DATA & REVIEW

An Overview of the

Effect of Moisture on Compaction and Compression

Ali Nokhodchi

T
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.
PHOTODISC, INC.

he identification and quantification of the numerous parameters that affect the compaction process are vital for product uniformity. For example, moisture adsorption plays an important role in physical and chemical stability, 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 content 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 substance, (b) temperature, (c) the surface area of solid drug exposed to the water vapor, (d) the velocity of moist airs movement, and (e) a reaction constant that is characteristic of the solid. Mikuliniskii and Rubinshtein studied the kinetics of magnesium 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 dependent on the product of the diffusion coefficient and the concentration gradient of water. The effect of moisture on tablets chemical and physical stability is outside the scope of this article.

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. 44 2 7848 4787, fax 44 2 7848 480, ali. nokhodchi@kcl.ac.uk. 46

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 determining the humidity control required during production and storage. The amount of moisture adsorbed by drugs and excipients effects the flow, compression characteristics, and hardness of granules and tablets. In addition, moisture transmission through
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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 chemical affinity for the solid and the number of available sites of interaction, 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 bonding, and crystalline hydrates have high EMCs. Shotton and Harb observed that the EMCs of starch, alginic acid, and tragacanth increased 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 temperatures, even at 50 C and 100% RH (4). Coelhi and Harnby noted that fine particle size fractions of sucrose and sodium chloride 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 atmosphere, the water will be relatively tightly bound as a nonfreely movable layer, which sometimes is denoted as monolayer adsorbed 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 moveable and may be denoted as condensed water (i.e., the water becomes solvent like) (8). When this occurs, the solids molecules can dissolve in the water and may cause its deliquescence. The critical humidity (RH0) at which this takes place is a characteristic 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 simplification 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 thickness of the adsorbed layer also enlarges until eventually, condensation occurs at the contact points and generates liquid bridges. 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 electrostatic 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 between 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 distribution. 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 watersoluble powders exposed to a high RH, is caused when moisture 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% magnesium oxide to the starch, or 1% magnesium oxide to the sugars or salts (4, 18). The fine, plate-shaped magnesium oxide particles adhered to the surfaces of the caking material by van der Waals and electrostatic forces. Their presence reduced interparticulate 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 powder 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 surface 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, however, 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 moisture content on the flow properties of some pharmaceutical excipients is listed in Table I (21). Peleg et al. (22) and Peleg and Moreyra (23) studied the effect of moisture content on food powders bulk density. They observed reduced bulk density and caking of water-soluble powders upon increasing moisture content. The reduction in powder 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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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 another particle at the points of contact. Frictional forces act at a tangent to the surface of the contact point. The adsorbed moisture 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 in48

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than for dry powders at low-compression Table I: Effect of moisture on flow creases and becomes insignificant; theatenpressures. sile strength exponentially decreases to 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 content (%) (g/min) Excipient measurements of the packed powder beds flow properties of an already cohesive powshear 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 pow0.40 739 effects of moisture content on the tensile 748 0.63 ders also has been quantified. Factors that properties of procaine penicillin powders 0.24 505 effect powder bed tensile strengths include Fast-flow and showed that the attraction forces be0.27 554 the nature of material, moisture, particle lactose tween particles decreased as the moisture 548 0.42 size, and material packing density. Studies content increased. At moisture levels 3.6%, 0.54 510 the tensile strength of the procaine penicillin have found that at a constant state of pack- Emedex 1.21 451 compacts decreased with increasing moising, the tensile strengths of coarse, nonco1.46 460 ture content. hesive fractions increased to a plateau as the 6.13 moisture content rose. This effect was at- Corn starch* 10.13 Effect of moisture on powder compaction tributed to a growth in the number and di 12.04 The need for optimal moisture content in mension of liquid pendular bonds. At higher Maltodextrin 2.97 241 the formation of strong tablets is indicated moisture content and packing densities, 7.68 237 by crystal hydrates that compress well and liquid bridges may progress from pendular do not form strong tablets when water crysto funicular bonds (18, 24, 25). *corn starch flows very poorly and no tallization is removed (e.g., ferrous sulfate Eaves and Jones observed that increas- flow rate could be obtained. heptahydrate) (28). Moisture increases the ing the liquid content of nonporous bulk solids beds at a fixed state of packing resulted in greater tensile compact strength by increasing the tensile strength of the powstrength 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 more of the applied force to be transmitted through the comtensile strength because of weakening pendular bonds (25). The effect of moisture on the cohesive properties of Avicel pact onto the lower punch (R value). Absorbed water also dePH-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). Tensile strength. Jaffe and Foss reported that the removal of was more cohesive than Emcocel MCC at moisture contents of 30% w/w, whereas their cohesive behavior was similar at higher water crystallization prevented the formation of tablet materimoisture 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 electroparticulate 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. resodium chlorides (3275 m) (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 -lactose monohydrate, by thermal and chemadditional 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 -lactose monothe 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 evalmore powerful than those at near-contact points. As moisture uated the effect of moisture content on the compression propcontent 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 reand 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 comMore potential sites of contact exist with nonporous and co- pression of -cyclodextrin and found that samples lost their hesive powders (e.g., fine sodium chloride particles [ 32 m]) 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% moisber and strength of the liquid bridges attractive forces are simi- ture content appeared to be optimum for maximum comlar for fine and coarse sodium chloride particles. With higher pactibility of the samples studied. moisture content, however, the particleparticle interaction deRees showed that moisture improved consolidation, espe50

