46 Pharmaceutical Technology JANUARY 2005 www.pharmtech.com D ATA & REVIEW Ali Nokhodchi is a lecturer in pharmaceutics, Department of Pharmacy, School of Health and Life Sciences, King’s College London, 150 Stamford Street, Franklin-Wilkins Building, London SE1 9NN, UK, tel. 44 2 7848 4787, fax 44 2 7848 480, ali. [email protected]. An Overview of the Effect of Moisture on Compaction and Compression Ali Nokhodchi PHOTODISC, INC. The effects of moisture on the flow properties, tensile strength, Heckel plot (particle rearrangement, yield pressure), energies involved in compaction (gross, plastic, and elastic energies), and elastic recovery are reviewed. he identification and quantification of the numerous pa- rameters that affect the compaction process are vital for product uniformity. For example, moisture adsorption plays an important role in physical and chemical stabil- ity, in the properties of solid dosage forms and excipients, and in polymers for sustained-release formulations. The vapor pressure of water in the atmosphere is quantified by the percent relative humidity (% RH). The moisture con- tent at which a solid material produces a water vapor pressure equal to that of the surrounding environment is defined as the equilibrium moisture content (EMC). The solid’s resultant weight gain at a specified temperature and % RH is expressed as a percentage of its initial dry weight. For a drug known to undergo hydrolysis in the presence of moisture, it is important to study EMC and hygroscopicity. In terms of powders’ hygroscopic behavior, studies find that five factors determine the moisture adsorbance rate: (a) the pressure gradient between the vapor pressure of water in the atmosphere over the sorbed moisture layer of the drug sub- stance, (b) temperature, (c) the surface area of solid drug ex- posed to the water vapor, (d) the velocity of moist air’s move- ment, and (e) a reaction constant that is characteristic of the solid. Mikuliniskii and Rubinshtein studied the kinetics of mag- nesium sulfate’s moisture uptake (1). They concluded that the kinetics depended on: (a) surface adsorption, occurring at a rate proportional to the difference between the partial pressure of water vapor in the atmosphere and that of the saturated salt solution, and (b) water diffusion into the crystal at a rate de- pendent on the product of the diffusion coefficient and the con- centration gradient of water. The effect of moisture on tablets’ chemical and physical sta- bility is outside the scope of this article. States of water in a powder The moisture adsorption of solid dosage forms and excipients provides information for selecting excipients (e.g., disintegrating agents) and direct-compression carriers and binders, and for de- termining the humidity control required during production and storage. The amount of moisture adsorbed by drugs and excipi- ents effects the flow, compression characteristics, and hardness of granules and tablets. In addition, moisture transmission through T
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46 Pharmaceutical Technology JANUARY 2005 www.pharmtech.com
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Ali Nokhodchi is a lecturer inpharmaceutics, Department ofPharmacy, School of Health andLife Sciences, King’s CollegeLondon, 150 Stamford Street,Franklin-Wilkins Building, LondonSE1 9NN, UK, tel. 144 2 78484787, fax 144 2 7848 480, [email protected].
An Overview of the
Effect of Moisture onCompaction and CompressionAli Nokhodchi
PH
OT
OD
ISC
, IN
C.
The effects of moisture on theflow properties, tensile strength,Heckel plot (particlerearrangement, yield pressure),energies involved in compaction(gross, plastic, and elasticenergies), and elastic recoveryare reviewed.
he identification and quantification of the numerous pa-rameters that affect the compaction process are vital forproduct uniformity. For example, moisture adsorptionplays an important role in physical and chemical stabil-
ity, in the properties of solid dosage forms and excipients, andin polymers for sustained-release formulations.
The vapor pressure of water in the atmosphere is quantifiedby the percent relative humidity (% RH). The moisture con-tent at which a solid material produces a water vapor pressureequal to that of the surrounding environment is defined as theequilibrium moisture content (EMC). The solid’s resultantweight gain at a specified temperature and % RH is expressedas a percentage of its initial dry weight. For a drug known toundergo hydrolysis in the presence of moisture, it is importantto study EMC and hygroscopicity.
In terms of powders’ hygroscopic behavior, studies find thatfive factors determine the moisture adsorbance rate: (a) thepressure gradient between the vapor pressure of water in theatmosphere over the sorbed moisture layer of the drug sub-stance, (b) temperature, (c) the surface area of solid drug ex-posed to the water vapor, (d) the velocity of moist air’s move-ment, and (e) a reaction constant that is characteristic of thesolid. Mikuliniskii and Rubinshtein studied the kinetics of mag-nesium sulfate’s moisture uptake (1). They concluded that thekinetics depended on: (a) surface adsorption, occurring at arate proportional to the difference between the partial pressureof water vapor in the atmosphere and that of the saturated saltsolution, and (b) water diffusion into the crystal at a rate de-pendent on the product of the diffusion coefficient and the con-centration gradient of water.
The effect of moisture on tablets’ chemical and physical sta-bility is outside the scope of this article.
States of water in a powder The moisture adsorption of solid dosage forms and excipientsprovides information for selecting excipients (e.g., disintegratingagents) and direct-compression carriers and binders, and for de-termining the humidity control required during production andstorage. The amount of moisture adsorbed by drugs and excipi-ents effects the flow, compression characteristics, and hardness ofgranules and tablets. In addition, moisture transmission through
T
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polymers and free films may help characterize the possible effectson the dissolution and transport of drugs from dosage forms.
Water interacts with pharmaceutical solids at virtually allstages of manufacture. Therefore, water–powder interaction isa major factor in the formulation, processing, and performanceof solid dosage forms. The amount of water associated with asolid at a particular RH and temperature depends on its chem-ical affinity for the solid and the number of available sites of in-teraction, surface area, and nature of the material (2).
