection. It has been demonstrated that if decompression occurs simultaneously in all directions capping is reduced or eliminated.

Stress relaxation of plastic deformation is time dependent. Materials having slow rates of stress relaxation crack in the die upon decompression. In Figure 4 the ratio of the pressure at time t to the maximum pressure is plotted against the logarithm of the time. The change of the initial slope suggests some prominent mechanism of bonding soon becomes negligible. The initial slope reflects the ability of the materials to relieve stress during decompression. The rate of stress relieve is slow for acetaminophen so cracking occurs while the tablet is within the die. With microcrystalline cellulose the rate of stress relieve is rapid, and intact tablets result. If stress relaxation is slow and cracking is a problem, a slower operational speed provides more time for stress relaxation. A shape of tablet may be selected to reduce stress gradients within the tablet. With deep oval punches the larger quantity of material in the dome is expanding radially during ejection, and as the main body of the tablet can not expand radially but is constrained by the die wall, larger shear stresses develop. Flat-faced punches would form tablets that avoid this large shear stress.

Figure 4. Relative punch pressure against logarithm of time.

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G. Ejection As the lower punch rises and pushes the tablet upward there is a con tinued residual die wall pressure and considerable energy may be expanded due to the die wall friction. As the tablet is removed from the die, the lateral pressure is relieved, and the tablet undergoes elastic recovery with an increase (2 to 10%) in the volume of that portion of the tablet removed from the die. During ejection that portion of the tablet within the die is under strain, and if this strain exceeds the shear strength of the tablet, the tablet caps adjacent to the region in which the strain had just been removed.

Description of Compaction Process: The process of compression has been described in terms of the relative volume (ratio of volume of the compressed mass to the volume of the mass at zero voids) and applied pressure as shown in Figure 5.

Figure 5. Events of the process of compression in terms of applied pressure and relative volume.

In transitional repacking the granules are packed to an arrangement in which the particles are immobile and the number of intergranular points of contact has increased. The decrease in relative volume during transitional repacking is represented by the segment AE. With a further increase in pressure, temporary supports between the particles are formed as represented by the segment EF. Fragmentation and/or plastic deformation is represented by the segment FG. At some higher pressures bonding and consolidation of the solid occur to some limiting value as indicated by segment GH.

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For the compressional process, Heckel proposed the equation

ln V/(V-V) = kP + V0/(V0-V)

in which V is the volume at pressure P, Vo is the original volume of the powder including voids, k is a constant related to the yield value of the powder, and V is the volume of the solid.

The Heckel relationship may be written in terms of relative density rel rather than volume

Log 1/(1-rel) = kP/2.303 + A

in which P is the applied pressure, and K and A are constants. The Heckel constant K has been related to the reciprocal of the mean yield pressure, which is the minimum pressure required to cause deformation of the material undergoing compression. The intercept of the curved portion of the curve at low pressure represents a value due to densifica tion by particle rearrangement. The intercept obtained from the slope of the upper portion of the curve is a reflection of the densification after consolidation. A large value of the Heckel constant indicates the onset of plastic deformation at relatively low pressures. A Heckel plot permits an interpretation of the mechanism of bonding. For dibasic calcium phosphate dihydrate, which undergoes fragmentation during compression, the Heckel plot in Figure 6 is nonlinear and has a small value for its slope (a small Heckel constant).

Figure 6. Density-applied pressure relationship according to the Heckel plot. Key: (●), dibasic calcium phosphate dihydrate; and (), with 4.5% starch.

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As dibasic calcium phosphate dihydrate fragments, the tablet strength is essentially independent of the original particle size. For sodium chloride a Heckel plot is linear indicating that sodium chloride undergoes plastic deformation during compression. With no significant change in particle size during compression, the strength of the compressed tablet depends on the original particle size of the sodium chloride. Binders (starch paste) are added to a material to increase bonding. As shown in Figure 6 the linear relationship and the lower mean yield pressure (1904 kg/cm2) with 4.5% starch compared to the nonlinear relationship and the mean yield pressure (4303 kg/cm2) of dibasic calcium phosphate dihydrate indicate that the addition of the binder had conferred plastic characteristics to the material.