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cially at low applied pressure (34). Armstrong and Griffiths reported some effects of moisture on granules compaction properties (35). Although the materials varied, their conclusions correspond 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 became harder as the moisture content increased (38). MCC is an important excipient that has been extensively investigated. Teng et al. noted that, when directly compressed, tablets containing MCC became harder as the moisture content 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 compact 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 binding between two anhydroglucose units, followed by the binding 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 molecular 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 prop52

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 cohesiveness did not vary when more water was added. Khan et al. also examined the effect of MCCs moisture content on the compression 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 exception 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% moisture content. Further moisture content increases resulted in decreased tensile strength of compacts, however. Despite the significant 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 compressible diluents, Emdex (Penwest Pharmaceuticals, Cedar Rapids, IA) and Sweetrex (Mendell) (48). Both diluents sorbed moisture rapidly at 60% RH. The pressures required to compress tablets to the same relative density decreased with increasing 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 anhydrous dextroses moisture content produced a corresponding increase in both strength parameters (tablet crushing strength and tablet toughness) because of recrystallization. Any moisture increase 8.9% produced a marked reduction in both tablet tensile strength and tablet toughness. For dextrose monohydrate, any increase in moisture content generated by exposure 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 resistance to consolidation that counteracted the lubricant effects. Despite the low viscosity of the liquid film, lubrication inhibited 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 particles in compacts prepared at low pressure from samples with 10% moisture (52). It was observed that compacts prepared in
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the presence of moisture and subsequently dried showed an increase in strength because of interparticulate recrystallization. Rees and Hersey investigated the role of liquids in the compaction of sodium chloride that contained moisture (29). For compacts containing moisture, compact strength decreased with reduced interparticulate bond strength. In the presence of nonsolvents (e.g., light liquid paraffin), compact strengths were a function of the compacts state of consolidation. Garr and Rubinstein found that the compressibility of paracetamol powder was strongly determined by moisture present during consolidation and that a 6% w/w moisture content produced tablets with optimal crushing strength, relative density, and capping pressure (53). Bangudu and Pilpel stated that paracetamolcellulose 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 pharmaceutical 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 content 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 adsorbed water assumes the character of a bulk solution or condensate (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 structure can change below RH0. For sodium chloride, an increase in tensile strength with RH has been suggested to be a result of a restructuring of the tablets surface (10, 56). Another possible explanation for increasing tensile strength is that immobile water layers sorbed at particle surfaces can enhance 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 surface 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 tensile 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 observed 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 increased tablet tensile strengths probably increase the contact between 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 tensile strength at a fixed packing fraction (0.9) by applying linear regression analysis between log tensile strength and packing frac54

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 attraction forces and thereby reduce tablet strength (55, 62, 63). Nokhodchi et al. showed that the crushing strength of ibuprofen 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 samples, tensile strength reached a maximum value and then decreased when moisture content was approximately double that corresponding 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 properties has been reviewed briefly (65, 66). Nokhodchi et al. explained the increase or decrease in tensile strength with moisture according to the type of moisture associated with polymers. Many researchers 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 increased (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, respectively (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 deformation and/or melting of powder particles should control the tensile 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 microirregularities and reducing interparticle separation (24). This monolayer-bound water can be regarded as part of the particles surface molecular structure (44, 70). These effects would increase the tensile strength of HPMC K4M tablets with inwww.phar mtech.com

