1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(98)00111-4

▼ Successful compaction and tableting of phar-maceutical powders requires an understanding ofthe fundamental properties of powders. Theseproperties include both physicochemical and me-chanical properties and dictate how formulationswill behave during tablet processing. Based on thecharacteristics of the drug substance, excipientsthat complement these properties or that havesynergistic effects may be chosen. Processingequipment can be selected based on the behaviorof materials under certain stress conditions.

It is possible to obtain a better understanding ofwhy certain materials are prone to problems dur-ing compaction. At the molecular level, work isongoing to develop an understanding of the im-pact of solid-state properties such as crystal struc-ture, crystal habit1,2, polymorphism and hygro-scopicity3 on the mechanical properties ofpowders in an attempt to identify and modifyphysical properties of bulk solids4. Parameters suchas the cohesive-energy density, calculated from thechemical structure of a variety of pharmaceuticalsolids, have been related to mechanical propertiessuch as Young’ modulus, indentation hardness,fracture properties, tensile strength and criticalstress intensity factor5,6. The desired mechanicalproperties of the drug substance that require con-trol during synthetic process development andscale-up can be communicated to the syntheticchemists7. Various synthetic steps, including pre-treatment, crystallization conditions8, alternative

crystallization procedures such as spherical crystal-lization9, and processing operations during manu-facturing can lead to changes in material proper-ties. Data modeling and simulations can predict theimpact of certain changes in the drug substance onproduct manufacturing. Because the drug sub-stance is available only in small quantities in theearly stages of product development, equipmentand techniques capable of small-scale screeningmust identify potential problems earlier in the de-velopment process.This is also important when ahigh drug loading in the dosage form is antici-pated. These techniques should be able to deter-mine the effect of different physicochemical prop-erties such as particle size10, shape, bulk density11,surface area, salt form12, polymorphic form13, crys-tal habit14, hydrates, moisture content15 and pro-cessing conditions on the compaction of powders.

In the evaluation of salt forms and formulationdevelopment, pharmaceutical scientists face manychallenging questions with regard to the tabletingof powders. In this review some questions with re-spect to mechanical properties will be dealt with,such as what properties of powder one must evalu-ate, how to determine these properties, and how toprioritize their evaluation with different phases ofdevelopment. How can one differentiate betweendrug substances that provide an ideal combinationof physical and mechanical properties? What cri-teria does one need to apply to select materials thatincrease the rate of success during the compactionprocess? How could an understanding of theseproperties help alleviate, or predict, challenges en-countered with high-speed presses upon large-scale manufacturing, such as loss of crushingstrength, sticking, picking, capping and lamination?

Tableting processDuring the tableting compression cycle, pow-ders go through initial packing and rearrange-ment of particles, formation of temporary

Mechanical properties of powders forcompaction and tableting: an overviewSunil Jain

Sunil JainGlaxo Wellcome Inc.Pharmaceutics and Chemical Analysis

PO Box 13398Research Triangle Park

NC 27709-3398USA

tel: 11 919 483 4258fax: 11 919 483 5929

e-mail:SJ41246@glaxowellcome.com

reviews research focus

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PSTT Vol. 2, No. 1 January 1999

This review provides an insight into mechanical properties that are

critical to understanding powder processing for tableting. Various pa-

rameters that reflect these basic fundamental properties of powder

and their evaluation by different techniques are described. Some re-

cent examples in which these techniques are used in drug substance

selection, formulation optimization or scale-up are also provided.

structures, elastic deformation, plastic deformation and break-age of particles, bond formation, and consolidation, followedby elastic recovery during the decompression process16,17.These events can happen sequentially or in parallel. Theamount of stress developed at the points of local deformationdepends on the magnitude of force, rate of application, du-ration of locally induced stress or contact time and physicalproperties of the material18. It is crucial to understand the me-chanical properties of materials that provide informationabout particle deformation behavior and deformation kinetics.Although these properties provide information about com-pressibility (ability of material to undergo volume reductionunder pressure), the compactibility (ability of material toyield and compact with adequate strength) of the materialmust also be ascertained. It is equally important to establishthe effect of dwell time and viscoelasticity on powder com-paction: these properties characterize the tabletability of indi-vidual components and mixtures.

Deformation behavior of powderThe material property that predominantly affects the tabletingof powders is the deformation behavior of powder understress. The deformation characteristics may be elastic, plastic,brittle fracture or a combination of these deformation mecha-nisms. Various parameters that characterize the deformationcharacteristics of powders include Young’s modulus, Poisson’sratio, yield stress, and fracture toughness.

Elastic deformation is time independent, reversible defor-mation of a particle, and can create residual stresses within thecompact during the decompression phase of the compactioncycle19. The force applied on a compact or powder divided bythe surface area of a compact is called ‘stress’.Application of theforce (stress) causes a change in dimensions, and the magni-tude of dimensional change is called ‘strain’, for example, rela-tive volume change. Hook’s law denotes the linear portion ofthe stress-strain plot and the proportionality constant betweenstress and strain is given by the Young’s modulus.

For elastic deformation:

sd = eE (1)

Where E is the Young’s modulus of elasticity of material, e isthe deformation strain and sd is the deformation stress.

Plastic deformation is the permanent deformation of a par-ticle that is controlled by the applied stress. The amount ofplastic deformation depends on the overall time of compres-sion, contact time or rate of application of compression forceand the time during which the material is subjected to maxi-mum force (dwell time). Plastic deformation facilitates the for-mation of permanent particle–particle contact regions during

compaction, and is given by:

sd = sy (2)

Where sy is the yield stress of material, which is the stressbeyond which material is not elastic. When the yield stress is exceeded, the material may either flow or break upon compaction20.