Such materials as nonporous talc and kaolin have low EMCs;conversely, organic sugars, polymers capable of hydrogen bond-ing, and crystalline hydrates have high EMCs. Shotton and Harbobserved that the EMCs of starch, alginic acid, and tragacanth in-creased as RH increased, but remained unaffected by increasedtemperatures (3). In contrast, higher temperature caused hydratesto form and dissolve at lower RHs. Lactose, however, did not showdeliquescence and its EMC increased only slightly at higher tem-peratures, even at 50 8C and 100% RH (4). Coelhi and Harnbynoted that fine particle size fractions of sucrose and sodium chlo-ride had higher EMCs compared with coarse particles of thesematerials (5).
If water adsorption onto the material is excluded, water caninteract with solids in two ways (5–7). In a fairly dry atmos-phere, the water will be relatively tightly bound as a nonfreelymovable layer, which sometimes is denoted as monolayer ad-sorbed moisture (8) or water vapor adsorption. At most, 2–3vapor layers will be adsorbed (7, 9). At higher RH (.80% RH),multilayer adsorption occurs and the water becomes more move-able and may be denoted as condensed water (i.e., the water be-comes “solvent like”) (8). When this occurs, the solid’s mole-cules can dissolve in the water and may cause its deliquescence.The critical humidity (RH0) at which this takes place is a char-acteristic of the solid and is the point above which the adsorbedwater assumes the character of a bulk solution or condensate (6,10). Zografi, however, has pointed out that this model is a sim-plification of the interaction that occurs between water in themoist air and a solid (7).
Coelho and Harnby studied the effect of humidity on the formof water retained in nonporous and insoluble powders (11). Theysuggested that at low RH, the moisture associated with a powder’sparticles is adsorbed water vapor. As the RH increases, the thick-ness of the adsorbed layer also enlarges until eventually, conden-sation occurs at the contact points and generates liquid bridges.
Effect of moisture on powder flowPowder properties such as flow will be affected by the surfacecondition of the constituent particles. The two fundamentalforces that can affect powder flow are cohesion and friction.Cohesion is the mutual attraction and resistance to separationof contacting powder particles of identical material. Friction isthe resistance exerted by one particle against the motion of an-other particle at the points of contact. Frictional forces act at atangent to the surface of the contact point. The adsorbed mois-ture film lubricates the particles and possibly prevents, to somedegree, the cold welding of asperities. Thus, the frictional forcethat opposes the relative motion of the particles is reduced.
Hiestand found that moisture may influence the force of in-
teraction between solid particles in at least three ways: (a) itmay adsorb on the surface and influence the surface energy, (b)it may alter the surface conductivity and, therefore, the electro-static charging of the particles, and (c) it may condense in thecapillary regions contiguous to the true area of contact (12).
Schepky showed that granules’ flowability falls sharply at 60%RH and stops completely at 70% RH (13). Free moisture existsin the beds of bulk solids in at least two states: a pendular statein which liquid bridges occur between individual particles, anda capillary state in which all the pores of the bed are filled withliquid concave menisci at the pore ends. A transition region be-tween these two states also has been suggested (14).
Cohesion in moist powders involves liquid bridges and mayalso involve solid bridges between particles. The connectionsof the liquid bridges depend on the water content and its dis-tribution. The contributing factors are interfacial tension andcapillary pressure. An expansion in the number of solid bridgescan result in increased cohesion and aggregation and, ultimately,the formation of a hard cake. Caking is the state in which thepowder cannot be moved by vigorously shaking or tapping thecontainer (2). The caking process, which often occurs in water-soluble powders exposed to a high RH, is caused when mois-ture forms a saturated solution on the particles’ surfaces. Thesubsequent moisture evaporation causes recrystallization andthe deposition of solid bridges between particles (15).
Caking has been observed at high RHs with several commonlyused powder excipients (e.g., starch) (4, 16, 17). Several researchersobserved that caking was suppressed by adding 0.25–0.5% mag-nesium oxide to the starch, or 1% magnesium oxide to the sug-ars or salts (4, 18). The fine, plate-shaped magnesium oxide par-ticles adhered to the surfaces of the caking material by van derWaals and electrostatic forces. Their presence reduced interpar-ticulate cohesion by decreasing the number of liquid bridges withinthe caking material (4, 17).
At present, bulk density and tapped density measurementsare much more widely used than angles of repose to assess pow-der cohesion and flow properties. Using such methods, Chanand Pilpel reported that a moisture uptake of ;15% w/w bysodium cromoglycate particles produced no effect on their sur-face properties (19). This observation was thought to be causedby the absorption of moisture into the interior of the particles,leaving little or no moisture on the particle surfaces. Cox, how-ever, indicated that high levels of moisture absorption by sodiumcromoglycate particles caused the crystal structure to expandreversibly (20). On the basis of this study, a small reduction inbulk density would be expected from increasing the moisturecontent of sodium cromoglycate powder. The effect of mois-ture content on the flow properties of some pharmaceutical ex-cipients is listed in Table I (21).
Peleg et al. (22) and Peleg and Moreyra (23) studied the ef-fect of moisture content on food powders’ bulk density. Theyobserved reduced bulk density and caking of water-soluble pow-ders upon increasing moisture content. The reduction in pow-der bulk density was attributed to the presence of interparticleliquid bridges which kept them further apart and produced amore-open structure than if the particles were noncohesive. Thiseffect also produced greater compressibility for moist powders
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than for dry powders at low-compressionpressures.
A powder bed’s tensile strength with ashear cell (which can be obtained frommeasurements of the packed powder bed’sshear strength) and the influence of mois-ture content on the flow properties of pow-ders also has been quantified. Factors thateffect powder bed tensile strengths includethe nature of material, moisture, particlesize, and material packing density. Studieshave found that at a constant state of pack-ing, the tensile strengths of coarse, nonco-hesive fractions increased to a plateau as themoisture content rose. This effect was at-tributed to a growth in the number and di-mension of liquid pendular bonds.At highermoisture content and packing densities,liquid bridges may progress from pendularto funicular bonds (18, 24, 25).
