The factors that effect the direct compression of microcrystalline cellulose


Tablet production by direct compression has steadily increased over the years because it is an economic and a simple procedure - The factors that effect the direct compression of microcrystalline cellulose introduction. Many high molecular weight polymers are currently being used in pharmaceutical formulations as drug excipients. The processing variables and physical characteristics of the polymer excipient, granulating fluid, and drug used can determine the physical properties and rate of drug release for the final preparation of these drug delivery systems.  Currently, there is not a single excipient that meets all of the above mentioned requirements. Some of the direct compression excipients commonly and widely used today are spray-dried lactose, anhydrous lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate dihydrate, tricalcium phosphate, direct compression starch, spray-crystallized dextrose/maltose, calcium sulphate dehydrate, Sorbitol and modified rice starch. (Alderbom and Nystrom 1996)

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However, cellulose based materials, such as microcrystalline cellulose (MCC) and powdered cellulose (PC), are among the most widely used direct compression excipients. Microcrystalline cellulose is perhaps the best filler-binder available today.  MCC, despite being considered the best dry binder, it possesses poor flow and disintegration properties and shows capping problems, especially when used in high amounts. Thus, there is an enormous interest among pharmaceutical scientists involved in this area of research to either modify the existing products or develop new materials with properties that satisfy as many requirements as possible for direct compression. (Swarbrick and Boylan 2002)

MCC was first introduced in 1964 under the brand name Avicel® PH. Currently, MCC is available from different vendors under different trade names. MCC is prepared by hydrolysis of native a-cellulose, a fibrous, semicrystalline material, with dilute mineral acids. During hydrolysis, the accessible amorphous regions are removed and a level-off degree of polymerization product is obtained. MCC serves as an excellent binder and possesses high dilution potential. However, it suffers from high sensitivity to moisture and lubricants. Addition of a lubricant in the formulation is required especially when high-speed tablet machine is used. MCC also shows poor flow and inconsistent disintegration properties. (Swarbrick and Boylan 2002)


Microcrystalline Cellulose: Description and Uses

Cellulose is the most abundant natural polymeric raw material from which a number of excipients have been prepared. Cellulose is a major component of plant materials, and has been an integral part of the man’s diet throughout human history. The name “cellulose” was coined by Payen, who showed that the cell walls of all plants were constructed from cellulose (Nevell 1985). Cellulose constitutes more than 98% of cotton fibers, as much as 50% of wood fibers, and about 30% of cereal fibers. Based on its nearly ubiquitous distribution in nature, and humankind’s long exposure to cellulose, cellulose and its derivatives are generally recognized as the safest and most acceptable polymer class for use in food and pharmaceutical products (Nevell 1985).

Microcrystalline cellulose is purified cellulose. The empirical formula of MCC is: (C12 H20 O10)n.  Its molecular weight is approximately 36 000. MCC a high molecular weight polymer (Mufson et al. 1986). The structure of MCC is derived from the linear polysaccharide cellulose shown in Figure 1, where n represents the degree of polymerization. Cellulose consists of glucose molecules bonded together by P-glycosidic linkages.  These linear cellulose chains aggregate to form fibers connected by intermolecular hydrogen bonds. The fibrous regions that are formed from these aggregated cellulose chains provide enough order to be considered microcrystalline in nature (Mufson et al. 1986).

Figure 1.  Structure of Cellulose (adapted from Nevell 1985)

The essential features of the cellulose chain are the intermediate units, the non-reducing end unit, the reducing end unit and the 0-1,4-glycosidic bonds. The CH2OH, OH, and the glycosidic bonds are all equatorial with respect to the planes of the pyranose rings. The reducing end unit of the cellulose chain contains a hemiacetal group (on C-l), and exhibits chemical properties similar to those of the glucose. The non-reducing end unit contains an additional secondary alcohol group (on C-4) and is useful in the determination of the number-average degree of polymerization (DP). Because of its high degree of polymerization, the general chemical and physical properties of cellulose are determined by the intermediate units (Mufson et al. 1986).

The pyranose rings are in the 4Ci conformation, as a result of the inter- and intra-chain hydrogen bonding network shown in Figure 2 (Kumar and Banker 1993, p.3). If the cellulose chain is fully extended, it is like a flat ribbon with hydroxyl groups protruding laterally. The surface of the ribbon consists mainly of hydrogen atoms linked to the carbon, which make the surface of cellulose hydrophobia. The long cellulose chains lie side by side in parallel. The lateral association of the chains holds them together by strong hydrogen bonds between hydroxyl groups on C2, C3 and C6 positions in the cellulose molecule (1983).

