DATA & REVIEW
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.
Ali Nokhodchi is a lecturer in
pharmaceutics, Department of
Pharmacy, School of Health and
Life Sciences, Kings College
London, 150 Stamford Street,
Franklin-Wilkins Building, London
SE1 9NN, UK, tel. 144 2 7848
4787, fax 144 2 7848 480, ali.
nokhodchi@kcl.ac.uk.
46 Pharmaceutical Technology JANUARY 2005
T
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 solids 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 airs move-
ment, and (e) a reaction constant that is characteristic of the
solid. Mikuliniskii and Rubinshtein studied the kinetics of mag-
nesium sulfates 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
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DATA & REVIEW
polymers and free films may help characterize the possible effects
on the dissolution and transport of drugs from dosage forms.
Water interacts with pharmaceutical solids at virtually all
stages of manufacture. Therefore, waterpowder interaction is
a major factor in the formulation, processing, and performance
of solid dosage forms. The amount of water associated with a
solid 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 Harb
observed that the EMCs of starch, alginic acid, and tragacanth in-
creased as RH increased, but remained unaffected by increased
temperatures (3). In contrast, higher temperature caused hydrates
to form and dissolve at lower RHs. Lactose, however, did not show
deliquescence and its EMC increased only slightly at higher tem-
peratures, even at 50 8C and 100% RH (4). Coelhi and Harnby
noted that fine particle size fractions of sucrose and sodium chlo-
ride had higher EMCs compared with coarse particles of these
materials (5).
If water adsorption onto the material is excluded, water can
interact with solids in two ways (57). In a fairly dry atmos-
phere, the water will be relatively tightly bound as a nonfreely
movable layer, which sometimes is denoted as monolayer ad-
sorbed moisture (8) or water vapor adsorption. At most, 23
vapor 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 solids 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 adsorbed
water 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 the
moist air and a solid (7).
Coelho and Harnby studied the effect of humidity on the form
of water retained in nonporous and insoluble powders (11). They
suggested that at low RH, the moisture associated with a powders
particles 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 flow
Powder properties such as flow will be affected by the surface
condition of the constituent particles. The two fundamental
forces that can affect powder flow are cohesion and friction.
Cohesion is the mutual attraction and resistance to separation
of contacting powder particles of identical material. Friction is
the resistance exerted by one particle against the motion of an-
other particle at the points of contact. Frictional forces act at a
tangent to the surface of the contact point. The adsorbed mois-
ture film lubricates the particles and possibly prevents, to some
degree, the cold welding of asperities. Thus, the frictional force
that opposes the relative motion of the particles is reduced.
Hiestand found that moisture may influence the force of in-
48 Pharmaceutical Technology JANUARY 2005
teraction between solid particles in at least three ways: (a) it
may 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 the
capillary 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 exists
in the beds of bulk solids in at least two states: a pendular state
in which liquid bridges occur between individual particles, and
a capillary state in which all the pores of the bed are filled with
liquid 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 may
also involve solid bridges between particles. The connections
of the liquid bridges depend on the water content and its dis-
tribution. The contributing factors are interfacial tension and
capillary pressure. An expansion in the number of solid bridges
can result in increased cohesion and aggregation and, ultimately,
the formation of a hard cake. Caking is the state in which the
powder cannot be moved by vigorously shaking or tapping the
container (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. The
subsequent moisture evaporation causes recrystallization and
the deposition of solid bridges between particles (15).
Caking has been observed at high RHs with several commonly
used powder excipients (e.g., starch) (4, 16, 17). Several researchers
observed that caking was suppressed by adding 0.250.5% 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 der
Waals and electrostatic forces. Their presence reduced interpar-
ticulate cohesion by decreasing the number of liquid bridges within
the caking material (4, 17).
At present, bulk density and tapped density measurements
are much more widely used than angles of repose to assess pow-
der cohesion and flow properties. Using such methods, Chan
and Pilpel reported that a moisture uptake of ;15% w/w by
sodium cromoglycate particles produced no effect on their sur-
face properties (19). This observation was thought to be caused
by 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 sodium
cromoglycate particles caused the crystal structure to expand
reversibly (20). On the basis of this study, a small reduction in
bulk density would be expected from increasing the moisture
content 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. They
observed 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 interparticle
liquid bridges which kept them further apart and produced a
more-open structure than if the particles were noncohesive. This
effect also produced greater compressibility for moist powders
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DATA & REVIEW

than for dry powders at low-compression

pressures.