Eaves and Jones observed that increas-ing the liquid content of nonporous bulksolids beds at a fixed state of packing resulted in greater tensilestrength which either remained constant or decreased depend-ing on whether the material, when dry, possessed inherent ten-sile strength. Lowering the surface tension of the liquid reducedtensile strength because of weakening pendular bonds (25).
The effect of moisture on the cohesive properties of “AvicelPH-101” microcrystalline cellulose (MCC, FMC BioPolymer,Philadelphia, PA) and “Emcocel” MCC (JRS Pharma, Patterson,NY) were evaluated by Staniford et al. (26). Avicel PH-101 MCCwas more cohesive than Emcocel MCC at moisture contents of,30% w/w, whereas their cohesive behavior was similar at highermoisture contents. When the powder mass’s water content washigh enough to cover much of the particle surface, advantageouslubrication by the liquid occurred, promoting the flow of theparticulate material with significantly reduced frictional forces.
As an example of a nonporous and noncohesive powder,sodium chloride’s (32–75 mm) (18, 24) tensile strength increasedas moisture content increased (as high as ;4%) because of theadditional liquid bridges initially at contact points (0.1% w/wmoisture) and eventually at near-contact points (at 4% w/wmoisture). Beyond a certain moisture content (.4% moisture),the number of liquid bridges of both types remained constant.The liquid bridges’ attraction force at actual contact points aremore powerful than those at near-contact points. As moisturecontent increased further, however, the tensile strength reacheda plateau. This effect is attributed to a growth in the numberand dimension of liquid pendular bonds. Therefore, an increasein moisture content decreases the powder flow of nonporousand noncohesive materials.
More potential sites of contact exist with nonporous and co-hesive powders (e.g., fine sodium chloride particles [,32 mm])than with coarse particles (24). The combined effects of the num-ber and strength of the liquid bridges’ attractive forces are simi-lar for fine and coarse sodium chloride particles. With highermoisture content, however, the particle–particle interaction de-
creases and becomes insignificant; the ten-sile strength exponentially decreases to a lowplateau value (18, 25). Thus, an increase inmoisture cannot be expected to improve theflow properties of an already cohesive pow-der (2). Walton and Pilpel (27) studied theeffects of moisture content on the tensileproperties of procaine penicillin powdersand showed that the attraction forces be-tween particles decreased as the moisturecontent increased. At moisture levels ,3.6%,the tensile strength of the procaine penicillincompacts decreased with increasing mois-ture content.
Effect of moisture on powder compactionThe need for optimal moisture content inthe formation of strong tablets is indicatedby crystal hydrates that compress well anddo not form strong tablets when water crys-tallization is removed (e.g., ferrous sulfateheptahydrate) (28). Moisture increases the
compact strength by increasing the tensile strength of the pow-der bed, by decreasing the density variation within the tablet,and by recrystallization. The reduction tablet density variationwas ascribed to the lubrication of the die wall, which allowsmore of the applied force to be transmitted through the com-pact onto the lower punch (R value). Absorbed water also de-creases particles’ surface energy and subsequently decreasestablets’ adhesion to the die wall. Any water expressed duringcompaction also functions as a low-viscosity lubricant (28, 29).
Tensile strength. Jaffe and Foss reported that the removal ofwater crystallization prevented the formation of tablet materi-als which normally compact by direct compression (28). Whenpressing magnesium carbonate immediately after drying, Trainobtained anomalous results which were attributed to electro-static effects and allowed the powder samples to equilibrate understandardized conditions before compression (30). Lerk et al. re-ported that the removal of water crystallization from organichydrates such as a-lactose monohydrate, by thermal and chem-ical means before compaction resulted in greater tablet strength(31). Thermal dehydration or desiccation by means of organicsolvents (e.g., methanol) converted crystals of a-lactose mono-hydrate into a stable anhydrous product with much increasedbinding capacity and excellent flowability. Shukla and Price eval-uated the effect of moisture content on the compression prop-erties of directly compressible, high beta-content, anhydrouslactose (32). An increase in the lactose’s moisture content re-duced tablet hardness and greater pressure was required toachieve specified hardness values (32).
Pande and Shangraw studied the role of moisture in the com-pression of b-cyclodextrin and found that samples lost theircompactibility upon the removal of water, thus demonstratingthat moisture is essential for compression (33). An ;14% mois-ture content appeared to be optimum for maximum com-pactibility of the samples studied.
Rees showed that moisture improved consolidation, espe-
Table I: Effect of moisture on flowrate of excipients.
*corn starch flows very poorly and noflow rate could be obtained.
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cially at low applied pressure (34). Armstrong and Griffiths re-ported some effects of moisture on granules’ compaction prop-erties (35). Although the materials varied, their conclusions cor-respond in many respects with those of Rees and Shotton (36).Armstrong and Griffiths also studied the effect of moisture onthe flow and compression properties of phenacetin, paracetamol,and dextrose monohydrate without the addition of an excipient(35). Their results suggested that the increases in compacts’strength on drying were in the same order as solubility. Substanceswith low water solubility would show little, if any, increase incompact strength caused by the loss of moisture on drying.
Sangekar et al. studied the effect of moisture on the physicalcharacteristics of tablets prepared by direct compression (37).Twenty-four formulations of placebo tablets—made from eightdirect compression excipients and three disintegrants—wereevaluated under various conditions of humidity. The volumeof tablets, moisture uptake, hardness, and disintegration timeswere studied. Every formulation gained .4% moisture at 100%RH within 48 h. Dibasic calcium phosphate, anhydrous lactose,and lactose beadlets absorbed minimal amounts of moisture,whereas sorbitol and sucrose absorbed large amounts. Sorbitol,dextrose, and monocalcium phosphate absorbed intermediateamounts (37). Among the direct compression sugars examined,mannitol exhibited the least sensitivity to moisture and thesmallest changes in volume. Tablets containing soy protein be-came harder as the moisture content increased (38).