Fracture toughness determines the extent to which the par-ticles or interparticle regions crash and break during com-paction21. For brittle fracture:

sd = AKic/√d (3)

Where Kic is the critical stress intensity factor of material thatprovides an indication of the stress required to produce propa-gation of crack, d is the particle size diameter and A is a con-stant depending on geometry and stress application. Kic de-scribes the state of stress around an unstable crack, and is ameasure of the resistance of material to cracking via tensilestresses normal to the crack walls22.

Evaluation of deformation behavior and compressibilityAssessment of deformation behavior and compressibility ofpowders is performed using a range of techniques. Thesetechniques include measurement of changes in bed density orporosity during compression, effect of punch velocity oncompression, strain-rate sensitivity index, stress-strain relax-ation, various tablet indices, stress transmission during com-pression, work involved in compaction, compaction force ver-sus time profiles, and elastic recovery during multiplecompression.

Changes in bed density or porosity during compressionDuring tableting, the bed density or porosity of the powderchanges as the compaction force is applied. This reduction involume or density of the compact upon application of forcecan be calculated using the Heckel equation23, and is given bythe mean yield pressure, PY :

Ln (1/1–D) = KP + A (4)

Where D is the relative density of the compact in die at thepressure P.

K and A are regression coefficients of the linear portion ofthe curve, and the reciprocal of K is the mean yield pressure, PY.

The relative density provides information about the solidfraction of a porous powder column and is given by:

D = rA/rT (5)

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Where rA is the apparent density obtained from the weightand dimensions of the powder column, and rT is the particledensity or true density of solid material.The results of apparentdensity measurement are sensitive to the testing equipment, in-cluding transducers and their mounting, amplifiers and ana-logue digital converters24.

The constant A is derived from curve fitting equations and ap-pears to be a function of the range of pressures applied or theoriginal compact volume.The constant A can be related to the den-sification during die filling and particle rearrangement prior tobonding and may not be a true constant23. Considerable deviationsof the experimental data occur at both low and high pressures be-cause of particle rearrangement and strain hardening, respectively,but over the middle pressure range a straight-line relationship ex-ists19. It has been pointed out that yield pressure results are affectedby at-pressure and zero-pressure measurements, history of pow-der, mode of die filling, dimensions of die and punch, rate of com-paction, contact time, state and type of lubrication, and techniqueused to measure dimensions of compact25. However, if at-pressuremeasurements are performed on the material below itsbrittle/ductile transition with lubricated punches and dies, and atlow speed, the reciprocal of K is identical to the yield stress of thematerial calculated from indentation hardness measurements26.

The Heckel equation is applicable to systems that deform plas-tically, but deviations from linearity at low applied stress tend tosuggest alternative compression mechanisms such as brittle frac-ture. The Heckel equation has been used to distinguish threetypes of volume reduction mechanisms based on the effect ofstress on initial powder bed density24,27,28.These materials werecategorized by compressing different particle size fractions ofvarious powders. In type A materials, the variation in initial beddensities results in different final bed densities under appliedstress. Particle size fractions had different initial packing fractionsand the plots remained parallel as the compression pressure wasincreased. In these densification takes place by plastic flow pre-ceded by particle rearrangement. In type B materials, irrespectiveof the initial bed density, a single linear relationship occurs abovecertain pressures. Below this pressure plots are slightly curved atinitial stages of compaction. Powder densification happens byfragmentation of particles.The initial structure of the powder col-umn is completely destroyed by fragmentation and hence differ-ences in initial packing have no effect on further densification. Intype C materials, the plots have an initial steep linear portion afterwhich they become coincidental with only trivial volume reduc-tion. Powder densification occurs by plastic flow but no initialparticle rearrangement is observed.

Effect of punch speedA comparison of mean yield pressures as a function of com-pression speed is used to identify the deformation behavior of

materials. The importance of the speed of application and du-ration of compression force in tablets has been recognized formany years29. Typical plastic deforming materials have yieldpressures reported to be in the range 40–135 MPa, whereasmaterials such as dicalcium phosphate dihydrate, which con-solidate mainly by fragmentation, have higher yield pressuresranging from 340–430 MPa19. Heckel indices have been shownby a number of researchers to be affected by punch speed.Materials, which consolidate by brittle fracture, show highyield pressures irrespective of punch speed, whereas plasticallydeforming materials produce higher yield pressures as thepunch speed increases. This was attributed to either a changefrom plastic to brittle behavior or a reduction in the amount ofplastic deformation because of the time-dependent nature ofthe plastic flow30.

Punch speed changes with the displacement-time wave pro-file and is affected by the type of material in contact withpunch during the dwell time. Compaction simulators allow agreater range in punch speed (0.03–640 mm s21), whereas thetableting press may only allow two to five-fold differences inthe punch speed. Compaction simulators can be programmedto follow compaction and ejection cycles of different tabletpresses. A comparison was made between the role of differentdisplacement-time waveforms in the determination of Heckelbehavior under dynamic conditions in a compaction simulatorand a fully instrumented rotary tablet machine. An increase inthe tableting rate and differently programmed displacement-time waveforms with the same gross punch speed changed theHeckel behavior of the formulations investigated.The instanta-neous punch-speed profile of the displacement-time waveformwas found to affect the determination of Heckel behavior ofmaterials, irrespective of the deformation mechanism31. Thesaw-tooth wave of compaction simulators allows for a constantpunch speed and may be a better choice for the characteriz-ation of formulations by Heckel indices and strain-rate sen-sitivity. Often, compaction simulators have been used in thesingle-ended rather than double-ended compaction mode ofrotary tablet presses, and these fail to capture the vibrations as-sociated with tablet presses, and carry the liability of not beinga realistic representation of tableting on a rotary tablet press.