Table I: Effect of moisture on flow creases and becomes insignificant; the ten-
sile strength exponentially decreases to a low
A powder beds tensile strength with a rate of excipients. plateau value (18, 25). Thus, an increase in
shear cell (which can be obtained from Moisture Flow rate moisture cannot be expected to improve the
measurements of the packed powder beds Excipient content (%) (g/min) flow properties of an already cohesive pow-
shear strength) and the influence of mois- Emcompress 0.32 749 der (2). Walton and Pilpel (27) studied the
ture content on the flow properties of pow- 0.40 739 effects of moisture content on the tensile
ders also has been quantified. Factors that 0.63 748 properties of procaine penicillin powders
effect powder bed tensile strengths include Fast-flow 0.24 505 and showed that the attraction forces be-
the nature of material, moisture, particle lactose 0.27 554 tween particles decreased as the moisture
size, and material packing density. Studies 0.42 548 content increased. At moisture levels ,3.6%,
have found that at a constant state of pack- Emedex 0.54 510 the tensile strength of the procaine penicillin
ing, the tensile strengths of coarse, nonco- 1.21 451 compacts decreased with increasing mois-
hesive fractions increased to a plateau as the 1.46 460 ture content.
moisture content rose. This effect was at- Corn starch* 6.13
tributed to a growth in the number and di- 10.13 Effect of moisture on powder compaction
mension of liquid pendular bonds. At higher 12.04 The need for optimal moisture content in
moisture content and packing densities, Maltodextrin 2.97 241 the formation of strong tablets is indicated
liquid bridges may progress from pendular 7.68 237 by crystal hydrates that compress well and
to funicular bonds (18, 24, 25). *corn starch flows very poorly and no do not form strong tablets when water crys-
Eaves and Jones observed that increas- flow rate could be obtained. tallization is removed (e.g., ferrous sulfate
ing the liquid content of nonporous bulk heptahydrate) (28). Moisture increases the
solids beds at a fixed state of packing resulted in greater tensile compact strength by increasing the tensile strength of the pow-
strength which either remained constant or decreased depend- der bed, by decreasing the density variation within the tablet,
ing on whether the material, when dry, possessed inherent ten- and by recrystallization. The reduction tablet density variation
sile strength. Lowering the surface tension of the liquid reduced was ascribed to the lubrication of the die wall, which allows
tensile strength because of weakening pendular bonds (25). more of the applied force to be transmitted through the com-
The effect of moisture on the cohesive properties of Avicel pact onto the lower punch (R value). Absorbed water also de-
PH-101 microcrystalline cellulose (MCC, FMC BioPolymer, creases particles surface energy and subsequently decreases
Philadelphia, PA) and Emcocel MCC (JRS Pharma, Patterson, tablets adhesion to the die wall. Any water expressed during
NY) were evaluated by Staniford et al. (26). Avicel PH-101 MCC compaction also functions as a low-viscosity lubricant (28, 29).
was more cohesive than Emcocel MCC at moisture contents of Tensile strength. Jaffe and Foss reported that the removal of
,30% w/w, whereas their cohesive behavior was similar at higher water crystallization prevented the formation of tablet materi-
moisture contents. When the powder masss water content was als which normally compact by direct compression (28). When
high enough to cover much of the particle surface, advantageous pressing magnesium carbonate immediately after drying, Train
lubrication by the liquid occurred, promoting the flow of the obtained anomalous results which were attributed to electro-
particulate material with significantly reduced frictional forces. static effects and allowed the powder samples to equilibrate under
As an example of a nonporous and noncohesive powder, standardized conditions before compression (30). Lerk et al. re-
sodium chlorides (3275 mm) (18, 24) tensile strength increased ported that the removal of water crystallization from organic
as moisture content increased (as high as ;4%) because of the hydrates such as a-lactose monohydrate, by thermal and chem-
additional liquid bridges initially at contact points (0.1% w/w ical means before compaction resulted in greater tablet strength
moisture) and eventually at near-contact points (at 4% w/w (31). Thermal dehydration or desiccation by means of organic
moisture). Beyond a certain moisture content (.4% moisture), solvents (e.g., methanol) converted crystals of a-lactose mono-
the number of liquid bridges of both types remained constant. hydrate into a stable anhydrous product with much increased
The liquid bridges attraction force at actual contact points are binding capacity and excellent flowability. Shukla and Price eval-
more powerful than those at near-contact points. As moisture uated the effect of moisture content on the compression prop-
content increased further, however, the tensile strength reached erties of directly compressible, high beta-content, anhydrous
a plateau. This effect is attributed to a growth in the number lactose (32). An increase in the lactoses moisture content re-
and dimension of liquid pendular bonds. Therefore, an increase duced tablet hardness and greater pressure was required to
in moisture content decreases the powder flow of nonporous achieve specified hardness values (32).