MCC is an important excipient that has been extensively in-vestigated. Teng et al. noted that, when directly compressed,tablets containing MCC became harder as the moisture con-tent increased and as the compression force increased until thetrue density of the material was reached (39). Lack of moisturewas responsible for tablet lamination because the yield forceand elastic recovery increases. It has been shown that ,3% w/w,moisture is internally chemisorbed by the particles (40). Highermoisture concentrations resulted in the formation of pendularbonds on the particle surfaces, which typically affect to the com-pact strength.
Pilpel and Ingham studied the effect of MCC’s moisture ondensity, compaction, and tensile strength. They related thechanges in mechanical properties of MCC and the tensilestrength of its compacts to the way in which water is sorbedinto the cellulose structure (41). A marked reduction in AvicelMCC tablet tensile strength was observed at ;8% w/w watercontent. This effect may be attributed to hydrostatic resistanceto consolidation caused by the presence of water in a relativelyunrestricted form (42). The effect of moisture on the binarymixtures of MCC-PVP also has been investigated (43). Pilpeland Ingham’s work and other studies support the conclusionthat moisture is sorbed into the amorphous part of Avicel MCC.Several steps are involved, including one water molecule bind-ing between two anhydroglucose units, followed by the bind-ing of one water molecule to each anhydroglucose unit. Finally,sorption of more-loosely bound water will occur as describedby Khan and Pilpel (44). This latter structure increases the mo-lecular mobility of MCC and may explain why water could actas a plasticizer of the amorphous part of MCC.
The effect of water on the rheological and mechanical prop-
erties of commercial Avicel PH-101 and Emcocel MCC alsowere studied (45). The addition of water caused an ;20–30%increase in cohesiveness for both samples, although the changein shear force with water content varied. The samples’ cohesive-ness did not vary when more water was added. Khan et al. alsoexamined the effect of MCC’s moisture content on the com-pression properties of formulations containing paracetamoland potassium phenethicillin (45). The strongest compacts wereproduced with MCC that contained 7.3% moisture.
The powder mass’s moisture content before compression mayinfluence the tablet strength indirectly by affecting the volumereduction of the powder mass during compression. Ahlneckand Alderborn studied the role of adsorbed water in volumereduction as well as on the tensile strengths of tablets for somecrystalline materials (e.g., sodium chloride, Emcompress, sodiumcitrate, or acetylsalicylic acid) (46). The results showed thatwater adsorbed at particle surfaces has a very limited effect onthe volume reduction behavior of a particulate solid. The ex-ception was when a fairly large amount of condensed water waspresent in the powder mass. Condensation of water vapor athigh RHs decreased tablet strength in most cases.
In addition, Li and Peck found that compacts produced bymaltodextrins with a lower degree of polymerization exhibiteda greater tensile strength for a given pressure at a ,8% mois-ture content. Further moisture content increases resulted in de-creased tensile strength of compacts, however. Despite the sig-nificant difference in compression behavior, the five maltodextrinsdid not exhibit noticeable differences in crystallinity (47).
Shukla and Price studied the effect of moisture content onthe compression properties of two dextrose-based, directly com-pressible diluents, “Emdex” (Penwest Pharmaceuticals, CedarRapids, IA) and “Sweetrex” (Mendell) (48). Both diluents sorbedmoisture rapidly at .60% RH. The pressures required to com-press tablets to the same relative density decreased with increas-ing moisture content. Armstrong and Patel examined moisture’seffect on the compressional properties of anhydrous dextroseand dextrose monohydrate (49). A 0–8.9% increase in the an-hydrous dextrose’s moisture content produced a correspondingincrease in both strength parameters (tablet crushing strengthand tablet toughness) because of recrystallization. Any mois-ture increase .8.9% produced a marked reduction in bothtablet tensile strength and tablet toughness. For dextrose mono-hydrate, any increase in moisture content generated by expo-sure to elevated humidity reduced both tensile strength andtoughness.
Strickland et al. (52) and Shotton and Rees (51) found that10% moisture in sodium chloride exerted a hydrodynamic re-sistance to consolidation that counteracted the lubricant effects.Despite the low viscosity of the liquid film, lubrication inhib-ited interparticulate shear forces and thus reduced the amountof bonding that occurred at high pressure. The lubricant effectof moisture during compaction of sodium chloride cannot beattributed simply to hydrodynamic properties (36). Shotton andGanderton examined fractured surfaces of hexamine and foundthat the failure had almost entirely occurred around the parti-cles in compacts prepared at low pressure from samples with10% moisture (52). It was observed that compacts prepared in
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the presence of moisture and subsequently dried showed an in-crease in strength because of interparticulate recrystallization.
Rees and Hersey investigated the role of liquids in the com-paction of sodium chloride that contained moisture (29). Forcompacts containing moisture, compact strength decreased withreduced interparticulate bond strength. In the presence of non-solvents (e.g., light liquid paraffin), compact strengths were afunction of the compact’s state of consolidation.
Garr and Rubinstein found that the compressibility of parac-etamol powder was strongly determined by moisture presentduring consolidation and that a 6% w/w moisture content pro-duced tablets with optimal crushing strength, relative density,and capping pressure (53). Bangudu and Pilpel stated that parac-etamol–cellulose mixtures containing ;2 or 4% w/w waterformed stronger tablets than those without moisture (54).
According to the literature, as the moisture content of pharma-ceutical substances increases, the tablets’ tensile strength increases(specifically at low moisture contents), reaches a maximum, andthen decreases (specifically at higher moisture content).