Strain rate sensitivity (SRS) indexTo compare materials, Roberts and Rowe proposed the term‘strain rate sensitivity’ (SRS); that is, the percentage increase inthe yield pressure at two different punch speeds. Strain ratesensitivity is given by the difference in the yield pressures atthe lowest (Py1) and highest compression speeds (Py2), nor-malized to the yield pressure at the highest compression speed.

SRS = {Py2–Py1/Py2} 3 100 (6)

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Strain rate sensitivity increases as the plastic deformation be-comes the more dominant mechanism during the compactionprocess. Materials with fragmentation mechanisms have low SRSvalues (,2%), whereas plastically deforming materials possesshigh SRS values30. Materials such as dicalcium phosphate andcalcium carbonate, which compact by brittle fracture, have highyield pressures that are independent of strain rate.

Stress–strain relaxationStress–strain relaxation measures the time dependence of defor-mation. Pharmaceutical materials often show a measure of vis-coelasticity and the compaction mechanisms are influenced bythe rate of deformation. Stress relaxation of the compacts ismeasured under constant applied stress. The upper punch israpidly brought into the die, and this is kept stationary whenthe compression pressure reaches the desired pressure. Thedecay of the upper punch force is measured during a holding-time interval to determine stress relaxation. As the time duringwhich material is subjected to compression increases, it may beexpected that the degree of bonding, and hence tablet strength,will increase for materials exhibiting time-dependent plasticdeformation32. Following plastic deformation of material, plas-tic flow may occur. Greater relaxation pressure indicates greaterenergy required for plastic flow, which promotes intimate par-ticle–particle contact and increases the bond strength33. It islikely that material with high stress relaxation will lead to fewerproblems of die sticking and hence require less lubrication, be-cause the compacts will be in substantially less contact with thedie wall following relaxation32. Materials that undergo brittlefracture are less affected by changes in the rate of compaction.

Various models have been proposed for the analysis of thestress-relaxation data. For example, according to the Maxwellmodel the viscoelastic slope, k, can be obtained from:

Ln DF = ln DF0–kt (7)

Where DF is the amount of compressional force remainingin the viscoelastic region at time t, and DF0 is the total magni-tude of this force at time zero34.

Strain movements under constant stress can be analysed interms of creep compliance, J, which is defined as35:

J = e/s (8)

Three compliance values can be calculated from the creepcurve: the Newtonian or plastic compliance, JN; the retarded orviscoelastic compliance, JR; and the elastic compliance, Jo. Theratio of elastic to plastic compliance is given by Jo/JN.

Heckel plots and stress relaxation may be correlated to thetensile strength of compacts produced under the same condi-

tions. Through the study of these results, some knowledge ofthe compaction mechanism of powders could be obtained be-fore attempting to improve compressibility32.

Tablet indicesThe basis for Hiestand’s tableting indices is the ability to relieveshear stresses by plastic deformation, which could prevent frac-ture of the compacts36. Mechanical properties such as tensilestrength, shear strength, elastic modulus and hardness of com-pacts are reduced to dimensionless indices in order to character-ize and compare the relative tabletability of single componentsand mixtures.These tableting indices are calculated by using theindentation hardness and the tensile-strength measurements oncylindrical compacts.To prevent fracture problems during de-compression, a split die that allows triaxial decompression isused for the determination of the magnitude of indices.

Bonding index (BI) is defined as the ratio of the tensilestrength, st to dynamic indentation hardness, P, where the for-mer is the strength after elastic recovery and the latter is ameasure of shear strength when under compressive load.

BI = st/P (9)

Bonding index estimates the success of true contact (bond-ing) areas, formed at maximum compression stress, in attemptsto survive during decompression36. High bonding indicescould also indicate sticking and picking problems duringtableting14,32. A material with a higher BI forms stronger com-pacts, which survive the die wall and ejection forces, whereas amaterial with a low BI may produce friable tablets37. In general,the values of BI range from 0 to 0.04.

Hiestand defined two bonding indices – a worst-case and abest-case BI – because most pharmaceutical materials are visco-elastic in nature. If a quassi-static indentation test is used, it ispossible to obtain the best-case bonding index, BIb, whereas useof a dynamic indentation test estimates the worst-case BI. In thedynamic method, a stainless steel pendulum is allowed to strikethe front face of a compact from a height and is in contact withthe compact for less than 1 ms, while the best-case BI involvesthe slow progression of an indentation to over a period of 15 min. The worst-case BI is a better indicator of the bondingcapacity of the material under production conditions. A com-parison of the two values indicates the extent of viscoelasticity37.

Strain index, P/E9, is obtained from dynamic indentationhardness, P, and the reduced Young’s Modulus, E9. E9 is given by:

E′ = E1/(1–v12) (10)

Where E1 is the elastic modulus of the compact and n itsPoisson’s ratio. Strain index is indicative of the relative strain or

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change in size during elastic recovery after plastic deformation,and is indirectly related to the proximity of surfaces that remainin contact after decompression.The values of P/E9 range from0–0.04. A high P/E9 implies potential structural failures such ascapping or lamination.

Brittle Fracture Index (BFI) is the ratio of the tensile strength ofthe tablets with, (sT), and without a hole, (sTo), at their center.This ratio may indicate the ability or inability of compact to relievestress at a crack tip within the compact by plastic deformation38.

BFI = {sT/sTo–1}/2 (11)

BFI is a measure of brittleness, which is the principal causeof capping and lamination.A BFI of ,0.2 indicates better com-pacting properties, whereas values .0.2 indicate tendencies tocap and laminate14.