and noncohesive materials. Pande and Shangraw studied the role of moisture in the com-
More potential sites of contact exist with nonporous and co- pression of b-cyclodextrin and found that samples lost their
hesive powders (e.g., fine sodium chloride particles [,32 mm]) compactibility upon the removal of water, thus demonstrating
than with coarse particles (24). The combined effects of the num- that moisture is essential for compression (33). An ;14% mois-
ber and strength of the liquid bridges attractive forces are simi- ture content appeared to be optimum for maximum com-
lar for fine and coarse sodium chloride particles. With higher pactibility of the samples studied.
moisture content, however, the particleparticle interaction de- Rees showed that moisture improved consolidation, espe-
50 Pharmaceutical Technology JANUARY 2005 www.phar mtech.com
DATA & REVIEW
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 on
the 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. Substances
with low water solubility would show little, if any, increase in
compact strength caused by the loss of moisture on drying.
Sangekar et al. studied the effect of moisture on the physical
characteristics of tablets prepared by direct compression (37).
Twenty-four formulations of placebo tabletsmade from eight
direct compression excipients and three disintegrantswere
evaluated under various conditions of humidity. The volume
of tablets, moisture uptake, hardness, and disintegration times
were 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 intermediate
amounts (37). Among the direct compression sugars examined,
mannitol exhibited the least sensitivity to moisture and the
smallest 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 the
true density of the material was reached (39). Lack of moisture
was responsible for tablet lamination because the yield force
and elastic recovery increases. It has been shown that ,3% w/w,
moisture is internally chemisorbed by the particles (40). Higher
moisture concentrations resulted in the formation of pendular
bonds on the particle surfaces, which typically affect to the com-
pact strength.
Pilpel and Ingham studied the effect of MCCs moisture on
density, compaction, and tensile strength. They related the
changes in mechanical properties of MCC and the tensile
strength of its compacts to the way in which water is sorbed
into the cellulose structure (41). A marked reduction in Avicel
MCC tablet tensile strength was observed at ;8% w/w water
content. This effect may be attributed to hydrostatic resistance
to consolidation caused by the presence of water in a relatively
unrestricted form (42). The effect of moisture on the binary
mixtures of MCC-PVP also has been investigated (43). Pilpel
and Inghams work and other studies support the conclusion
that 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 described
by Khan and Pilpel (44). This latter structure increases the mo-
lecular mobility of MCC and may explain why water could act
as a plasticizer of the amorphous part of MCC.
The effect of water on the rheological and mechanical prop-
52 Pharmaceutical Technology JANUARY 2005
erties of commercial Avicel PH-101 and Emcocel MCC also
were studied (45). The addition of water caused an ;2030%
increase in cohesiveness for both samples, although the change
in shear force with water content varied. The samples cohesive-
ness did not vary when more water was added. Khan et al. also
examined the effect of MCCs moisture content on the com-
pression properties of formulations containing paracetamol
and potassium phenethicillin (45). The strongest compacts were
produced with MCC that contained 7.3% moisture.
The powder masss moisture content before compression may
influence the tablet strength indirectly by affecting the volume
reduction of the powder mass during compression. Ahlneck
and Alderborn studied the role of adsorbed water in volume
reduction as well as on the tensile strengths of tablets for some
crystalline materials (e.g., sodium chloride, Emcompress, sodium
citrate, or acetylsalicylic acid) (46). The results showed that
water adsorbed at particle surfaces has a very limited effect on
the volume reduction behavior of a particulate solid. The ex-
ception was when a fairly large amount of condensed water was
present in the powder mass. Condensation of water vapor at
high RHs decreased tablet strength in most cases.
In addition, Li and Peck found that compacts produced by
maltodextrins with a lower degree of polymerization exhibited
a 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 maltodextrins
did not exhibit noticeable differences in crystallinity (47).
Shukla and Price studied the effect of moisture content on
the compression properties of two dextrose-based, directly com-
pressible diluents, Emdex (Penwest Pharmaceuticals, Cedar
Rapids, IA) and Sweetrex (Mendell) (48). Both diluents sorbed
moisture 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 moistures
effect on the compressional properties of anhydrous dextrose
and dextrose monohydrate (49). A 08.9% increase in the an-
hydrous dextroses moisture content produced a corresponding
increase in both strength parameters (tablet crushing strength
and tablet toughness) because of recrystallization. Any mois-
ture increase .8.9% produced a marked reduction in both
tablet 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 and
toughness.