An increase in tensile strength with increasing moisture con-tent or RH has been explained by two possible mechanisms. First,adsorbed water could function as a surface-restructuring medium,thus increasing the amount of solid bridges (55). Such an effectis expected to occur at fairly low RHs (i.e., below the RH0). RH0
is a characteristic of the solid and is the point above which ad-sorbed water assumes the character of a bulk solution or con-densate (6). Although it is normally assumed that this point mustbe reached before adsorbed water can begin to dissolve a solid,it does not exclude the possibility that the particle surface struc-ture can change below RH0. For sodium chloride, an increase intensile strength with RH has been suggested to be a result of a re-structuring of the tablets’ surface (10, 56).
Another possible explanation for increasing tensile strength isthat immobile water layers sorbed at particle surfaces can en-hance particle–particle interaction. According to this theory, anadsorbed water vapor layer can contribute to the interactions’strength in two ways: (a) tightly bound water vapor layers can beregarded the parts of the particles that reduce interparticular sur-face distances and increase intermolecular attraction forces (5),and (b) adsorbed layers can touch or penetrate each other, thusincreasing the attraction forces between neighboring particles(57–59). These theories were applied to increases in tensile strengthof HPMC K4M tablets with increasing moisture content from 0to 14.9% (60). Nokhodchi et al. showed that when the moisturecontent of HPMC K4M increased from 10 to 15% w/w, the ten-sile strength of HPMC K4M tablets increased from 5.6 to 8.5 Mpaat a compression force of 10 kN (60). A similar trend was ob-served when HPMC K4M was compressed at various forces (5–20kN) in the presence of moisture. Because the thicknesses of HPMCK4M tablets also decreased with moisture, at least part of the in-creased tablet tensile strengths probably increase the contact be-tween the particle surfaces (60).
To eliminate the effects of particle packing on tensile strengthand to evaluate the effect of bonding strength, Malamataris andKaridas determined the overall interparticle bonding force as ten-sile strength at a fixed packing fraction (0.9) by applying linearregression analysis between log tensile strength and packing frac-
tion of tablets compressed at increasing pressure (10–100 MPa)(55). At a packing fraction of 0.9, the tensile strength exhibited aninitial plateau as high as 6% w/w moisture content; tensile strengthdecreased as the moisture content increased. Similar observationsalso have been reported for MCC (41, 48, 61).
A decrease in tensile strength is a result of the formation ofwater multilayers or the presence of free water at the surfaces.Such water may then disturb or reduce intermolecular attrac-tion forces and thereby reduce tablet strength (55, 62, 63).Nokhodchi et al. showed that the crushing strength of ibupro-fen tablets initially increased with increasing moisture content,reached a maximum at ;2.5% w/w, and then decreased as themoisture content further increased from 2.5 to 10% w/w (63).They explained that the subsequent reduction in ibuprofentablets’ crushing strength could be caused by the presence of freewater. Similar results were obtained by Garr and Rubinstein fornonhygroscopic paracetamol tablets (53).
Malamataris et al. obtained moisture sorption and desorptiondata for direct-compression excipients and calculated the fractionof moisture corresponding to various forms of water in powder(64). The distribution of moisture in various forms could accountfor variations in the materials’ tableting performance and thephysicochemical properties of the resulting tablets. For all sam-ples, tensile strength reached a maximum value and then decreasedwhen moisture content was approximately double that correspon-ding to a tightly bound monomolecular layer. The changes in themechanical characteristics were explained by the combined effectof moisture on the interparticle and intermolecular forces.
The effect of moisture content on a polymer’s compaction prop-erties has been reviewed briefly (65, 66). Nokhodchi et al. explainedthe increase or decrease in tensile strength with moisture accord-ing to the type of moisture associated with polymers. Many re-searchers have found that the presence of moisture in varyingquantities could either increase or reduce the mechanical strengthsof various powders (53, 61, 63–68). Their conflicting findings canbe ascribed to the fact that moisture can be present in powders inthree varying physical states (see Figure 1).
The internally absorbed and externally adsorbed water in the45–125-mm fraction of HPMC K4M increased as the RH in-creased (see Table II). An increase in RH from 23 to 75% caused7.5-, 4.8-, and 2.3-fold increases in internally absorbed water,externally adsorbed water, and monolayer-adsorbed water, re-spectively (see Table II). Similarly, the tensile strengths of HPMCK4M tablets concomitantly increased. For example, as the RHincreased from 23 to 75%, the tensile strengths increased from2.15 to 8.54 Mpa (see Table II).
The distribution of moisture in a material; the range andmagnitude of the van der Waals’ forces between the particles;and the development of additional bonds by plastic deforma-tion and/or melting of powder particles should control the ten-sile strength of the tablets. Water molecules initially adsorbedon the surfaces may form a monomolecular layer and increasethe van der Waals forces, thereby smoothing out the surface mi-croirregularities and reducing interparticle separation (24). Thismonolayer-bound water can be regarded as part of the parti-cles’ surface molecular structure (44, 70). These effects wouldincrease the tensile strength of HPMC K4M tablets with in-
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creasing moisture content. An increasein the monolayer of water in HPMCK4M occurs (see Table II).
As more water molecules adhere tothe surface, moisture may transfer intothe material (8, 71–72). This effect maysoften the particles’ surfaces; under highpressure, the area of contact between theparticles will increase with plastic defor-mation and more solid bonds may form(44). These effects could account for thedecreases in mean yield pressure, whichindicate greater plasticity of the HPMC (see Table II) and ac-count for the tablets’ increased tensile strength.