A single index number alone is insufficient for an under-standing of tableting performance. For example, compoundswith a large BI value can withstand larger stresses than mostother materials. A very low BI, below 0.01, indicates a lack ofruggedness39.The combination of a large value for both the BFIand SI may result in fracture, but it occurs during ejection whenthe concentrated stresses develop at the edge of the die36. Theindices do not measure the intrinsic properties of the com-pound, but rather measure properties that influence the tablet-ing performance of a specific lot of the material.

In an attempt to maximize the differences between materialswith respect to their indices of tableting performance, frac-tional factorial design was performed to identify the experi-mental conditions that affect raw measurements and the de-rived values of tableting indices37. Factors such as compact size,compact weight, indenter diameter, indenter release angle,compact storage temperature and storage time, time at themaximum compression pressure, and strain rate applied duringtensile break, may have significant influence on the calculatedindices.The measurement factors may interact with the materialbeing studied and influence the tableting indices. Potential two-factor interactions involving the chosen materials were ob-served in both BFI and SI. The results obtained were furtherconfounded as some of the measurements, such as indenter re-lease angle and dent diameter, which go into the calculations ofindices, were also used as responses. Porosity as a covariate ac-counted for tensile strength factors but not for the dent diam-eter, rebound height, BFI or SI.The results indicated that BI, ten-sile strength and indentation hardness were able to differentiatebetween pure materials better than BFI and SI.

Stress transmission during compression: axial to radial stressA compaction profile is a plot of radial versus axial stresses forone compression cycle of a tablet machine.The hysteresis loop

observed is characteristic of the material and is related to themaximum pressure used to form a tablet40. The slope, inter-cepts and the area of hysteresis loop indicate the deformationbehavior. Compaction profiles can be related to lamination andcapping tendencies and have been used to distinguish betweenthe compression characteristics of different polymorphicforms of drugs41. Most of the earlier data were obtained usingsingle punch presses and a limited number of measured points.Augsberger used an instrumented rotary press and a fast digi-tal-data acquisitions system and demonstrated that curves with500 or more data points had smooth envelops that did not looklike the parallelograms illustrated in most research papers42.Also, curves were dependent on machine variables, and crossedover one another because of the time lag between the appear-ances of peak axial and radial pressures. Considerable careneeds to be exercised in the interpretation of these results andit is probably safer to restrict their use to the machine onwhich they are generated.

Work involved in compaction: force displacement curvesBy adding a displacement transducer to the instrumentedpress, the upper punch force is measured against punch-tipdisplacement. The resulting curve shows a progressively in-creasing slope, reaching maximum force as the punch achievesmaximum penetration40. The characteristic shape of the force-displacement curves, recognizable in terms of its slope andelastic recovery, can be correlated to the ability of material toundergo plastic deformation and form strong compacts. Thegross work done in compaction and the proportion of the totalapplied energy absorbed by the material are indicated by thearea under the curve and are considered a measure of the tabletstrength, although this value includes the work done to over-come die wall friction. Several limitations to the use of this ap-proach include concerns with accurate measurement of punchdisplacement, errors introduced because of multiplication of alarge number (punch pressure) with a small number (punchdisplacement at maximum pressure), die wall friction, defor-mation of machine parts under pressure43, and separation ofnet work from gross work40.

Elastic recovery during multiple compressionForce-displacement curves for multiple compression cycles areused to obtain information about the elasticity of material.Each sample is compressed multiple times at a given compres-sion pressure and at a given speed before being ejected fromthe die. Work done in each compression cycle is calculated byintegration of each force/displacement curve. When this workbecomes constant, this force-displacement value is assumed asthe work done to produce the elastic deformation during com-paction and is an indicator of the elasticity of material40. Elastic

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recovery (ER) is defined as percentage of axial expansion ofthe compact after ejection, relative to its height at maximumpressure:

ER = (h–hc/hc) 100 (12)

Where hc and h are the heights under compression and afterejection, respectively. The plastic deformation takes place dur-ing initial compression and, after a certain number of com-pression cycles, elastic deformation is predominant.The fewerthe number of compression cycles required for arriving at con-stant work, the more readily is plastic deformation completed,exhibiting increased plasticity.

Evaluation of compactibility and tablet strengthAssessment of compactibility and mechanical strength is doneby measurement of deformation hardness, compression forceversus tablet strength, tensile strength, friability, indentationhardness, tableting indices and by measurement of mechanicalmoduli and constants, for example beam bending, fracturemechanics and single crystals.

Deformation hardnessBased on the concept of effective contact points or bondingpoints across a cross-sectional area of a compact, Leuenbergerand co-workers proposed that deformation hardness of a tabletcan be correlated with the compressive stresses during com-paction44. They have assumed that increasing the relative den-sity of the compact allows more particles to come into contactand increases the deformation hardness, P:

P = Pmax (l–e–y Sc r) (13)

Pmax denotes the theoretical maximum deformation (Brinell)hardness when the number of non-bonding points is reduced tozero and the applied compressive stress, Sc, is highest or infinite.A low Pmax value shows a relatively poor compactibility, for evenwith high compression stress this limiting value cannot be ex-ceeded.The parameter g specifies the rate at which the compacthardness P builds-up with an increase in applied compressionstress and provides information about compressibility. A highvalue of g will imply P = Pmax and a sharp decrease in compactporosity may be attained with low compression forces. A plasti-cally deforming material will have a high value of g and a lowvalue of Pmax, whereas the reverse is the case for brittle materials45.

To better understand powder compactibility, the dominatingbonding mechanism and the surface area over which the bondsare active have been investigated. Nystrom and co-workers re-ported that the dominating mechanism of compaction forpharmaceutical materials is the interparticulate forces46.