Strickland et al. (52) and Shotton and Rees (51) found that
10% 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 amount
of bonding that occurred at high pressure. The lubricant effect
of moisture during compaction of sodium chloride cannot be
attributed simply to hydrodynamic properties (36). Shotton and
Ganderton examined fractured surfaces of hexamine and found
that the failure had almost entirely occurred around the parti-
cles in compacts prepared at low pressure from samples with
10% moisture (52). It was observed that compacts prepared in
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DATA & REVIEW
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). For
compacts containing moisture, compact strength decreased with
reduced interparticulate bond strength. In the presence of non-
solvents (e.g., light liquid paraffin), compact strengths were a
function of the compacts state of consolidation.
Garr and Rubinstein found that the compressibility of parac-
etamol powder was strongly determined by moisture present
during 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-
etamolcellulose mixtures containing ;2 or 4% w/w water
formed 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, and
then 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 effect
is 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 must
be 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 in
tensile 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 is
that immobile water layers sorbed at particle surfaces can en-
hance particleparticle interaction. According to this theory, an
adsorbed water vapor layer can contribute to the interactions
strength in two ways: (a) tightly bound water vapor layers can be
regarded 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, thus
increasing the attraction forces between neighboring particles
(5759). These theories were applied to increases in tensile strength
of HPMC K4M tablets with increasing moisture content from 0
to 14.9% (60). Nokhodchi et al. showed that when the moisture
content 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 Mpa
at a compression force of 10 kN (60). A similar trend was ob-
served when HPMC K4M was compressed at various forces (520
kN) in the presence of moisture. Because the thicknesses of HPMC
K4M 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 strength
and to evaluate the effect of bonding strength, Malamataris and
Karidas determined the overall interparticle bonding force as ten-
sile strength at a fixed packing fraction (0.9) by applying linear
regression analysis between log tensile strength and packing frac-
54 Pharmaceutical Technology JANUARY 2005
tion of tablets compressed at increasing pressure (10100 MPa)
(55). At a packing fraction of 0.9, the tensile strength exhibited an
initial plateau as high as 6% w/w moisture content; tensile strength
decreased as the moisture content increased. Similar observations
also have been reported for MCC (41, 48, 61).
A decrease in tensile strength is a result of the formation of
water 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 the
moisture content further increased from 2.5 to 10% w/w (63).
They explained that the subsequent reduction in ibuprofen
tablets crushing strength could be caused by the presence of free
water. Similar results were obtained by Garr and Rubinstein for
nonhygroscopic paracetamol tablets (53).
Malamataris et al. obtained moisture sorption and desorption
data for direct-compression excipients and calculated the fraction
of moisture corresponding to various forms of water in powder
(64). The distribution of moisture in various forms could account
for variations in the materials tableting performance and the
physicochemical properties of the resulting tablets. For all sam-
ples, tensile strength reached a maximum value and then decreased
when moisture content was approximately double that correspon-
ding to a tightly bound monomolecular layer. The changes in the
mechanical characteristics were explained by the combined effect
of moisture on the interparticle and intermolecular forces.
The effect of moisture content on a polymers compaction prop-
erties has been reviewed briefly (65, 66). Nokhodchi et al. explained
the 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 varying
quantities could either increase or reduce the mechanical strengths
of various powders (53, 61, 6368). Their conflicting findings can
be ascribed to the fact that moisture can be present in powders in
three varying physical states (see Figure 1).
The internally absorbed and externally adsorbed water in the
45125-mm fraction of HPMC K4M increased as the RH in-
creased (see Table II). An increase in RH from 23 to 75% caused
7.5-, 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 HPMC
K4M tablets concomitantly increased. For example, as the RH
increased from 23 to 75%, the tensile strengths increased from
2.15 to 8.54 Mpa (see Table II).
The distribution of moisture in a material; the range and
magnitude 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 adsorbed
on the surfaces may form a monomolecular layer and increase
the van der Waals forces, thereby smoothing out the surface mi-
croirregularities and reducing interparticle separation (24). This
monolayer-bound water can be regarded as part of the parti-
cles surface molecular structure (44, 70). These effects would
increase the tensile strength of HPMC K4M tablets with in-
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DATA & REVIEW

creasing moisture content. An increase found that increasing the moisture con-
Monomolecular
in the monolayer of water in HPMC adsorption tent from 0 to 13.05% increased the
K4M occurs (see Table II). Externally compacts tensile strength. At a higher
absorbed
As more water molecules adhere to moisture moisture content (13.05), compression
the surface, moisture may transfer into force had no significant effect on tablets
the material (8, 7172). This effect may tensile strengths.
soften the particles surfaces; under high To explain this observation, one must
pressure, the area of contact between the Internally consider the compaction properties of
absorbed
particles will increase with plastic defor- moisture
pure HPMC and pure ibuprofen in the
mation and more solid bonds may form presence of various moisture contents.