Figure 2. Inter- and Intra-chain hydrogen bonding in cellulose chains (adapted from Kumar and Banker 1993, p.3).

Colvin (1983) reported that the lateral association of the chains of molecules leads to the formation of long thin sheets by hydrogen bonding. These sheets stack together by London forces to form bundles of thread-like structures called microfibrils. Colvin (1983)  further proposed that the formation of the sheets was due to the fact that the edges of the glucans are hydrophilic, while their faces are hydrophobia There is thus a perpendicular hydrophobic attraction between the cellulose sheets that holds the structure together. This structure is supported by X-ray diffraction and packing analysis data. Large numbers of microfibrils, in turn, are bound together and make up a cellulose fibril, the basic unit to build cell walls of cellulose fiber. Fibrils are arranged in layers to form the cell wall of plant fibers (Kamide 2005).

The molecular arrangement of cellulose chains in the microfibrils is shown in Figure 3. The fringe micellar model depicts the ordered or crystalline regions of the cellulose chains arranged in a parallel array, while the chain fold model shows the long cellulose chains folded back and forth giving the parallel arrays of ordered or crystalline regions. Interspersed between the ordered regions are distorted regions (fringe micellar model), or spaces/voids (chain fold model), which represent the amorphous regions of cellulose.

Figure 3. Molecular arrangement of cellulose chains (adapted from Kumar and Banker 1993, p. 5)

These amorphous regions occur as a result of the formation of a beta-1,6-glycosidic bond instead of the regular beta-l, 4-glycosidic bond, or from any mechanical damage to the material during handling and processing. The strong X-ray diffraction pattern seen for cellulose is because of the high regularity in which these thread-like bundles are arranged (Kumar and Banker 1993).

Strong hydrogen bonding dominates the interactions between the hydroxyl groups among the anhydroglucose units and determines the ordered alignment of cellulose molecules in the crystalline region. Evidence indicates that the structure of cellulose is composed of about 80% crystalline and 20% amorphous regions (Nevell 1985). In the crystalline regions, the cellulose molecules are arranged in highly ordered lattices in which hydroxyl groups are bonded by hydrogen bonding. Therefore, the reactivity of cellulose is limited to the amorphous regions. Owing to its high cohesive energy density and limited reactivity, cellulose is water insoluble and inert to most chemicals (Kamide 2005).


Preparation of Microcrystalline Cellulose
The chemical hydrolysis of cellulose to produce microcrystalline cellulose (MCC) for use as a dry binder, which is currently the most commonly and widely used direct compression excipient, was first reported in 1961 by Battista and Smith (Nevell 1985). Since then microcrystalline cellulose has been extensively studied to reveal its mechanisms and broaden its applications. The material has been continuously modified, primarily into selected particle size fractions, to meet the demanding requirements for direct compression materials. Searching for new ways to prepare microcrystalline cellulose, or for alternative raw material resources other than cotton or wood pulp, has also been a continuous endeavour (Kamide 2005).

Although there are various ways to prepare microcrystalline cellulose, the basic method is to treat cellulose with a dilute solution of a strong mineral acid. Strong mineral acids, such as 2M hydrochloric acid or sulphuric acid, can dissolve the amorphous regions by severe acid hydrolysis when employed for a period of 15 minutes to 2 hours at boiling temperature (Kamide 2005). In reacting cellulose with a strong mineral acid, the degree of polymerisation (DP) of cellulose decreases sharply and then approaches a plateau value, referred to as the level-off DP (LODP). Once the LODP has been attained, no further decrease in DP occurs regardless of the strength of the acid being used. In general, the LODP of MCC prepared from native cellulose fibers is in the range of 200-300 (Kamide 2005).

Dilute solutions of strong mineral acid do not cause decrystallisation of cellulose, and the removal of the amorphous regions by hydrolysis results in a highly crystalline product. The product obtained on acid hydrolysis is termed hydrocellulose, which exists as a very fibrous material. It is unsuitable for use as a dry binder because of the flow problems caused by its fibrous nature. The product from acid hydrolysis typically has a high crystallinity and a relatively constant chain length. Higher concentrations of strong acids, however, rapidly hydrolyse cellulose to sugars and other soluble oligosaccharides (Nevell 1985).

The crystalline cellulose bundles obtained from acid hydrolysis can be converted to porous and random structured microcrystalline cellulose particles by mechanical shearing through a wet milling disintegration process, followed by purification or extensive washing in order to remove the residual acid, and finally hydrogen bonded agglomeration through spray-drying, or drying at room temperature for a week (Kamide 2005).   Microcrystalline cellulose has achieved pharmaceutical acceptance for use in tablet formulations, primarily because of its aggregate nature and free flowing properties, associated with the advantages provided by an extremely large surface area.