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found that increasing the moisture concreasing moisture content. An increase Monomolecular tent from 0 to 13.05% increased the in the monolayer of water in HPMC adsorption Externally compacts tensile strength. At a higher K4M occurs (see Table II). absorbed moisture content (13.05), compression As more water molecules adhere to moisture force had no significant effect on tablets the surface, moisture may transfer into tensile strengths. the material (8, 7172). This effect may To explain this observation, one must soften the particles surfaces; under high consider the compaction properties of pressure, the area of contact between the Internally absorbed pure HPMC and pure ibuprofen in the particles will increase with plastic deformoisture presence of various moisture contents. mation and more solid bonds may form In the case of HPMC K4M, when the (44). These effects could account for the Figure 1: Various states of moisture. moisture content increased from 0 to 15, decreases in mean yield pressure, which indicate greater plasticity of the HPMC (see Table II) and ac- the tablet tensile strength increased (60). At a higher moisture content, a compression force increase resulted in increased tencount for the tablets increased tensile strength. It has been suggested that water adsorption reduced tablet ten- sile strength of HPMC, whereas the tensile strengths of the mixsile 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). Thereternally adsorbed moisture values. Although the amount of mul- fore, it can be concluded that the reverse effect of the comprestilayer 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 3.5% (63). for the decreases in mean yield pressure and elastic recovery of Because HPMC has a primarily amorphous structure and HPMC tablets with increasing RH or moisture content. 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 disperature (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 ibuproHancock 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 struc15% 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 plaswaters 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 temperabove 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 interacproperties of the polymer. At temperatures exceeding Tg, poly- tion between the drug and HPMC (80). Such interactions might mers exhibit highly increased chain mobility and elasticity, which will have major Table II: Moisture distribution, tensile strength at 10 kN, and compressional consequences for compaction properties. parameters (mean yield pressure and elastic recovery) for HPMC K4M at Low-moisture starches are not applicable various relative humidities. as direct-compression materials because they compact poorly. Water is needed to Moisture distribution (%) Tensile Mean yield enhance the compressibility and facilitate Monolayer External Internal strength pressure Elastic Relative the plastic deformation of glassy starches, (Mpa) recovery (%) (Mpa) humidity (%)* adsorption adsorption adsorption 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) 3.45 44.18 11.62 3.3 3.1 1.9 investigated (76). Nokhodchi and Rubin8.21 36.18 5.6 5.5 4.6 2.4 58 (9.6) 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
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Armstrong et al. studied the relationship between porosity and water content of dicalcium phosphate tablets (Emcompress, JRS Pharma, Patterson, NY) (88). They showed that increasing the moisture content of Emcompress A Da tablets increased apparent tablet denDb Da Do sity, both under compression and after Do ejection. This effect continued with critical water contents as high as 8.38, 7.53, and 6.48% w/w for compression forces of 12, 18, and 24 kN, respectively, beCompression pressure (Mpa) yond which a reduction in densification was obtained. The magnitude of this Figure 2: Heckel plot of plasticity, fragmentation, critical water content was dependent on and particle rearrangement. the applied compression force in that it decreased as compression force increased. Li and Peck showed that an increase in the powder moisture [1] ln[1 (1 D)] = KP A 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 polyyield pressure are classified as brittle-fracturing or fragmentary, merization. Mollan and elik also studied the effects of humidand 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. Emthe measure of the plasticity of a compressed material (i.e., greater compress showed only a slight change in its yield pressure valmean 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 informulations. 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 conlow pressures and improved compressibility as the materials ditions caused the materials to exhibit the most brittle behavmoisture 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 comNokhodchi 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 moisplots (Da); and the changes in the relative densities attributed to ture contents greater than that of the original diluent. Differenparticle 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 crysto 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 consmoothing out the surface microirregularities, reducing the fric- tent on the consolidation and compaction properties of paractional 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 despeed 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, howEnergy 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 forcedistributed to the assumption that water facilitates the deformation placement plots. Plastic energy is energy that is permanently imof particles in combination with reduced interparticle friction. parted to the tableted material; elastic energy is energy that is deslope1 mean yield pressure

alter the systems mechanical properties. In addition, a change in the glass transition temperature would be expected to affect the molecular mobility of the solid and produce significant changes in its viscoelastic and mechanical properties. Heckel analysis (yield pressure). The compression behavior of powders may be characterized by Heckel plots (see Figure 2) (81, 82). Several researchers have successfully applied Heckels equation to pharmaceutical powders to identify the types of mechanisms occurring during compression (83, 84). In the Heckel equation [1], the relative density (D) is related to the applied compression pressure (P).