(44). These effects could account for the Figure 1: Various states of moisture. In the case of HPMC K4M, when the
decreases in mean yield pressure, which moisture content increased from 0 to 15,
indicate greater plasticity of the HPMC (see Table II) and ac- the tablet tensile strength increased (60). At a higher moisture
count for the tablets increased tensile strength. content, a compression force increase resulted in increased ten-
It has been suggested that water adsorption reduced tablet ten- sile strength of HPMC, whereas the tensile strengths of the mix-
sile strength (53) because of condensation and multilayer adsorp- ture were not affected by the compression force (76). It was shown
tion (12). The extent of multilayer adsorption in Table II can be that 10 kN is the maximum compression force for ibuprofen
estimated by subtracting the monolayer adsorption from the ex- tablets, and higher forces lower that crushing strength (63). There-
ternally adsorbed moisture values. Although the amount of mul- fore, it can be concluded that the reverse effect of the compres-
tilayer adsorption increased, tensile strength did not decrease. sion force on the tensile strengths of the mixture components at
Therefore, the effect of moisture on tablet tensile strength is the this moisture content is the reason for the identical tensile
result of the balance between the amount of monolayer-adsorbed strengths of the mixture at various compression forces. At higher
moisture, internally absorbed moisture, and externally adsorbed moisture contents, however, the moisture has a negative effect
moisture. The monolayer adsorbed moisture and internally ab- on HPMC tablets tensile strength (61). Increasing the moisture
sorbed moisture dominate the compaction properties of HPMC, content of pure ibuprofen to ;2.5% increases compact strength;
as assessed by tensile strength values. Similar explanations account tensile strength of compacts decreased with moisture content
for the decreases in mean yield pressure and elastic recovery of .3.5% (63).
HPMC tablets with increasing RH or moisture content. Because HPMC has a primarily amorphous structure and
An alternative explanation for the effects of moisture on the ibuprofen has a crystalline structure, any water sorbed by the
compaction properties of HPMC involves the glass transition tem- mixture is almost entirely associated with the HPMC. The dis-
perature (Tg). The Tg of amorphous materials such as HPMC E5 ordered state of the amorphous solid makes it possible for water
(73) or PVP (73, 74) reduces as the moisture content increases. to dissolve in HPMC. Water uptake by the crystalline ibupro-
Hancock and Zografi showed that the Tg of HPMC E5 reduced fen would occur in no more than two or so molecular layers at
from 428 to 345 K as the moisture content increased from 0 to the highest RH relative to absorption into the amorphous struc-
;15% w/w (73). The water sorbed by amorphous solids is deter- ture (68). Waters effect on solid properties is attributed to the
mined by the waters chemical affinity for the polymer and the fact that water dissolved in an amorphous solid can act as a plas-
waters role as a plasticizer (73, 74). Water changes the viscoelas- ticizer to greatly increase the solids free volume by reducing
tic properties of polymers. Therefore, the plasticizing effect of hydrogen bonding between adjoining molecules of the solid
water was related to Tg (73, 75). At a certain moisture content with a corresponding reduction in its glass transition temper-
above the level consistent with the transition from the glassy to ature (7779). Sorbed water located at the points of physical
the rubbery state, significant changes occur in the mechanical contact between drug and excipient can facilitate an interac-
properties of the polymer. At temperatures exceeding Tg, poly- tion between the drug and HPMC (80). Such interactions might
mers exhibit highly increased chain mo-
bility and elasticity, which will have major
consequences for compaction properties.
Table II: Moisture distribution, tensile strength at 10 kN, and compressional
Low-moisture starches are not applicable parameters (mean yield pressure and elastic recovery) for HPMC K4M at
as direct-compression materials because various relative humidities.