The differences in the bonding characteristics of material areprimarily due to their mechanical properties. They identifiedproperties of material that could provide high compactstrength, such as limited elastic deformation, extreme plasticdeformation and viscoelasticity, and high compact surface area.Presence of fine particulates, highly fragmented fine particu-lates, or particulates with high surface roughness in the startingmaterial will provide high compact surface area. Gas adsorp-tion, gas permeametry or porosimetry can measure the surfacearea of the compacted powdered systems47.

Effect of particle fragmentation and deformation on the inter-particulate bond-formation process during compaction was eval-uated using sodium chloride, sodium bicarbonate, lactose and su-crose as model compounds48. Particles of a series of size fractionswere used and tablet surface areas and yield pressures were de-rived to obtain information about the propensity of particles tofragment or deform. It was assumed that the original particle sizewould affect both the number and the bonding force of interpar-ticulate bonds.The compactibility of a powder will be influencedmainly by the deformability of the particles, whereas the frag-mentation propensity and the original particle size will have lessimpact on the tablet strength, except in cases in which milling orparticle fragmentation introduces surface protuberances, whichincrease surface deformability and hence tablet strength.

Compression force versus tablet strengthThe effect of compression force on tablet strength is obtainedby operating the tablet press at any given speed for an extendedrange of compression forces.The crushing strength and friabil-ity of the resulting tablets are evaluated to obtain the range ofcompression parameters in which the formulation performsbest. Tablet compression profiles and crushing-strength dataprovide useful information for limiting compression forcesduring tableting and can provide additional information aboutlamination or capping.The slope of a compression-force versuscrushing-strength profile provides qualitative informationabout the ability of material to produce strong tablets. A veryhigh slope value may suggest potential problems in produc-tion processes as a small change in the compression forcecould cause significant increases in the tablet crushingstrength, which could result in capping or variability indisintegration and dissolution of resultant tablets32.

Crushing strength or breaking force F measures the force,which when applied across a specific plane of a compact pro-duces fracture in tablets. It is a function of compact geometry anddoes not take into account the mode of fracture or the dimen-sions of the tablet49. Crushing strength can be affected by thepresence of lubricant50, its concentration, and state of sub-division and location of particles; precompression processing, in-cluding wet or dry processes; time and scale of mixing; storage

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condition; compaction force; variations in time of consolidation,dwell and contact; die residence and ejection51; amount of boundor free moisture and initial porosity of the powder bed.

Crushing strength is only a limited index of the compressionproperties of starting materials. Most materials will either de-form elastically or plastically, or fracture under the influence ofapplied stress. Therefore, measuring the final force required toproduce fracture does not truly reflect the conditions duringcompaction. The strain rate and thus the time during whichmaterials are subjected to compressive stress is another impor-tant variable for consideration52.

Tensile strengthIn pharmaceutical practice, tensile strength is usually measuredby diametral compression involving failure of the tablets. Inthese testers the load being applied is monitored electronicallyand the moving plunger is instantly stopped once a failureplane is established. The determination of the tensile strengthof the tablet depends on the development of a correct state ofstress within the compact53, but is less dependent on the com-pact geometry than the crushing strength measurements.

The radial tensile strength, which measures the tablet failureas a result of the application of tensile stress only, is given bythe relationship:

sx = 2F/pD T (14)

Where sx is the tensile strength, F is the force required tobreak the tablet, D is the diameter of the tablet, and T is the tabletthickness.Various factors, such as test conditions, deformationproperties of the material, homogeneity of the compact, adhe-sion conditions between the compact and its support, and tabletshape, may influence the tensile strength measurement54. Theconditions of the test must ensure that a calculable stress stateprevails at the section where the fracture occurs so that the frac-ture stress can be readily calculated from the fracture load49.

Some authors have suggested use of axial tensile strength be-cause radial strength measurements are sensitive to the variationin the propagation of the crack55,56. In the axial tensile strengthtest, the tablet cleaves in a plane along its axis. It is measured bystraining the face of the tablet, mounted between a pair ofadapters, and determining the maximum force required to causefailure due to tensile stresses44. The axial tensile strength, sz, isgiven by:

sz = 4F/pD2 (15)

Where F is the force required to break the tablet and D is thediameter of the tablet. A comparison of radial and axial tensilestrengths is indicative of the bonding strength in two directions

and may provide information about the laminating and cappingtendencies of the material57.The ratio of radial and axial tensilestrength is the tensile strength isotropy, which is a measure of interparticle bonding isotropy. A log-linear correlation wasrecorded between the apparent Young’s modulus of elasticity andthe tensile-strength isotropy, indicating their similar relationshipto the composition of the tablets58.The tensile-strength isotropyof tablets could be improved by increasing the apparent Young’smodulus, through incorporation of a component that possessesa high-yield pressure or particles that undergo fragmentation.

Indentation hardnessWhile the tensile-strength measurements indicate the globalstrength of tablets, indentation hardness describes the local plas-ticity of material45,49. Hardness can be defined as the resistance ofa solid to local, permanent deformation and is usually measuredby nondestructive indentation. Indentation hardness is approxi-mately three-times the uniaxial yield stress59. Indentation hard-ness can be determined by either static or dynamic methods.

The static indentation methods (such as the Brinell,Vickers andRockwell hardness tests) involve the formation of a permanent in-dentation on the surface of the material being tested.The hardnessis then determined by the means of loads applied and the size ofindentation formed, and is usually expressed as force per unitarea60.The Brinell hardness number is obtained from recovery ofthe penetration depth of the indenter following removal of theload and is a measure of elastic recovery or Young’s modulus.