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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 mothe 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 area under this curve will be the work amounts ( 4% w/w), the ratio increased. done or energy (J). The plastic and elasWith Avicel MCC, the ratio only increased. tic energies of compaction of the polyThe 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 penduplot. Figure 3 illustrates a typical force lar bonds that hold the particles together. D A C punch separation plot, in which A is the The researchers explained that the ERSR Punch separation (mm) punch separation at the first measurable 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 debecause 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 bethe 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 content increased, the net work required to compress the materi- taining 75% w/w or more of cellulose exhibited virtually no deals 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 partiture 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. inw/w) throughout the pressure range. The bonding properties vestigated the effect of moisture content on HPMC tablets elasof 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 recovfer much from those of the dried material at the highest pres- eries were 8.9 and 4.9%, at 33 and 52% RH, respectively. Lubrication effect of moisture. The amount of moisture present sure level. To achieve a constant strength, a higher net work was 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 efduced resistance to deformation of the particles, reduced inter- fect, various measurements of tablet friction have been used. Punch force ratio. R-value or punch force (transmission) ratio was particle friction caused by the lubricating effect of water, and 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 in contact with the die wall increased. As the porosity of the comenergy or decompression work was generated. 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 conprobably 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 reing 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. Force lost to the die wall. Rees and Shotton investigated the role of ture content. For example, to obtain tablets with a tensile strength 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
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Table III: Values of D0, Da, and Db at low- and highcompression speeds at various moisture contents.
Moisture content (% w/w) 0 2.2 3.8 5.9 9.6 14.9 D0 0.401 0.407 0.410 0.414 0.421 0.425 Compression speed (mm/s) 15 500 Da Db D0 Da Db 0.542 0.141 0.321 0.401 0.080 0.552 0.145 0.331 0.416 0.085 0.547 0.137 0.333 0.421 0.088 0.551 0.137 0.345 0.435 0.090 0.567 0.146 0.363 0.463 0.100 0.616 0.191 0.384 0.514 0.130

The critical moisture content in MCC to optimize tensile strength and ejection force is 5% w/w.