they compact poorly. Water is needed to Moisture distribution (%) Tensile Mean yield
enhance the compressibility and facilitate Relative Monolayer External Internal strength pressure Elastic
the plastic deformation of glassy starches, humidity (%)* adsorption adsorption adsorption (Mpa) (Mpa) recovery (%)
thus leading to lower tablet porosities (70). 23 (2.2) 1.2 1.5 1.1 2.15 53.14 17.11
Moistures effect on the compaction 33 (3.8) 1.6 2.3 2.1 3.02 50.08 13.40
properties of binary mixtures also has been 43 (5.9) 1.9 3.1 3.3 3.45 44.18 11.62
investigated (76). Nokhodchi and Rubin- 58 (9.6) 2.4 4.6 5.5 5.6 36.18 8.21
stein studied the effect of moisture on the 75 (14.9) 2.8 7.2 8.2 8.54 31.12 6.02
compaction properties of binary mixtures
* figures in parentheses are the moisture content (% w/w)
of HPMC K4MIbuprofen (50:50). They
56 Pharmaceutical Technology JANUARY 2005 www.phar mtech.com
DATA & REVIEW

alter the systems mechanical properties. Armstrong et al. studied the relation-
In addition, a change in the glass transi- slope1 5 mean yield pressure ship between porosity and water con-
tion temperature would be expected to tent of dicalcium phosphate tablets
affect the molecular mobility of the solid (Emcompress, JRS Pharma, Patterson,

ln[14(1 D)]
and produce significant changes in its NY) (88). They showed that increasing
viscoelastic and mechanical properties. A Da the moisture content of Emcompress
Heckel analysis (yield pressure). The tablets increased apparent tablet den-
compression behavior of powders may Db 5 Da Do sity, both under compression and after
be characterized by Heckel plots (see Fig- Do ejection. This effect continued with crit-
ure 2) (81, 82). Several researchers have ical water contents as high as 8.38, 7.53,
successfully applied Heckels equation to and 6.48% w/w for compression forces
pharmaceutical powders to identify the Compression pressure (Mpa)
of 12, 18, and 24 kN, respectively, be-
types of mechanisms occurring during yond which a reduction in densification
compression (83, 84). In the Heckel Figure 2: Heckel plot of plasticity, fragmentation,
was obtained. The magnitude of this
equation [1], the relative density (D) is and particle rearrangement.
critical water content was dependent on
related to the applied compression pres- the applied compression force in that it
sure (P). decreased as compression force increased.
ln[1 4 (1 D)] = KP 1 A [1] Li and Peck showed that an increase in the powder moisture
content reduced the yield pressure and improved the densifica-
(1 D) represents the pore fraction or porosity. K is propor- tion for each of five maltodextrins evaluated (47). At equivalent
tional to the reciprocal of the mean yield pressure (Py) and A is moisture levels, the extent of densification during compaction
a function of the initial porosity. Materials with a high mean was greater for the maltodextrins with lower degrees of poly-
yield pressure are classified as brittle-fracturing or fragmentary, merization. Mollan and elik also studied the effects of humid-
and materials with low mean yield pressures are classified as plas- ity and storage time on the behavior of maltodextrins for direct
tic or elastic deforming substances. compression (21). They compared the mean yield pressures of
Increased moisture content yields lower mean yield pressures various pharmaceutical excipients at 11.3 and 70.90% RHs. Em-
the measure of the plasticity of a compressed material (i.e., greater compress showed only a slight change in its yield pressure val-
mean yield pressure indicated a lower degree of plasticity of ma- ues as a result of the two humidity conditions, as was expected
terial)and lower plastic energy during compaction. Esezobo from an insoluble fragmenting material. The maltodextrins all
and Pilpel (85) investigated moistures effect on the interparticle behaved similarly to each other, with an increased moisture load
attractive forces and the compression behavior of oxytetracycline from storage under high humidity conditions causing an in-
formulations. The increase in moisture contents increased the crease in the plasticity of the powder, shown by decreases in yield
Heckel plot slope, indicating a greater degree of densification at pressures. Mollan and elik stated that the low humidity con-
low pressures and improved compressibility as the materials ditions caused the materials to exhibit the most brittle behav-
moisture contents increased. The yield forces and porosity gen- ior, whereas increasing the moisture load caused the materials
erated under compression for anhydrous dextrose decreased with to deform plastically to a much greater extent (21).
increasing moisture content as high as 9.2% (48). Shukla and Price stated that Heckel plots obtained from com-
Nokhodchi et al. showed that the initial relative densities (D0); pressing of diluents were linear for all moisture contents (32).
the extrapolated densities from the linear portions of the Heckel Yield pressures (calculated from Heckel plots) increased at mois-
plots (Da); and the changes in the relative densities attributed to ture contents greater than that of the original diluent. Differen-
particle rearrangement (Db) could be affected by the presence of tial scanning calorimetry, performed on the diluent with 5.13%
moisture content (see Table III) (86). Da is a parameter relating moisture, showed that the added water was bound as the crys-
to densification caused by the slippage and rearrangement of par- talline hydrate.
ticles. The values indicate that moisture may act as a lubricant by Garr and Rubinstein investigated the effect of moisture con-
smoothing out the surface microirregularities, reducing the fric- tent on the consolidation and compaction properties of parac-
tional forces, and facilitating particle rearrangement and slippage etamol (53). The mean yield pressure decreased with increasing
during the densification phase of compaction. The mean yield moisture content because of moistures overall plasticizing effect.