In dynamic indentation tests, the test object is exposed to anabrupt stress impact, such as a pendulum striking from aknown distance or an indenter falling under gravity, onto thesurface of test material. The hardness is then determined fromthe rebound height of the pendulum or the volume of the re-sulting indentation.The volume of indentation is directly pro-portional to the kinetic energy of the indenter. The material offers an average pressure of resistance to the indenter, alsoknown as mean deformation pressure, which is calculated bydividing the energy consumed during impact by the volume ofindentation61. This has dimensions of pressure and is some-times referred to as the ‘dynamic hardness number’44.

Because pharmaceutical compacts have voids, it is difficult toascertain if the indentation has been made into a particle or avoid, or a combination of the two, thus raising doubts aboutthe meaning of the indentation figure. Also, if elastic recoveryis time dependent, it is difficult to assess when the elastic re-covery should be measured49.

Summary of techniques used to measure mechanical propertiesThe deformation characteristics of a range of pharmaceuticalpowders have been evaluated through the use of a number of

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techniques, including measurements of the forces and the dis-placement of the upper and lower punches, axial to radial loadtransmissions (compaction profile), die wall friction, force-time profiles, ejection force and temperature changes, andcompaction simulators. Several authors have presented de-tailed reviews about the analysis of the compaction data40,60. Asummary of the techniques used for measuring different me-chanical properties and mechanical constants is provided inTable 1.

Fracture-mechanics approaches from engineering have beenadopted in which samples of materials prepared into rectangu-lar beams, with and without notches, are used to determine theYoung’s modulus, critical stress-intensity factors, fracturetoughness and indentation hardness. By extrapolating data ob-tained from beams at known porosities back to zero porositythe material constants are obtained. Rowe and Roberts have re-cently presented a detailed review of the fracture-mechanicstechniques19.

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Table 1. Characterization of mechanical properties of powdered materials by mechanical constants/parameters and techniques

Property Mechanical parameters or Technique or method Information derivedconstants

Plasticity or Yield strength Density pressure profiles (Heckel Equation) Minimum pressure to form coherent compactductility Yield pressure Indentation hardness Local plasticity of materials

Compression cycles Capping potential, plastic/elastic deformationPrecompression possibilities

Network of plastic Force displacement curves Work of die wall frictionmdeformation m(compaction simulator) Simulated final scale compaction

Brittleness Brittle fracture index Hiestand tableting indices (Instron universal Laminating tendenciestester)

Critical stress Notched beam fracture, double torsion, Fracture toughnessIntensity factor radial edge cracked tablet or disc

Vicker’s indentation

Elasticity Young’s modulus Beam bending, indentation testing,Brinell hardness number compression testingElastic recovery (%) Force displacement curves Work of elastic deformation

Work done on the lower punch in a second compression

Strain index Hiestand tableting index

Viscoelasticity Stress relaxation Plastic flow, die sticking potential, Viscoelastic slope laminating tendencyStrain rate sensitivity Heckel analysis Effect of scaling-up to high speed tablet

Compaction simulator pressesCreep complianceElastic and viscous moduli

Compactibility Tablet strength Compression force versus crushing strength Laminating tendenciesprofile

Deformation hardness Leuenberger equation, indentation Maximum compaction pressureshardness

Bonding index Hiestand tableting indices Capping and sticking potential

Compressibility Compressibility, g Leuenberger equationHeckel equation

Adapted from References 32, 60 and 63.

Fracture toughness and the critical stress-intensity factor is ameasure of the resistance of a material to cracking and can bemeasured by three-point or four-point single-edge notched-beam fracture, double torsion62, radial-edge cracked tablet ordisc and Vickers indentation on single crystals.The choice of thetest and its associated specimen geometry depend on the rate oftesting, ease of formation of the specimen and the porosity ofthe specimen.

Microindentation techniques suppress the propagation of thecrack and allow for the evaluation of mechanical parameters in-cluding plasticity, elasticity, fracture toughness, and the acti-vation volume and activation energies of associated deforma-tion kinetics using only a few measurements on single crystals.These values have been used in the models to predict pseudo-static compaction and tablet-stress relaxation for a number ofpharmaceutical materials21.

Compaction simulators have facilitated compression studiesusing very small amounts of material under conditions relevantto the full-scale machine operation. The rate of strain in thecompact during compression is varied by adjusting the rate ofmovement of the punch to approximate conditions, whichoccur in rotary machines32. Piezoelectric transducers, straingauges and linear variable differential transformers (LVDT)have been used to monitor force and displacement experiencedby punches during compression. During a compression cycle,data including ejection force and forces necessary to separatethe tablet from the punch are collected from the punch LVDTand upper- and lower-load cells64.The data are graphically pre-sented and analysed. Information such as Heckel plots, com-paction energy and power measurements is typically generated.

Recent examples of the application of these techniquesThe use of the compaction simulator in tableting research suchas formulation development, process and scale-up, productiontroubleshooting, fundamental research, compaction data banksand fingerprinting new actives and excipients has recentlybeen reviewed65. Some recent examples in which a compactionsimulator and other techniques have been evaluated in the me-chanical characterization of drug substance, formulation de-velopment or scale-up and screening/evaluation of excipientswill be described.

Mechanical characterization of drug substanceThe compression behavior of two crystal habits of paraceta-mol, orthorhombic and monoclinic crystals was evaluated bycomparing the changes in tensile strength, porosity and elasticrecovery to compression pressures for tabletability, compress-ibility and compactibility, respectively1. Heckel’s equation wasused to study the densification behavior and deformationmechanism. Compared with the monoclinic form, orthorhom-

bic paracetamol exhibited greater fragmentation at low pres-sure, increased plastic deformation at higher pressure andlower elastic recovery during decompression, indicating bettertabletability of orthorhombic crystals than the monoclinicform.