References
1. S. Mikuliniskii and R.I. Rubinshtein, Velocity of Moisture Absorption by MgSO4 J. Phys. Chem. 9 (431), (1937). 2. S. Dawoodbahai and C.T. Rhodes, The Effect of Moisture on Powder Flow and on Compaction and Physical Stability of Tablets, Drug Dev. Ind. Pharm. 15 (10), 15771600 (1989). 3. E. Shotton and N. Harb, The Effect of Humidity and Temperature on the Equilibrium Moisture Content of Powders, J. Pharm. Pharmacol. 17 (8), 504508 (1965). 4. D.J. Craik and B.F. Miller, The Flow Properties of Powders Under Humid Conditions, J. Pharm. Pharmacol. 10 (2), 136T144T (1958). 5. M.C. Coelho and N. Harnby, Moisture Bonding in Powders, Powder Technol. 20 (3), 201205 (1978). 6. L. Van Campen, G.L. Amidon, and G. Zografi, Moisture Sorption Kinetics for Water-Soluble Substances: I. Theoretical Considerations of Heat Transport Control, J. Pharm. Sci. 72 (12), 13811388 (1983). 7. G. Zografi, States of Water Associated with Solids, Drug Dev. Ind. Pharm. 14 (14), 19051926 (1988). 8. P. York, Analysis of Moisture Sorption Hysteresis in Hard Gelatin Capsules, Maize Starch, and Maize Starch:Drug Powder Mixtures, J. Pharm. Pharmacol. 33 (5), 269273 (1981). 9. L. Van Campen, G. Zografi, and J.T. Carstensen, An Approach to the Evaluation of Hygroscopicity for Pharmaceutical Solids, Int. J. Pharm. 5 (1), 118 (1980). 10. N. Lordi and P. Shiromani, Mechanisms of Hardness of Aged Compacts, Drug Dev. Ind. Pharm. 10 (5), 729752 (1984). 11. M.C. Coelho and N. Harnby, The Effect of Humidity on the Form of Water Retention in a Powder, Powder Technol. 20 (3), 197200 (1978). 12. E.N. Hiestand, Powders: ParticleParticle Interactions, J. Pharm. Sci. 55 (12), 13251344 (1966). 13. G. Schepky, Preformulation: The Role of Moisture in Solid Dosage Forms, Drug Dev. Ind. Pharm. 15 (10), 17151741 (1989). 14. W.B. Pietsch, Tensile Strength of Granules Materials, Nature, 217 (13), 736737 (1968). 15. N. Burak, Chemicals for Improving the Flow Properties of Powders, Chem. and Ind. 21, 844846 (1966). 16. E. Shotton and N. Harb, The Effect of Humidity and Temperature on the Cohesion of Powders, J. Pharm. Pharmacol. 18 (3), 175178 (1966). 17. D.J. Craik, The Flow Properties of Starch Powders and Mixtures, J. Pharm. Pharmacol. 10 (2), 7378 (1958). 18. T. Eaves and T.M. Jones,Effect of Surface Tension on the Tensile Strength of Beds of Moist Bulk Solids, Pharm. Acta Helv. 47 (8), 537545 (1972). 19. S.Y. Chan and N. Pilpel, Absorption of Moisture by Sodium Cromoglycate and Mixtures of Sodium Cromoglycate and Lactose, J. Pharm. Pharmacol. 35 (8), 477481 (1983). 20. J.S.G. Cox, E.D. Woodward, and W.C. McCrone, Solid State Chemistry of Cromolyn Sodium (Disidium Cromoglycate), J. Pharm. Sci. 60 (8), 14651468 (1971). 21. M.J. Mollan and M. elik, The Effects of Humidity and Storage Time on the Behavior of Maltodextins for Direct Compression, Int. J. Pharm. 114 (1), 2332 (1995). 22. M. Peleg, C.H. Manheim, and N. Passy, Flow Properties of Some Food Powders, J. Food Sci. 38 (6), 959963 (1973). 23. M. Peleg and M. R. Moreyra,Effect of Moisture on the Stress Relaxation Pattern of Compacted Powders, Powder Technol. 23 (2), 277279 (1979). 24. T. Eaves and T.M. Jones, Effect of Moisture on Tensile Strength of Bulk Solids: I. Sodium Chloride and Effect of Particle Size, J. Pharm. Sci. 61 (2), 256261 (1972). 25. T. Eaves and T.M. Jones, Effect of Moisture on Tensile Strength of Bulk Solids: II. Fine Particle Size Materials with Varying Inherent Coherence, J. Pharm. Sci. 61 (3), 342348 (1972). 26. J.N. Staniforth et al., Effect of Addition of Water on the Rheological