pressures of HPMC K4M (86) and ibuprofen (87) tablets were Malamataris et al. studied the effect of sorbed moisture on
affected by the moisture content. A 014.9% w/w increase in mois- the compression behavior of HPMC polymers (89). They
ture content caused a marked reduction in the mean yield pres- showed that particle slippage and rearrangement increases, as
sures of HPMC tablets from 58.80 to 31.22 Mpa at a compression expected, with increasing RH. The mean yield pressures de-
speed of 15 mm/s (86). A 02.5% w/w increase in ibuprofen tablets creased as the RH increased from 33 to 75%.
moisture content resulted in reduced mean yield pressures, how- Energy analysis (plastic and elastic energies). The net work of
ever (87). As the moisture content increased .2.5% w/w, mean compression (plastic energy) and expansion work (elastic energy)
yield pressures increased. Increased mean yield pressures were at- of compression are measured using energy analysis on forcedis-
tributed to the assumption that water facilitates the deformation placement plots. Plastic energy is energy that is permanently im-
of particles in combination with reduced interparticle friction. parted to the tableted material; elastic energy is energy that is de-
58 Pharmaceutical Technology JANUARY 2005 www.phar mtech.com
DATA & REVIEW

livered by the compact back to the punch ture on the plasto-elasticity and tableting of
B
during the decompression phase. For a paracetamol and MCC mixtures (54). For all
system in which both punches are mo- the mixtures, adding small amounts of water
bile, the punch separation may be plot- (,4% w/w) decreased the elastic recovery
ted against the upper punch force. The stress relaxation ratio (ERSR); at higher

Compression force (kN)

area under this curve will be the work amounts (.4% w/w), the ratio increased.
done or energy (J). The plastic and elas- With Avicel MCC, the ratio only increased.
tic energies of compaction of the poly- The initial decrease in values of ERSR in
mer tablets are measured using energy the mixtures was caused presumably by the
analysis on the forcepunch separation development of surface tension and pendu-
plot. Figure 3 illustrates a typical force lar bonds that hold the particles together.
D C A
punch separation plot, in which A is the The researchers explained that the ERSR
punch separation at the first measurable Punch separation (mm)
values increased when more water was added;
force, B is the force at the minimum the tablets tensile strength then decreased
Figure 3: Forcepunch separation plot for
punch separation (D), and C is the de- because at these levels, the water probably
plastic and elastic energy measurements.
compression force. The area under the was beginning to form multilayers on the
curve ABD yields the gross energy (total energy), while the area particles surface. These layers act as a lubricant, thus reducing the
under curve CBD corresponds to the decompression or elastic en- frictional forces responsible for interparticle attraction.
ergy. The net compaction or plastic energy was determined from Liquid water also tends to rupture the hydrogen bond be-
the difference between areas ABD and CBD. tween cellulose particles, that contribute to the tensile strength
Ragnarsson and Sjogren showed that as the moisture con- of the compacts (53). This result explained why samples con-
tent increased, the net work required to compress the materi- taining 75% w/w or more of cellulose exhibited virtually no de-
als decreased (90). The elastic work lessened at high moisture crease in ERSR ratio (and consequent increase in tensile
levels because of retarded tablet expansion. The effect on the strength) when as much as 2% w/w of water was added. The
calculated net work was small. Avicel MCC with a low mois- addition of moisture increased the surface energy of the parti-
ture content (1.1% w/w) yielded considerably lower tablet cles and the binding forces between them. Similar results also
strength than the one with a normal moisture content (4.9% were presented by Khan and Pilpel (40). Malamataris et al. in-
w/w) throughout the pressure range. The bonding properties vestigated the effect of moisture content on HPMC tablets elas-
of the moist sample (8.2% water) were satisfactory at low pres- tic recovery (88). They showed that as the RH increased, the
sure, but were less affected by pressure increase and did not dif- elastic recoveries reduced. For HPMC K4M, the elastic recov-
fer much from those of the dried material at the highest pres- eries were 8.9 and 4.9%, at 33 and 52% RH, respectively.
sure level. To achieve a constant strength, a higher net work was Lubrication effect of moisture. The amount of moisture present
needed for the dried material (91). Increased moisture content in powders and granules can affect the frictional properties of the
probably affects the plastic energy by a combined effect of re- compact formed. In studies covering this aspect of moisture ef-
duced resistance to deformation of the particles, reduced inter- fect, various measurements of tablet friction have been used.