Tableting performance of two different crystal habits of L-lysine monohydrochloride was evaluated by Hiestand’s indicesand pressure density plots. The two crystal habits obtainedupon recrystallization, long-rod-shaped (LH-L) and short an-gular crystals (LH-S), affected the packing orientation andchanged their deformation and fragmentation characteristics2.The force displacement curve generated with LH-S demon-strated multiple failures that were possibly due to fragmen-tation. LH-L compacts showed greater porosity but low tensilestrength, indentation hardness and elastic modulus. Hiestandindices predicted better tableting performance of LH-L.

Modification of the crystal habit of SDZ 266-975 from platesto granular, by optimizing the recrystallizing conditions, re-sulted in a drug substance with high bulk density, adequate flowand good compactibility14.Tableting performance characteristicsshowed agreement between Hiestand indices (BFI ,0.02) andthe hardness-compression profile for granular material. In addi-tion, the lowest compression force needed with granular ma-terial to achieve a compact with a solid fraction of 0.8 suggestedbetter compactibility. The Heckel equation, however, did notpredict relative compactibility and showed dissimilar behaviorfor different crystal habits and drug substance lots.

A comparison of the tabletability and static compression be-havior of original and spherically agglomerated crystals of ace-butolol hydrochloride was done by measuring mechanicalproperties such as stress relaxation, elastic recovery, pressuretransmission ratio upon compression, ejection pressures andtablet strength7.The compressibility and tabletability of aggre-gated crystals were much improved because of increased plas-tic deformation, lower elastic recovery and higher tensilestrength.

A melted disc technology was used to prepare tablet-shapeddiscs of zero porosity for the amorphous form and forms I, II,III of phenobarbitone13. Bending strength and Vicker’s hardnessnumbers were determined for some specimen discs and singlecrystals. This new methodology minimizes the influence ofcompaction force, porosity, particle size and possibly crystalhabit on correlating mechanical strength of solids and poly-morphic forms.The amorphous form and form III provided thetoughest discs, implying that these forms are the most suitablematerial for the manufacture of coherent tablets.

The tableting of four salts of chlordiazepoxide sulphate, hy-drobromide, besylate, mesylate and commercially available hy-drochloride salt was measured by using an instrumented sin-gle-punch press (type F3, Manesty Machines) and upper-punch

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PSTT Vol. 2, No. 1 January 1999reviews research focus

pressures and displacement were monitored12.Tableting behav-ior assessed by using Heckel analysis showed a range of meanyield pressure values with a 2.5-fold difference in mean yieldpressure values for hydrochloride and besylate salt, suggestinga different consolidation mechanism.The authors emphasizedthe potential of salts for the modification of the compaction be-havior of the active ingredient.

Formulation optimization and scale-upA compaction simulator was used in the design of a high-dosetablet formulation by evaluating the effect of punch velocityover a range of 30–640 mm sec21 on the compaction proper-ties of pure drug and formulations66.The compaction mecha-nism for the drug outlined using Heckel’s equation was pre-dominantly fragmentation and elastic deformation, with a slowplastic-deforming component. Note that plastic deforming ex-cipients, such as microcrystalline cellulose and pregelatinizedstarch, were added as excipients.The inclusion of these excipi-ents and PVP (povidone) 29/32 to increase particle size andflow properties further improved the mechanical strength ofthe tablets.

In a study evaluating the tableting properties of single com-ponent systems, Hiestand’s indices were compared to variousparameters obtained from Heckel plots, hardness compressionprofiles and net work of compaction67. Hiestand’s tableting in-dices were found to be the best predictors of the tableting per-formance (slope of tensile strength versus compression pressureprofiles obtained from actual tablet machines). Heckel plots ob-tained from compaction-simulation data predicted the defor-mation mechanism, but did not correlate well with the com-pactibility of the material. The strain-rate sensitivity indexobtained from Heckel plots correlated well with the viscoelas-ticity index.The net work and total work of compaction did notcorrelate with the tensile strength of the materials studied. Theauthors suggested the use of Hiestand’s indices, developed on theInstron universal testing apparatus, to predict the tableting be-havior very early in the drug development process by using asmall amount of the drug substance.

In the development of triple-layered tablets, Yang andcoworkers determined porosity and tensile-strength measure-ments and strain-rate sensitivity values for each layer as well ascombined triple-layer Heckel profiles. They concluded that in-dividual layers in triple-layered tablets should preferably have asimilar consolidation mechanism or, alternatively, well balancedproportions of both brittle and plastic materials in order toproduce acceptable tablet quality68.

Evaluation of excipients/new materialsThe deformation behavior for plastically deforming (low mol-ecular weight polyethylene glycol) and brittle (sucrose or

sodium citrate) materials was confirmed by the compressioncycle profiles obtained using an Instron universal testing appa-ratus and a specially instrumented die that was coupled withdata acquisition systems69.The upper-punch pressure and cor-responding die wall pressures were measured during the com-paction cycle and parameters such as hysteresis areas, loadingslopes and unloading slopes were compared. Polyethylene gly-col showed a similar compression cycle profile for the first andsubsequent cycles, indicating that plastic deformation occursto the same extent on the first as well as subsequent compres-sion cycles. Sucrose or sodium citrate showed brittle fractureduring the first compression cycle, did not undergo furtheryield or fracture and primarily underwent elastic deformationduring subsequent cycles.

The densification behavior of cyclodextrins (CD) such asHP-b -CD, b-CD, g-CD and a-CD was investigated by using asingle-sided saw tooth displacement-time profile at rates of 3and 300 mm sec21 in a compaction simulator70.Time-dependentplastic deformation was observed with the Heckel plots profileand yield pressure values.The authors suggested the categoriza-tion of materials according to their capping tendency by usingthe ratio between the SRS of fast elastic recovery and total elas-tic recovery as a parameter. Examples include HP-b-CD and b-CD, which were prone to fast elastic recovery with increasingpunch velocities and which yielded higher ratios.