Microcrystalline cellulose is one inert excipient that meets many of the qualities desired in an ideal direct compression excipient. It is recognized in the literature as the best direct compression binder available for tablets (Swarbrick and Boylan 2002). The high degree of crystallinity of microcrystalline cellulose aggregates render them extremely compressible.  Microcrystalline cellulose has been demonstrated as having the strongest compressibility among all the available direct compression excipients (Swarbrick and Boylan 2002).

The manufacture of microcrystalline cellulose is associated with certain drawbacks, which include the utilization of strong mineral acids, especially the highly corrosive hydrochloric acid, at boiling temperature. The production of MCC by such methods requires special equipment coated with materials that are resistant to strong acids. The manufacturing area needs to be isolated and carefully designed, since the acid vapour produced will corrode any susceptible metal parts so exposed. When dealing with a strong acid at boiling temperature and high pressure, job safety and environmental pollution are also of major concern (Swarbrick and Boylan 2002).

The product does have limitations. The tablet formulations often require a large quantity of microcrystalline cellulose to form reasonably intact tablets. The high degree of crystallinhy of microcrystalline cellulose results in less accessibility to water for interaction with its polar hydroxyl groups. The microcrystalline cellulose particles are fibrous, unless agglomerated into more spherical particles. In solid dosage formulation, its fibrous shape renders microcrystalline cellulose powder less flowable. In liquid dosage formulation, it has suspendability limitations due to its high crystallinity, which gives it a low rate and extent of hydration. In addition, microcrystalline cellulose is a higher cost excipient material and its benefits of incorporation must typically justify that higher cost (Swarbrick and Boylan 2002).


Physicochemical Properties
Cellulose excipients may be obtained either from mechanical disintegration or by chemical hydrolysis. In both cases, the starting raw material goes through a series of processing steps, which account for the physicochemical properties of the final product, such as the crystallinity of the final product, the degree of polymerisation or the cellulose chain length, the porosity or the bulk density of the particles, and the equilibrium moisture content The degree of polymerisation of alpha cellulose, which is the raw material for all these excipients, varies according to the product source and the method of determination. Most commonly reported values are between 600 and 14,000 units. After extraction and purification, the DP values of purified wood cellulose have been reported to be between 600 and 1000 (Nevell 1985).

The mechanical disintegration of alpha cellulose to prepare powdered cellulose or microfine cellulose results in partial amorphisation and limited depolymerisation of the cellulose. In a comprehensive literature survey, Doelkar et al. (1993) reported the degree of crystallinity of commercially available microfine cellulose powders ranging from 26% to 59%, and the degree of polymerisation between 517 and 784. In the chemical hydrolysis of alpha cellulose, as mentioned earlier, hydrolysis occurs in the amorphous regions and highly crystalline microfibrils are left behind, with a level-off degree of polymerisation between 200 and 250.

However, intensive agitation during processing can destroy the crystal structure, and also short chains are unfavorable to the building of crystalline regions. For a variety of commercially available microcrystalline celluloses, Doelkar et al. (1993) reported the degree of crystallinity to be between 55% and 82% and the DP between 113 and 202 units. Low crystallinity cellulose, prepared using 85%w/w phosphoric acid, showed a DP value ranging between 50 and 120, due to the extensive hydrolysis of cellulose. The degree of crystallinity for this product ranges from 20% to 50% (Wei et al. 1996).

The equilibrium moisture content in cellulose excipients depends on the nature of the material, such as its degree of crystallinity, particle size, surface area, the degree of polymerization and the method employed for drying. The moisture content in microcrystalline and microfine celluloses should be less than 5% w/w. The moisture content of these materials also depends on the packaging of the final product (Kamide 2005).

The porosity of cellulose particles depends on the degree of aggregation that takes place during the processing of the material. Typically, both microcrystalline and microfine cellulose powders are fairly porous as they contain bundles of microfibrils that are not tightly packed, or agglomerates of several primary particles that leave large void spaces The porosity of these materials is between 70% and 90%. The porosity as well as the size of the particles directly reflect their surface area Doelkar et al. (1993).