particle friction caused by the lubricating effect of water, and Punch force ratio. R-value or punch force (transmission) ratio was
increased bonding. Armstrong and Patel showed that water con- used by Shotton and Rees (51). They stated that in the presence
tent affects the elasticity of Emcompress compressed at 20 kN of 0.55% moisture, an increased sodium chloride punch force
(88). A reduction in elastic energy occurs upon increasing the ratio (R) at low applied force will caused compaction. This effect
water content from 0 to 6.5%, thus supporting the theory that may be explained by reduced friction caused by the formation of
moisture may induce plasticity into the brittle Emcompress par- moisture film acting as a lubricant at the die wall. The force lost
ticles. At higher water content, a significant increase in elastic to the die wall increased with applied force as the compact area
energy or decompression work was generated. in contact with the die wall increased. As the porosity of the com-
For a given compression force, a moisture content increase sig- pact decreased, the void spaces became filled with liquid. Then,
nificantly decreased the plastic energy. Moisture content increases an increase in applied force caused liquid expulsion to form a con-
probably affected the net compaction energies (plastic energies) tinuous film at the die wall. Consequently, the liquid reduced the
by a combined effect of reducing particle resistance and enhanc- friction coefficient between particles and the die wall, and also re-
ing particle deformation, thus reducing interparticle friction be- stricted movement of the solid in contact with the die. Shotton
cause of moistures lubrication effects. If plastic energy is plotted and Rees showed that a lower moisture content (0.02 or 0.16%)
as a function of tablet tensile strength for various moisture con- provided less die-wall lubrication at all values of applied force
tents, a higher plastic energy for the dried material was needed to (51). Liquid did not migrate to the die wall even at high applied
achieve a specific tablet strength. Thus, to achieve a constant ten- force, because sufficient void space remained to accommodate
sile strength, a lower plastic energy is needed with increasing mois- the small volume of liquid.
ture content. For example, to obtain tablets with a tensile strength Force lost to the die wall. Rees and Shotton investigated the role of
of ;2 MPa, the plastic energy needed was 7.65, 4.06, and 2.86 J moisture in the compaction process by using an ideal particulate
at moisture contents of 0, 5.9, and 14.9%, respectively. system of crystalline sodium chloride and three liquids: water,
Elastic recovery. Bangudu and Pilpel studied the effects of mois- decahydronaphthalene, and light liquid paraffin (36). They stated
60 Pharmaceutical Technology JANUARY 2005 www.phar mtech.com
DATA & REVIEW
Table III: Values of D0, Da, and Db at low- and high-
compression speeds at various moisture contents.
Moisture Compression speed (mm/s)
content 15 500
(% w/w) D0 Da Db D0 Da Db
0 0.401 0.542 0.141 0.321 0.401 0.080
2.2 0.407 0.552 0.145 0.331 0.416 0.085
3.8 0.410 0.547 0.137 0.333 0.421 0.088
5.9 0.414 0.551 0.137 0.345 0.435 0.090
9.6 0.421 0.567 0.146 0.363 0.463 0.100
14.9 0.425 0.616 0.191 0.384 0.514 0.130
D0 is initial relative densities, Da is extrapolated densities from the
linear portions of the Heckel plot, and Db is changes in relative
densities attributed to particle rearrangement.
that although differences in the three liquids behavior could be
attributed partly to the differences in viscosity, water apparently
exerted a boundary lubrication in addition to hydrodynamic
properties. In the presence of moisture, the force lost to the die
wall (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. High
Fd values were attributed to an increase in the radial component
of applied force by interparticulate lubrication.
During particulate material compaction, the proportion of the
applied 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 at
the die wall. Because interparticulate lubrication increases the
ratio of radial stress to axial stress, the application of lubricant to
the 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-wall
friction because reducing the coefficient of interparticulate fric-
tion usually has little effect on die-wall friction compared with a
decrease 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 that
the granulation contained a high proportion of starch, which ob-
scured the moistures effect on phenacetin and lactose behavior.
Ejection force
Obiorah and Shotton investigated the effect of waxes, hydrolyzed
gelatin, and moisture on the compression characteristics of
paracetamol and phenacetin (92). The behavior of paraceta-
mol or phenacetin and their mixtures with gelatin hydrolysate
or water was similar to a Mohr body; the die wall pressure was
affected by the particle size of the material compressed and by
the additives present. Good transmission of radial force implied
that the material could be consolidated initially, but alone, it
did not indicate that the tablet formed was physically stable.
Hydrolyzed gelatin, water, or both together produced paraceta-
mol and phenacetin mixtures with satisfactory compression
characteristics. The lowest ejection forces were associated with
compacts produced from MCC containing 5% w/w moisture.
62 Pharmaceutical Technology JANUARY 2005
The critical moisture content in MCC to optimize tensile
strength and ejection force is ;5% w/w.
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