It has been suggested that water adsorption reduced tablet ten-sile strength (53) because of condensation and multilayer adsorp-tion (12). The extent of multilayer adsorption in Table II can beestimated by subtracting the monolayer adsorption from the ex-ternally adsorbed moisture values. Although the amount of mul-tilayer adsorption increased, tensile strength did not decrease.Therefore, the effect of moisture on tablet tensile strength is theresult of the balance between the amount of monolayer-adsorbedmoisture, internally absorbed moisture, and externally adsorbedmoisture. The monolayer adsorbed moisture and internally ab-sorbed moisture dominate the compaction properties of HPMC,as assessed by tensile strength values. Similar explanations accountfor the decreases in mean yield pressure and elastic recovery ofHPMC tablets with increasing RH or moisture content.
An alternative explanation for the effects of moisture on thecompaction properties of HPMC involves the glass transition tem-perature (Tg). The Tg of amorphous materials such as HPMC E5(73) or PVP (73, 74) reduces as the moisture content increases.Hancock and Zografi showed that the Tg of HPMC E5 reducedfrom 428 to 345 K as the moisture content increased from 0 to;15% w/w (73). The water sorbed by amorphous solids is deter-mined by the water’s chemical affinity for the polymer and thewater’s role as a plasticizer (73, 74). Water changes the viscoelas-tic properties of polymers. Therefore, the plasticizing effect ofwater was related to Tg (73, 75). At a certain moisture contentabove the level consistent with the transition from the glassy tothe rubbery state, significant changes occur in the mechanicalproperties of the polymer. At temperatures exceeding Tg, poly-mers exhibit highly increased chain mo-bility and elasticity, which will have majorconsequences for compaction properties.Low-moisture starches are not applicableas direct-compression materials becausethey compact poorly. Water is needed toenhance the compressibility and facilitatethe plastic deformation of glassy starches,thus leading to lower tablet porosities (70).
Moisture’s effect on the compactionproperties of binary mixtures also has beeninvestigated (76). Nokhodchi and Rubin-stein studied the effect of moisture on thecompaction properties of binary mixturesof HPMC K4M–Ibuprofen (50:50). They
found that increasing the moisture con-tent from 0 to 13.05% increased thecompact’s tensile strength. At a highermoisture content (13.05), compressionforce had no significant effect on tablets’tensile strengths.
To explain this observation, one mustconsider the compaction properties ofpure HPMC and pure ibuprofen in thepresence of various moisture contents.In the case of HPMC K4M, when themoisture content increased from 0 to 15,
the tablet tensile strength increased (60). At a higher moisturecontent, a compression force increase resulted in increased ten-sile strength of HPMC, whereas the tensile strengths of the mix-ture were not affected by the compression force (76). It was shownthat 10 kN is the maximum compression force for ibuprofentablets, and higher forces lower that crushing strength (63). There-fore, it can be concluded that the reverse effect of the compres-sion force on the tensile strengths of the mixture components atthis moisture content is the reason for the identical tensilestrengths of the mixture at various compression forces. At highermoisture contents, however, the moisture has a negative effecton HPMC tablets’ tensile strength (61). Increasing the moisturecontent of pure ibuprofen to ;2.5% increases compact strength;tensile strength of compacts decreased with moisture content.3.5% (63).
Because HPMC has a primarily amorphous structure andibuprofen has a crystalline structure, any water sorbed by themixture is almost entirely associated with the HPMC. The dis-ordered state of the amorphous solid makes it possible for waterto dissolve in HPMC. Water uptake by the crystalline ibupro-fen would occur in no more than two or so molecular layers atthe highest RH relative to absorption into the amorphous struc-ture (68). Water’s effect on solid properties is attributed to thefact that water dissolved in an amorphous solid can act as a plas-ticizer to greatly increase the solid’s free volume by reducinghydrogen bonding between adjoining molecules of the solidwith a corresponding reduction in its glass transition temper-ature (77–79). Sorbed water located at the points of physicalcontact between drug and excipient can facilitate an interac-tion between the drug and HPMC (80). Such interactions might
Monomolecular adsorption
Internally absorbed moisture
Externally absorbed moisture
Figure 1: Various states of moisture.
Table II: Moisture distribution, tensile strength at 10 kN, and compressional parameters (mean yield pressure and elastic recovery) for HPMC K4M at various relative humidities.
* figures in parentheses are the moisture content (% w/w)
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alter the system’s mechanical properties.In addition, a change in the glass transi-tion temperature would be expected toaffect the molecular mobility of the solidand produce significant changes in itsviscoelastic and mechanical properties.
Heckel analysis (yield pressure). Thecompression behavior of powders maybe characterized by Heckel plots (see Fig-ure 2) (81, 82). Several researchers havesuccessfully applied Heckel’s equation topharmaceutical powders to identify thetypes of mechanisms occurring duringcompression (83, 84). In the Heckelequation [1], the relative density (D) isrelated to the applied compression pres-sure (P).
ln[1 4 (1 – D)] = KP 1 A [1]
(1 – D) represents the pore fraction or porosity. K is propor-tional to the reciprocal of the mean yield pressure (Py) and A isa function of the initial porosity. Materials with a high meanyield pressure are classified as brittle-fracturing or fragmentary,and materials with low mean yield pressures are classified as plas-tic or elastic deforming substances.
Increased moisture content yields lower mean yield pressures—the measure of the plasticity of a compressed material (i.e., greatermean yield pressure indicated a lower degree of plasticity of ma-terial)—and lower plastic energy during compaction. Esezoboand Pilpel (85) investigated moisture’s effect on the interparticleattractive forces and the compression behavior of oxytetracyclineformulations. The increase in moisture contents increased theHeckel plot slope, indicating a greater degree of densification atlow pressures and improved compressibility as the materials’moisture contents increased. The yield forces and porosity gen-erated under compression for anhydrous dextrose decreased withincreasing moisture content as high as 9.2% (48).