Ryshkewitch observed that

log σx = log σmax - bƐin which σx is the radial tensile strength, σmax is the theoretical radial tensile strength at zero void, Ɛ is the porosity, and b is a constant.

In the Ryshkewitch plot in Figure 7 the increase in concentration of starch from 1.2 to 4.5% increases the radial tensile strength 47% at a porosity of 25%. This increase in starch increases the radial tensile strength only 12% as zero voids is approached. Similarly, with lactose granulated with povidone, an increase in concentration of povidone from 1 to 9% increases the radial tensile strength 58% at a porosity of 20% and only 34% near zero voids.

Figure 7. Tensile strengths-porosity relationship of the logarithmic form of the Ryshkewitch equation for dibasic calcium phosphate dihydrate granules with 1. 2 (______ ) and 4. 5% (----------) starch. (●) axial and (o) radial tensile strength.

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It appears that the concentration of binder has a greater influence in more porous tablets than in those approaching zero voids. As the applied pressure is increased and the porosity of the tablet is decreased, the interparticular distances through which bonding forces operate are shorter. Thus, the bonding force of the material is stronger at lower porosity, and a lesser quantity of binder is required to produce a tablet of desired strength.

The quotient of the applied force and the area of true contact is the applied deformation pressure at the areas of true contact. Thus, under pressure a desired maximum area of true contact is established merely by applying adequate pressure. However, when the applied force is removed, the area of true contact may change. It has been stated that smaller particles yield larger areas of true contact and thus bond more strongly. However, the compression process is not independent of permanent deformation pressure (hardness) which may vary with size. Also plastic deformation tends to increase the number of dislocations in a crystal. In practice the magnitude of the permanent deformation pressure is unknown, and the particle size and shape may alter the packing density. As a consequence of these unknowns, a speculation on the effect of particle size on the strength of a tablet is questionable.

The materials compressed in pharmacy are nonmetallic and are generally mixtures of organic compounds. The relative significance of each event in the process of compression depends on the mechanical properties (plastic behavior, crushing strength) of the mixture, its chemical nature and surface effects (friction, adsorbed films, lubrication).

PROPERTIES OF TABLETS INFLUENCED BY COMPRESSION

Higuchi and Train were probably the first pharmaceutical scientists to study the effect of compression on tablet characteristics (density, disintegration, hardness, porosity, and specific surface) and on distribution of pressure. The relationship between applied pressure and weight, thickness, density, and the force of ejection are relatively independent of the material being compressed. Hardness, tensile strength, friability, disintegration, and dissolution are properties that depend predominately on the formulation.

A. Density and PorosityThe apparent density of a tablet is the quotient of the weight and the geometric

volume. The apparent density of a tablet is exponentially related to the applied pressure (or compressional force), until the limiting density of the material is approached. As shown in Figure 8, a plot of the apparent density against the logarithm of applied pressure is linear except at high pressures.

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Figure 8. The effect of applied pressure on the apparent density of sulfathiazole tablets. As the porosity and apparent density are inversely proportional, the plot of porosity against the logarithm of applied pressure is linear with a negative slope, as shown in Figure 9.

Figure 9. The effect of applied pressure on the porosity of various tablets.

When equal weights of aspirin and lactose are compressed with 10% starch, the porosity of the lactose-aspirin tablet, as indicated in Figure 9, is of a magnitude between that of the individual lactose and aspirin tablets at corresponding pressure. Thus, in tablet formulation it may be anticipated that a change in percent composition will have a corresponding arithmetic (or averaging) effect on porosity and apparent density.

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B. Hardness and Tensile StrengthThe ability of a tablet to withstand mechanical handling and transport has been

evaluated by various types of tests (abrasion, bending, indentation, hardness, diametral crushing); however, the data from these tests seldom can be correlated in a precise manner. Although hardness is not a fundamental property, diametral crushing is most frequently used for in-process control because of its simplicity. There is a linear relationship between tablet hardness and the logarithm of applied pressure except at high pressures. As shown in Figure 10 for lactose-aspirin tablets, compressed mixtures have hardness values between those of tablets composed of the individual ingredients.