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 appreciably less than with light liquid paraffin or decahydronaphthalene, 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 factors 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 powder before compression. Lubrication of both the die wall and interparticulate junctions produces a net decrease in the die-wall friction because reducing the coefficient of interparticulate friction 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 containing phenacetin and starch and concluded that the optimal moisture content was 2.7% w/w (91). They have been criticized that the granulation contained a high proportion of starch, which obscured 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 paracetamol 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 paracetamol and phenacetin mixtures with satisfactory compression characteristics. The lowest ejection forces were associated with compacts produced from MCC containing 5% w/w moisture.
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and Mechanical Properties of Microcrystalline Cellulose, Int. J. Pharm. 41 (3), 231236 (1988). C.A. Walton and N. Pilpel,The Effect of Particle Size, Shape and Moisture Content on the Tensile Properties of Procaine Penicillin Powders, J. Pharm. Pharmacol. 24 (Suppl.), 10P16P (1972). J. Jaffe and N.E. Foss, Compression of Crystalline Substances, J. Amer. Pharm. Ass. Sci. Ed. 48 (1), 2629 (1959). J.E. Rees and J.A. Hersey, The Strength of Compacts Containing Moisture, Pharm. Acta. Helv. 47 (3), 235243 (1972). D. Train, An Investigation into the Compaction of Powders, J. Pharm. Pharmacol. 8 (10), 745760 (1956). C.F. Lerk et al., Increased Binding Capacity and Flowability of Lactose Monoydrate after Dehydration, J. Pharm. Pharmacol. 35 (11), 747748 (1983). A.J. Shukla and J.C. Price, Effect of Moisture Content on Compression Properties of Directly Compressible High Beta-Content Anhydrous Lactose, Drug Dev. Ind. Pharm. 17 (15), 20672081 (1991). G.S. Pande and R.F. Shangraw, Characterisation of -Cyclodextrin for Direct Compression Tableting: II. The Role of Moisture in the Compactibility of -Cyclodextrin, Int. J. Pharm. 124 (2), 231239 (1995). J.E. Rees, The Use of Compression Modulus to Describe Compaction Behavior, J. Pharm. Pharmacol. 22 (3), 245246 (1970). N.A. Armstrong and R.V. Griffiths, The Effects of Moisture on the Flow Properties and Compression of Phenacetine, Paracetamol and Dextrose Monohydrate, Acta Pharm. Helv. 45 (11), 692700 (1970). J.E. Rees and E. Shotton, Effects of Moisture in Compaction of Particulate Material, J. Pharm. Sci. 60 (11), 17041708 (1971). S.A. Sangekar, M. Sarli, and P.R. Sheth, Effect of Moisture on Physical Characteristics of Tablets Prepared from Direct Compression Excipients, J. Pharm. Sci. 61 (6), 939944 (1972). G.E. Reier and R.F. Shangraw, Microcrystalline Cellulose in Tableting, J. Pharm. Sci. 55 (5), 510514 (1966). C.D. Teng, M.H. Alkan, and M.J. Groves,The Effect of Adsorbed Water on Compaction Properties and the Dissolution of Quinacrine Hydrochloride from Compacted Matrices by Soy Protein, Drug Dev. Ind. Pharm. 12 (1113), 23252336 (1986). F. Khan and N. Pilpel, The Effect of Particle Size and Moisture on the Tensile Strength of Microcrystalline Cellulose Powder, Powder Technol. 48 (1), 145150 (1986). N. Pilpel and S. Ingham, The Effect of Moisture on the Density, Compaction and Tensile Strength of Microcrystalline Cellulose, Powder Technol. 54 (3), 161164 (1988). A.R. Fassihi, Interrelationships Between Yield Pressure, Moisture Content and Tensile Strength of Microcrystalline Cellulose Compacts, J. Pharm. Pharmacol. 40 (Suppl.), 76P (1988). L. Stubberud et al., WaterSolid Interactions: II. Effect of Moisture Sorption and Glass Transition Temperature on Compactibility of Microcrystalline Cellulose Alone or in Binary Mixtures with Polyvinyl Pyrrolidone, Int. J. Pharm. 134 (12), 7988 (1996). F. Khan and N. Pilpel, An Investigation of Moisture Sorption in Microcrystalline Cellulose Using Sorption Isotherms and Dielectric Response, Powder Technol. 50 (3), 237241 (1987). K.A. Khan, P. Musikabhumma, and J.P. Warr, The Effect of Moisture Contents of Microcrystalline Cellulose on the Compressional Properties of Some Formulations, Drug Dev. Ind. Pharm. 7 (5), 525528 (1981). C. Ahlneck and G. Alderborn, Moisture Adsorption and Tableting: I. Effect on Volume Reduction Properties and Tablet Strength for Some Crystalline Materials, Int. J. Pharm. 