Nokhodchi et al. showed that the initial relative densities (D0);the extrapolated densities from the linear portions of the Heckelplots (Da); and the changes in the relative densities attributed toparticle rearrangement (Db) could be affected by the presence ofmoisture content (see Table III) (86). Da is a parameter relatingto densification caused by the slippage and rearrangement of par-ticles. The values indicate that moisture may act as a lubricant bysmoothing out the surface microirregularities, reducing the fric-tional forces, and facilitating particle rearrangement and slippageduring the densification phase of compaction. The mean yieldpressures of HPMC K4M (86) and ibuprofen (87) tablets wereaffected by the moisture content.A 0–14.9% w/w increase in mois-ture content caused a marked reduction in the mean yield pres-sures of HPMC tablets from 58.80 to 31.22 Mpa at a compressionspeed of 15 mm/s (86).A 0–2.5% w/w increase in ibuprofen tablets’moisture content resulted in reduced mean yield pressures, how-ever (87). As the moisture content increased .2.5% w/w, meanyield pressures increased. Increased mean yield pressures were at-tributed to the assumption that water facilitates the deformationof particles in combination with reduced interparticle friction.
Armstrong et al. studied the relation-ship between porosity and water con-tent of dicalcium phosphate tablets(Emcompress, JRS Pharma, Patterson,NY) (88). They showed that increasingthe moisture content of Emcompresstablets increased apparent tablet den-sity, both under compression and afterejection. This effect continued with crit-ical water contents as high as 8.38, 7.53,and 6.48% w/w for compression forcesof 12, 18, and 24 kN, respectively, be-yond which a reduction in densificationwas obtained. The magnitude of thiscritical water content was dependent onthe applied compression force in that it
decreased as compression force increased.Li and Peck showed that an increase in the powder moisture
content reduced the yield pressure and improved the densifica-tion for each of five maltodextrins evaluated (47). At equivalentmoisture levels, the extent of densification during compactionwas greater for the maltodextrins with lower degrees of poly-merization. Mollan and Çelik also studied the effects of humid-ity and storage time on the behavior of maltodextrins for directcompression (21). They compared the mean yield pressures ofvarious pharmaceutical excipients at 11.3 and 70.90% RHs. Em-compress showed only a slight change in its yield pressure val-ues as a result of the two humidity conditions, as was expectedfrom an insoluble fragmenting material. The maltodextrins allbehaved similarly to each other, with an increased moisture loadfrom storage under high humidity conditions causing an in-crease in the plasticity of the powder, shown by decreases in yieldpressures. Mollan and Çelik stated that the low humidity con-ditions caused the materials to exhibit the most brittle behav-ior, whereas increasing the moisture load caused the materialsto deform plastically to a much greater extent (21).
Shukla and Price stated that Heckel plots obtained from com-pressing of diluents were linear for all moisture contents (32).Yield pressures (calculated from Heckel plots) increased at mois-ture contents greater than that of the original diluent. Differen-tial scanning calorimetry, performed on the diluent with 5.13%moisture, showed that the added water was bound as the crys-talline hydrate.
Garr and Rubinstein investigated the effect of moisture con-tent on the consolidation and compaction properties of parac-etamol (53). The mean yield pressure decreased with increasingmoisture content because of moisture’s overall plasticizing effect.
Malamataris et al. studied the effect of sorbed moisture onthe compression behavior of HPMC polymers (89). Theyshowed that particle slippage and rearrangement increases, asexpected, with increasing RH. The mean yield pressures de-creased as the RH increased from 33 to 75%.
Energy analysis (plastic and elastic energies). The net work ofcompression (plastic energy) and expansion work (elastic energy)of compression are measured using energy analysis on force–dis-placement plots. Plastic energy is energy that is permanently im-parted to the tableted material; elastic energy is energy that is de-
Compression pressure (Mpa)ln
[14
(1–
D)]
slope–1 5 mean yield pressure
A Da
Db 5 Da – Do
Do
Figure 2: Heckel plot of plasticity, fragmentation,and particle rearrangement.
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60 Pharmaceutical Technology JANUARY 2005
livered by the compact back to the punchduring the decompression phase. For asystem in which both punches are mo-bile, the punch separation may be plot-ted against the upper punch force. Thearea under this curve will be the workdone or energy (J). The plastic and elas-tic energies of compaction of the poly-mer tablets are measured using energyanalysis on the force–punch separationplot. Figure 3 illustrates a typical force–punch separation plot, in which A is thepunch separation at the first measurableforce, B is the force at the minimumpunch separation (D), and C is the de-compression force. The area under thecurve ABD yields the gross energy (total energy), while the areaunder curve CBD corresponds to the decompression or elastic en-ergy. The net compaction or plastic energy was determined fromthe difference between areas ABD and CBD.
Ragnarsson and Sjogren showed that as the moisture con-tent increased, the net work required to compress the materi-als decreased (90). The elastic work lessened at high moisturelevels because of retarded tablet expansion. The effect on thecalculated net work was small. Avicel MCC with a low mois-ture content (1.1% w/w) yielded considerably lower tabletstrength than the one with a normal moisture content (4.9%w/w) throughout the pressure range. The bonding propertiesof the moist sample (8.2% water) were satisfactory at low pres-sure, but were less affected by pressure increase and did not dif-fer much from those of the dried material at the highest pres-sure level. To achieve a constant strength, a higher net work wasneeded for the dried material (91). Increased moisture contentprobably affects the plastic energy by a combined effect of re-duced resistance to deformation of the particles, reduced inter-particle friction caused by the lubricating effect of water, andincreased bonding. Armstrong and Patel showed that water con-tent affects the elasticity of Emcompress compressed at 20 kN(88). A reduction in elastic energy occurs upon increasing thewater content from 0 to 6.5%, thus supporting the theory thatmoisture may induce plasticity into the brittle Emcompress par-ticles. At higher water content, a significant increase in elasticenergy or decompression work was generated.