Figure 10. The effect of applied pressure on the hardness of various tablets.

The strength of a tablet may be expressed as a tensile strength (break ing stress of a solid unit cross section in kg/cm2). As shown in Figure 11, the radial tensile strength is proportional to the applied pressure.

Figure 11. The effect of applied pressure on tensile strengths of tablets of dibasic calcium phosphate dehydrate granulated with 1.2% starch. At each applied pressure,

the value is given for σz /σx .

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For an isotropic, homogeneous tablet, the radial and axial tensile strengths are equal. In practice the distribution of pressure, differences in density within the tablet, and the mixture of several ingredients contribute to the nonhomogeneity of the tablet and to the nonuniformity of tensile strength. When a brittle material is compressed axially, the stress upon each particle does not necessarily compress the particles along the axial direction because of random packing and alignment of the particles toward each other during the events of compression. A greater probability exists for vertical stress on the particles during the arrangement and fragmentation events due to the movement of the punch. The overall result is that more clean surfaces are created when they are normal to the radial direction. As applied pressure is increased, fragmentation results in a stronger, radial tensile strength than axial tensile strength as shown in Figure 11. If more bonds are formed in the radial direction, the potential for the presence of cracks or dislocations is greater in the axial than in the radial direction.

The radial tensile strength σx is determined by a diametral compression test in which the maximum force Fσ to cause tensile failure (fracture) is measured. The radial tensile strength is then calculated by

σx = 2 Fσ / Dt

in which D is the diameter, and t is the thickness of the tablet. The axial tensile strength is determined by measurement of the maximum force Fσ to pull the tablet apart in tensile failure. The axial tensile strength is then calculated by

σz = 4 Fσ / D2 A blend of powders may be granulated with a granulating solution to increase the

adhesiveness of a formulation. The influence of the concentration of povidone on the tensile strengths of hydrous lactose is shown in Figure 12.

The radial strength is little affected by the concentration of povidone, but the axial tensile strength is increased by increased concentrations of povidone to a strength greater than the radial strength. The influence of applied pressure on the tensile strengths of lactose with 1 and 9% povidone is shown in Figure 13.

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Figure 12. The effect of povidone on the tensile strengths of tablets of hydrous lactose compressed at 890 kg/cm2. At each applied pressure the value is given for σz /σx .

Figure 13. The effect of applied pressure on the tensile strengths of tablets of hydrous lactose granulated with 1% ( ________ ) and 9% (- - - - - - - -) povidone.

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The relationship of the crushing strength of granulations of lac tose with povidone to the axial and radial tensile strengths of tablets compressed at 890 kg/cm2 from the granulations is shown in Figure 14.

Figure 14. Relationship of binder concentration to granule strength and tensile strengths of tablets compressed at 890 kg/cm2 from lactose monohydrate granulated with povidone. () granule strength, (O) axial, and (●) radial tensile strength.

Figure 15. The relationship of hardness and axial tensile strength for dibasic calcium phosphate dihydrate with various concentrations of magnesium stearate. (●) 0%, (Δ) 0.075%, () 0.125%, (O) 0.25%, () 0.5%, () 1.0%, and (+) 2.0%.

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The tensile strengths of the tablet are increased as the resistance to crushing of the granules is increased. The strength of the granule is increased as the concentration of the binder is increased; thus, the effect of the strength of the granule on the tensile strengths of the tablet is inseparable from the effect of concentration. Although the crushing strength of granules is important in the handling of the granulation in the tableting process, the applied pressure and the concentration of the binder determine the tensile strengths of a tablet.

With a hardness tester of the diametral compression type, weak tablets tend to fail due to tensile stresses, and strong tablets tend to fail due to compressive stresses. Hardness is proportional to radial tensile strength. As shown in Figure 15, the relationship of hardness to axial tensile strength is nonlinear.

As the hardness is increased, at higher values of hardness, there is a progressive lessening of the rate of increase of the axial tensile strength until a limiting axial tensile strength is attained. Thus, if the mechanical strength of a tablet is considered only in terms of its hardness, nothing is known of its axial strength; and if the axial tensile strength were weak, the tablet would laminate under stress.