54 (2), 131141 (1989). L.C. Li and G.E. Peck, The Effect of Moisture Content on the Compression Properties of Maltodextrins, J. Pharm. Pharmacol. 42 (4), 272275 (1990). A.J. Shukla and J.C. Price, Effect of Moisture Content on Compression Properties of Two Dextrose-Based Directly Compressible Diluents, Pharm. Res. 8 (3), 336340 (1991). N.A. Armstrong and A. Patel, The Compressional Properties of Dextrose Monohydrate and Anhydrous Dextrose of Varying Water Content, Drug Dev. Ind. Pharm. 12 (1113), 18851901 (1986). W.A. Strickland et al., The Physics of Tablet Compression: IX. Fundamental Aspects of Tablet Lubrication, J. Amer. Pharm. Ass. Sci. Ed. 45 (1), 5155 (1956). E. Shotton and J.E. Rees,The Compaction Properties of Sodium Chloride in Presence of Moisture, J. Pharm. Pharmacol. 18 (Suppl.), 160S167S (1966). E. Shotton and D. Ganderton, The Tensile Strength of Compressed tablets: III. The Relation of Particle Size, Bonding and Capping in Tablets of Sodium Chloride, Aspirin and Hexamine, J. Pharm. Pharmacol. 13 (Suppl.), 144T151T (1961). J.S.M. Garr and M.H. Rubinstein, The Influence of Moisture on Consolidation and Compaction Properties of Paracetamol, Int. J. Pharm. 81 (23), 187192 (1992). A.B. Bangudu and N. Pilpel, Effects of Composition, Moisture and Stearic Acid on the Plasto-Elasticity and Tableting of ParacetamolMicrocrystalline Cellulose Mixtures, J. Pharm. Pharmacol. 37 (5), 289293 (1985). S. Malamataris and T. Karidas, Effect of Particle Size and Sorbed Moisture on the Tensile Strength of Some Tableted Hydroxypropylmethylcellulose (HPMC) Polymers, Int. J. Pharm. 104 (1), 115123 (1994). C. Ahlneck and G. Alderborn, Moisture Adsorption and Tableting: II. The Effect on Tensile Strength and Air Permeability of the Relative Humidity During Storage of Tablets of Three Crystalline Materials, Int. J. Pharm. 56 (1), 143150 (1989). G.R.B. Down and J.N. McMullen, The Effect of Interparticulate Friction and Moisture on the Crushing Strength of Sodium Chloride Compacts, Powder Technol. 42 (2), 169174 (1985). H. Rumpf, The Strength of Granules and Agglomerates, in Agglomeration, W.A. Knepper, Ed. (John Wiley and Sons, New York, NY, 1962), pp. 379418. E. Turba and H. Rumpf, Zugfestigkeit von Presslingen Mitvorwiegender Bindung Durch van der Waals-Krafte Undihre Beeinflussung Durch Adsorptionsschichten, Chem. Ing. Technol. 36 (4), 230240 (1964). G.A. Turner and M. Balasubramanian, Investigations of the Contributions to the Tensile Strength of Weak Particulate Masses, Powder Technol. 10 (3), 121127 (1974). S. Malamataris, K. Tsiri, and P. Goidas, Sorption of Moisture in Different Size Fractions of Some Direct Compression Excipients and Tensile Strength of Corresponding Tablets, 6th Int. Conf. Pharm. Technol. Paris, V, 195204, 1992. H.G. Kristensen, P. Holm, and T. Schaefer, Mechanical Properties of Most Agglomerates in Relation to Granulation Mechanisms: Part. I. Deformability of Moist Densified Agglomerates, Powder Technol. 44 (3), 227237 (1985). A. Nokhodchi et al., The Effect of Moisture on the Properties of Ibuprofen Tablets, Int. J. Pharm. 118 (2), 191197 (1995). S. Malamataris, P. Goidas, and A. Dimitriou, Moisture Sorption and Tensile Strength of Some Tableted Direct Compression Excipients, Int. J. Pharm. 68 (5), 5160 (1991). A. Nokhodchi and M.H. Rubinstein, An Overview on the Effect of Materials and Process Variables on the Compaction and Compression Properties of Hydroxypropylmethylcellulose and Ethylcellulose, S.T.P. Pharma Sci. 11 (3), 195202 (2001) A. Rajabi-Siahboomi, A. Nokhodchi, and M.H. Rubinstein, The Compaction Behavior of Hydrophilic Cellulose Ether Polymers, Pharm. Technol. 10 (Oct.), 4248 (1998). A. Nokhodchi, J.L. Ford, and M.H. Rubinstein, Studies on the Interaction Between Water and HPMC, J. Pharm. Sci. 86 (5), 608615 (1997). A. Nokhodchi et al., The Influence of Moisture Content on the Consolidation Properties of Hydroxypropylmethylcellulose K4M (HPMC 2208), J. Pharm. Pharmacol. 48 (11), 11161121 (1996). S. Malamataris and N. Pilpel, Tensile Strength and Compression of Coated Pharmaceutical Powders: Tablets, J. Pharm. Pharmacol. 35 (1), 16 (1983). G. Zografi and M.J. Kontny, The Interactions of Water with Cellulose and Starch-Derived Pharmaceutical Excipients, Pharm. Res. 3 (4), 187194 (1986). J.H. Young and G.H. Nelson, Theory of Hysteresis Between Sorption
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27.