For a given compression force, a moisture content increase sig-nificantly decreased the plastic energy. Moisture content increasesprobably affected the net compaction energies (plastic energies)by a combined effect of reducing particle resistance and enhanc-ing particle deformation, thus reducing interparticle friction be-cause of moisture’s lubrication effects. If plastic energy is plottedas a function of tablet tensile strength for various moisture con-tents, a higher plastic energy for the dried material was needed toachieve a specific tablet strength. Thus, to achieve a constant ten-sile strength, a lower plastic energy is needed with increasing mois-ture content. For example, to obtain tablets with a tensile strengthof ;2 MPa, the plastic energy needed was 7.65, 4.06, and 2.86 Jat moisture contents of 0, 5.9, and 14.9%, respectively.
Elastic recovery. Bangudu and Pilpel studied the effects of mois-
ture on the plasto-elasticity and tableting ofparacetamol and MCC mixtures (54). For allthe mixtures, adding small amounts of water(,4% w/w) decreased the elastic recovery–stress relaxation ratio (ER–SR); at higheramounts (.4% w/w), the ratio increased.With Avicel MCC, the ratio only increased.The initial decrease in values of ER–SR inthe mixtures was caused presumably by thedevelopment of surface tension and pendu-lar bonds that hold the particles together.The researchers explained that the ER–SRvalues increased when more water was added;the tablets’ tensile strength then decreasedbecause at these levels, the water probablywas beginning to form multilayers on the
particles’ surface. These layers act as a lubricant, thus reducing thefrictional forces responsible for interparticle attraction.
Liquid water also tends to rupture the hydrogen bond be-tween cellulose particles, that contribute to the tensile strengthof the compacts (53). This result explained why samples con-taining 75% w/w or more of cellulose exhibited virtually no de-crease in ER–SR ratio (and consequent increase in tensilestrength) when as much as 2% w/w of water was added. Theaddition of moisture increased the surface energy of the parti-cles and the binding forces between them. Similar results alsowere presented by Khan and Pilpel (40). Malamataris et al. in-vestigated the effect of moisture content on HPMC tablets’ elas-tic recovery (88). They showed that as the RH increased, theelastic recoveries reduced. For HPMC K4M, the elastic recov-eries were 8.9 and 4.9%, at 33 and 52% RH, respectively.
Lubrication effect of moisture. The amount of moisture presentin powders and granules can affect the frictional properties of thecompact formed. In studies covering this aspect of moisture ef-fect, various measurements of tablet friction have been used.
Punch force ratio. R-value or punch force (transmission) ratio wasused by Shotton and Rees (51). They stated that in the presenceof 0.55% moisture, an increased sodium chloride punch forceratio (R) at low applied force will caused compaction. This effectmay be explained by reduced friction caused by the formation ofmoisture film acting as a lubricant at the die wall. The force lostto the die wall increased with applied force as the compact areain contact with the die wall increased. As the porosity of the com-pact decreased, the void spaces became filled with liquid. Then,an increase in applied force caused liquid expulsion to form a con-tinuous film at the die wall. Consequently, the liquid reduced thefriction coefficient between particles and the die wall, and also re-stricted movement of the solid in contact with the die. Shottonand Rees showed that a lower moisture content (0.02 or 0.16%)provided less die-wall lubrication at all values of applied force(51). Liquid did not migrate to the die wall even at high appliedforce, because sufficient void space remained to accommodatethe small volume of liquid.
Force lost to the die wall. Rees and Shotton investigated the role ofmoisture in the compaction process by using an ideal particulatesystem of crystalline sodium chloride and three liquids: water,decahydronaphthalene, and light liquid paraffin (36). They stated
Punch separation (mm)C
om
pre
ssio
n fo
rce
(kN
)
B
D C AC
Figure 3: Force–punch separation plot forplastic and elastic energy measurements.
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62 Pharmaceutical Technology JANUARY 2005
that although differences in the three liquids’ behavior could beattributed partly to the differences in viscosity, water apparentlyexerted a boundary lubrication in addition to hydrodynamicproperties. In the presence of moisture, the force lost to the diewall (Fd) and to consecutive compression increases were appre-ciably less than with light liquid paraffin or decahydronaphtha-lene, both of which had a negligible die wall lubricant effect. HighFd values were attributed to an increase in the radial componentof applied force by interparticulate lubrication.
During particulate material compaction, the proportion of theapplied force transmitted to the die wall is affected by several fac-tors including: (a) the radial component of the applied force, (b)the effective area of contact, and (c) the coefficient of friction atthe die wall. Because interparticulate lubrication increases theratio of radial stress to axial stress, the application of lubricant tothe die is more effective than the addition of lubricant to a pow-der before compression. Lubrication of both the die wall and in-terparticulate junctions produces a net decrease in the die-wallfriction because reducing the coefficient of interparticulate fric-tion usually has little effect on die-wall friction compared with adecrease in the coefficient of friction at the die wall.
Seth and Munzel studied a lactose-based granulation contain-ing phenacetin and starch and concluded that the optimal mois-ture content was ;2.7% w/w (91). They have been criticized thatthe granulation contained a high proportion of starch, which ob-scured the moisture’s effect on phenacetin and lactose behavior.
Ejection force Obiorah and Shotton investigated the effect of waxes, hydrolyzedgelatin, and moisture on the compression characteristics ofparacetamol and phenacetin (92). The behavior of paraceta-mol or phenacetin and their mixtures with gelatin hydrolysateor water was similar to a Mohr body; the die wall pressure wasaffected by the particle size of the material compressed and bythe additives present. Good transmission of radial force impliedthat the material could be consolidated initially, but alone, itdid not indicate that the tablet formed was physically stable.Hydrolyzed gelatin, water, or both together produced paraceta-mol and phenacetin mixtures with satisfactory compressioncharacteristics. The lowest ejection forces were associated withcompacts produced from MCC containing 5% w/w moisture.
The critical moisture content in MCC to optimize tensilestrength and ejection force is ;5% w/w.
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