C. Specific Surface

Specific surface is the surface area of 1 g of material. The influence of applied pressure on the specific surface area of a tablet is typified by Figure 16.

Figure 16. The effect of applied pressure on the specific surface of various tablets.

As the lactose granules, which were granulated by adding 10% starch paste, are compressed, the specific surface is increased to a maximal value (four times that of the initial granules), indicating the formation of new surfaces due to fragmentation of the granules. Further increases in applied pressure produce a progressive decrease in specific surface as the

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particles bond. A similar relation is shown for aspirin containing 10% starch. When an equal weight of aspirin and lactose is blended with 10% starch and then compressed, the specific surface is between that of the aspirin and lactose tablets individually. As the relationship between applied pressure and apparent density is independent of the material being compressed, the influence of starch on the specific surface and porosity is not significant.

For these aspirin, lactose, and aspirin-lactose tablets, the maximum specific surface occurs at a porosity of approximately 10%, even though the applied pressures at which the maxima occur vary with the different materials.

D. DisintegrationUsually, as the applied pressure used to prepare a tablet is increased, the

disintegration time is longer. Frequently, there is an exponential relationship between the disintegration time and the applied pressure, as shown for aspirin and lactose in Figure 17.

Figure 17. The effect of applied pressure on disintegration time of various tablets.

In other formulations there is a minimum value when the applied pressure is plotted against the logarithm of disintegration time, as shown in Figures 17 and 18 with 10% starch. For tablets compressed at low pressures, there is a large void, and the contact of starch grains in the interparticular space is discontinuous. Thus, there is a lag time before the starch grains, which are swelling due to imbibitions of water, contact and exert a force on the surrounding tablet structure. For tablets compressed at a certain applied pressure, the contact of the starch grains is continuous with the tablet structure, and the swelling of the starch grains immediately exerts pressure, causing the most rapid disintegration, as dem-onstrated by a minimum in a plot of applied pressure against the logarithm of disintegration time. For tablets compressed at pressures greater than that producing the minimum disintegration time, the porosity is such that more time is required for the penetration of water into the tablet, with a resulting increase in disintegration time.

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Figure 18. The effect of applied pressure on the disintegration time of sulfadiazine tablets with various percentages of dried corn starch.

As shown in Figure 18 for sulfadiazine tablets, the concentration of a disintegrating agent influences the relationship between applied pressure and disintegration time. For low starch concentrations, a small change in the applied pressure causes a large change in disintegration time. Thus, for formulations containing a small percent of starch, fluctuations in applied pressure during tablet production cause a large variance in disintegration time.

E. DissolutionThe effect of applied pressure on dissolution rate may be considered from the viewpoint

of non-disintegrating tablets and disintegrating tablets. Under sink conditions, the dissolution rate is independent of applied pressures from 53 to 2170 kg/cm 2 for non-disintegrating spheres of aspirin, benzoic acid, salicylic acid, an equimolar mixture of aspirin and salicylic acid, and an equimolar mixture of aspirin and caffeine.

In another study it is found that the dissolution rate of aspirin disks to be independent of the pressure over the range 2000 to 13,000 kg/ cm2 and independent of the particle size of the granules used to prepare the disks. The dissolution rate of benzoic acid disks is independent of particle size and applied pressure.

The effect of applied pressure on the dissolution of disintegrating tablets is difficult to predict; however, for a conventional tablet it is dependent on the pressure range, the dissolution medium, and the properties of the medicinal compound and the excipients. If fragmentation of the granules occurs during compression, the dissolution is faster as the applied pressure is increased, and the fragmentation increases the specific surface. If the bonding of the particles is the predominate phenomena in compression, the increase in applied pressure causes a decrease in dissolution.

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The four most common dissolution-pressure relations are:1. The dissolution is more rapid as the applied pressure is increased.2. The dissolution is slowed as the applied pressure is increased.

3. The dissolution is faster, to a maximum, as the applied force is increased, and then a further increase in applied pressure slows dissolution.

4. The dissolution is slowed to a minimum as the applied pressure is increased, and then further an increase in applied pressure speeds dissolution.

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