51.

28. 29. 30. 31.

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53.

54.

32.

55.

33.

34. 35.

56.

57.

36. 37.

58.

38. 39.

59.

60.

40.

61.

41.

62.

42.

63. 64.

43.

44.

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50.
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77. 78.

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and Desorption Isotherms in Biological Materials, Trans. Am. Soc. Agric. Eng. 10 (5), 260263 (1967). J.H. Young and G.H. Nelson, Research of Hysteresis Between Sorption and Desorption Isotherms of Wheat, Trans. Am. Soc. Agric. Eng. 10 (5), 756761 (1967). B.C. Hancock and G. Zografi,The Relationship Between the Glass Transition Temperature and Water Vapor Absorption by Poly(vinylpyrrolidone), Pharm. Res. 11 (4), 471477 (1994). C.A. Oksanen and G. Zografi,The Relationship Between the Glass Transition Temperature and Water Vapor Absorption of Polyvinylpyrrolidone, Pharm. Res. 7 (6), 654657 (1990). R. Steendam, H.W. Frijlink, and C.F. Lerk, Plasticisation of Amylodextrin by Moisture: Consequences for Compaction Behavior and Tablet Properties, Eur. J. Pharm. Sci. 14 (3), 245254 (2001). A. Nokhodchi and M.H. Rubinstein, The Effect of Moisture on the Compaction Properties of the Binary Mixture of HPMC K4M/Ibuprofen, S.T.P. Pharma Sci. 8 (6), 349356 (1998). F. Franks, Water, A Comprehensive Transite: Vol. 7 (Plenum Press, New York, NY, 1982), pp. 215338. H. Levine and L. Slade,Water as a Plasticizer: Physicochemical Aspects of Low Moisture Polymeric Systems, in Water Science Reviews, F. Franks Ed. (Cambridge University Press, Cambridge, UK, 1987), pp. 179185. L. Slade and H. Levine, Non-equilibrium Behavior of Small Carbohydrate/Water Systems, Pure Appl. Chem. 60 (12), 18411864 (1988). C. Ahlneck and G. Zografi, The Molecular Basis of Moisture Effects on the Physical and Chemical Stability of Drugs in Solid-State, Int. J. Pharm. 62 (23), 8795 (1990). R.W. Heckel, DensityPressure Relationship in Powder Compaction, Trans. Metall. AIME 222 (4), 671675 (1961). R.W. Heckel, An Analysis of Powder Compaction Phenomena, Trans. Metall. AIME 222 (5), 10011008 (1961). X.P. Hou and J.T. Carstensen, Compression Characteristics of Basic Tricalcium Phosphate, Int. J. Pharm. 25 (2), 207215 (1985). R.J. Roberts and R.C. Rowe, The Effect of Punch Velocity on the Compaction of Variety of Materials, J. Pharm. Pharmacol. 37 (6), 377384 (1985). S. Esezobo and N. Pilpel, Moisture and Gelatin Effects on the Interparticle Attractive Forces and Compression Behavior of Oxytetracycline Formulations, J. Pharm. Pharmacol. 28 (2), 7581 (1976). A. Nokhodchi et al., The Effect of Moisture on the Heckel and Energy Analyses of Hydroxypropylmethylcellulose 2208, J. Pharm. Pharmacol. 48 (11), 11211127 (1996). A. Nokhodchi et al., The Effect of Moisture Content on the Energies Involved in the Compaction of Ibuprofen, Int. J. Pharm. 120 (1), 1320 (1995). N.A. Armstrong, A. Patel, and T.M. Jones,Relationship Between Porosity and Water Content of Dicalcium Phosphate Tablets, Int. J. Pharm. 48 (13), 173177 (1988). S. Malamataris, T. Karidas, and P. Goidas, Effect of Particle Size and Sorbed Moisture on the Compression Behavior of Some Hydroxypropylmethylcellulose, Int. J. Pharm. 103 (3), 205215 (1994). G. Ragnarsson and J. Sjogren, Force-Displacement Measurement in Tableting, J. Pharm. Pharmacol. 37 (3), 145150 (1985). P.L. Seth and K. Munzel, Der Einfluss des Feuchtigkeitsgehaltes Eines Granulates auf die Press Barkeit und die Eigenschaften der Tabletten, Pharm. Ind. 21 (1), 913 (1959). B.A. Obiorah and E. Shotton, The Effect of Waxes, Hydrolyzed Gelatin and Moisture on the Compression Characteristics of Paracetamol and Phenacetin, J. Pharm. Pharmacol. 28 (8), 629632 (1976). P T

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