The compaction mechanisms of lactose based on direct com-pression excipients, such as Fast Flo Lactose, Ludipress, Cellac-tose and Tablettose, were evaluated using indentation hardnessand Heckel plots71. The authors suggested the use of an ab-solute value of the difference between the upper and lower sur-face hardness of tablets made on an eccentric press as an alter-native method for the determination of the consolidationmechanisms of different substrates.

The compactibility of granular pectins was studied by usinga compaction simulator72. Heckel plots and changes in porosityat different compaction pressures and punch velocities weredetermined. Granular pectin was found to consolidate mainlyby fragmentation with little plastic deformation and high elas-tic recovery. Its compactibility was increased by the formationof a 1:1 binary mixture with microcrystalline cellulose. Usingsimilar techniques, the authors also studied polyethylene oxidepolymers of various molecular weights. A plastic deformationmechanism was suggested by low yield pressure, increasingyield stress with increasing punch speed and strain rate sensi-tivity values73. However, tablets of low strength were producedbecause of viscoelastic behavior and large axial expansion, im-plying a need to add highly compactable excipients in order toproduce tablets on high-speed presses.

In another study, the effect of strain rate on compaction andmicrostructural evolution was evaluated, using a compaction

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simulator, for polyethylene glycol (PEG) and high-density poly-ethylene (HDPE) particles by compacting tablets 10 mm (diam-eter) at 1 mm s21 and 100 mm s21 to varying densities74. Force-displacement analysis revealed that a PEG particle showedvisco-plastic behavior, developing rate-dependent permanent de-formation and a small amount of springback after ejection. High-density polyethylene particles exhibited visco-elastic behaviorwith an increase in particle stiffness with increasing strain rateand a larger amount of springback. Microstructural analysisshowed PEG tablets formed at low rates have round pores,whereas those formed at high rates have long, narrow pores thatresemble cracks, causing failure at lower loads. High-densitypolyethylene and PEG showed a strong difference in mi-crostructure evolution with strain rate.

ConclusionsThis article provided an overview of the importance of me-chanical properties in compaction and tableting, identifiedproperties and parameters, assessed available techniques andcited recent applications of these techniques. The most com-mon techniques used to interpret compaction data includecompression forces versus crushing strength profiles, yieldpressure and strain-rate sensitivity data from Heckel analyses,and Hiestand’s tableting indices. However, none of the availabletechniques alone can provide comprehensive analysis of themechanism involved in the compaction of powders because ofthe complexity of the system being compacted. More than oneevaluation technique may have to be applied in order to in-crease the validity of the conclusions from the results of a com-paction study. Instrumented punches75,76 and a laboratory-scalecompaction simulator77 are being evaluated as new approachesto tablet machine instrumentation for compression researchand troubleshooting. Compaction and consolidation of powdermixtures are being investigated for the prediction of tabletingperformance78,79.

There is a need to develop predictive correlations betweenmolecular structure, solid-state properties and mechanicalproperties. Recently, tensile strength and critical stress intensityfactor were related to cohesive energy density by a simple fac-tor. These equations allowed for the prediction of these me-chanical properties from knowledge of the materials’ chemicalstructure.The applications of concepts in metallurgy, ceramics,chemical engineering and polymers to powder technology mayallow for the enhancement of the solid state and mechanicalproperties of powders. Mathematical equations and models areneeded that can predict and correlate the processability of ma-terials in large-scale manufacturing based on the use of infor-mation obtained with small-scale equipment and techniques.These models must be validated to ensure efficacy, accuracy andconsistency.

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In brief…

Glaxo Wellcome (Stevenage, UK) has initiated an arrangement with the Service Division of Cambridge Molecular(Cambridge, UK) for the provision of DNA extraction services for Glaxo Wellcome’s genetic research.

Under the terms of the agreement, Cambridge Molecular has been contracted to provide an ongoing extraction servicefrom blood/lymphocyte pellets provided by a number of worldwide laboratories for analysis by Glaxo Wellcome. The sam-ples are from clinical trials performed in the USA and Europe.

Shyama Brewster, a member of Glaxo Wellcome Research and Development’s Clinical Genetics Directorate said, “GlaxoWellcome is using genetics in many clinical trials to evaluate pharmacogenetics. Pharmacogenetics is about studying genetic differences that determine whether one will respond to and/or tolerate certain medications: the right medicine forthe right patient. The number of DNA sample extractions required to achieve our research objectives is quite large, thus it makes good sense to contract out this work.”

According to the company, Glaxo Wellcome has high demands for DNA extraction of samples from individuals in Phase I toIV studies. Peter Jones, Chief Scientific Officer at Cambridge Molecular, said, “In the light of the volume of work for GlaxoWellcome, we are accelerating our own ongoing development programmes, working on novel technologies to enable us toprovide a faster service in the future.”

In a further agreement in the industry, Actigen (Cambridge, UK) has been granted exclusive rights for the UK distribution ofprotein research products from DIATEC (Oslo, Norway). This distribution agreement allows Actigen to sell DIATEC’s mono-clonal antibodies alongside Actigen’s existing range of affinity protein products.

According to DIATEC, its antibodies are produced under ISO 9001 and synthsized in vitro, thus avoiding the use of mice.FITC and PE-conjugated antibodies are available with a wide range of conjugates in addition to unconjugated forms, report-edly allowing protein detection and quantification to a high standard with choices available for all research applications.