Direct Compression
Solid dosage forms are defined as drug delivery systems presented as solid-dose units. Tablets and capsules are the most popular and preferred drug delivery vehicles because they can be accurately dosed, easily manufactured and packaged on a large scale, have good physical and chemical stability, and can contribute to good patient compliance given their ease of administration. (Marshall and Rudnic 1990)

Tablets can be produced by the following methods: wet granulation, dry granulation and direct compression (Bolhuis and Chowhan 1996).  Wet granulation is the oldest technique. Granulation is the process of particle enlargement and its purpose is to transform the powdered starting materials, which could otherwise be unsuitable for tableting, into a form that will run smoothly on a tableting machine. In forming granules, individual particles of the starting materials are agglomerated together while retaining their original integrity. (Banker and Rhodes 2002)

In direct compression the mixtures of powders, without any pre-treatment, are compacted directly in a die to produce tablets (Banker and Rhodes 2002). Of these, direct compression has steadily increased over the years because of its ease of manufacture offers economic advantages as the process involves fewer unit operations, that means, it requires less equipment, less space area, and less processing time, incurs lower labor costs, and consumes lower energy (Bolhuis and Chowhan 1996).

Because of the elimination of the granulation and heating steps in the process, drugs that are sensitive to heat and moisture can be processed by this method (Bolhuis and Chowhan 1996).  The major disadvantage of the method is that most direct compression excipients currently commercially available are expensive and they offer limited dilution potential for high dose drugs. Such drugs often have low bulk density and show poor compactability and flow characteristics (Bolhuis and Chowhan 1996).

Other problems that may occur during manufacture by direct compression include segregation during mixing, if the particle size distribution of the drug and excipients do not match, and inhomogeneity of the powder mixture, especially with low dose drugs (Marshall and Rudnic 1990). When these problems are an issue, wet granulation is the method of choice. Dry granulation is used if the drug is sensitive to heat and moisture and shows poor flow and compactability.

The number and type of components in a solid dosage formulation typically contains the drug, a diluent, a binder, a lubricant, a disintegrant and a glidant (Marshall and Rudnic 1990). A diluent is used to increase the bulk of the tablet, a binder is employed to add cohesiveness to the powder bed, and a lubricant helps to reduce the friction between the powder bed and the die wall during compression and ejection by interposing a film of low shear strength between them. A disintegrant facilitates the breakup of the tablet after administration, and finally, a glidant is added to improve the flow characteristics by modifying the interaction between particles. Most lubricants also act as anti-adherents, which prevent sticking of the powder to the punches and die (Marshall and Rudnic 1990).

Most direct compression excipients used in the manufacture of tablets have existed for the past two or three decades, many of them continue to be used today but their production is now regulated by more controlled specifications (Bolhuis and Chowhan 1996).  Some of the requisites for excipients used in solid dosage forms, besides meeting all the compendial/regulatory requirements, include: high compactability, good flowability, good blending, low lubricant sensitivity, good stability, inertness, reworking capability, batch-to-batch reproducibility, inexpensive, availability worldwide and from multiple suppliers, well characterized for tableting applications, and made under GMP conditions (Bolhuis and Chowhan 1996).

Tableting is a compaction process that involves two steps: compression and consolidation. When pressure is applied onto a powder bed, the following processes take place: (i) particle rearrangement; (ii) elastic deformation of the particles; (iii) plastic deformation of the particles and/or fragmentation of the particles; and (iv) interparticulate bonds formation (Nystrom and Karehill 1996).

Compressibility has been used to describe the process of volume reduction, while compactability represents the whole process of the compact formation including the bond formation (Nystrom and Karehill 1996). The greater the compactability of a material the higher the compact strength is. During compression, the particles are brought together so that the interparticle forces may form permanent bonds. Thus, the compact strength is a function of the nature of the attractive forces as well as the surface area over which they act (Nystrom and Karehill 1996).

There are various mechanisms by which volume reduction takes place. Plastic deformation is an irreversible process, which brings about a permanent change in the particle shape, whereas elastic deformation is a reversible process that allows the particles to recover their original shape (Nystrom and Karehill 1996).  Fragmentation causes the particles to break into smaller components. Sodium chloride, microcrystalline cellulose, starch, sodium bicarbonate, polyethylene glycol and amorphous lactose are considered to deform by a plastic mechanism (Nystrom and Karehill 1996).

On the other hand, crystalline lactose, sucrose, and dicalcium phosphate dihydrate are believed to undergo fragmentation. In general, pharmaceutical materials deform by a combination of these mechanisms, i.e., plastic deformation and fragmentation.  The degree of volume reduction depends on the deformation mechanism(s) involved, which, in turn, depends on the physical/mechanical properties of the material (Nystrom and Karehill 1996).


Effect of Moisture on the Properties of Cellulose
The glass transition temperature (Tg) is the temperature at which the amorphous polymer changes from a hard glassy form into a rubber-like plastic or a viscous fluid. At this temperature, both physical and mechanical properties of the polymer change. The glass transition temperature is related to the onset of a certain degree of movement in the main chain, and is explained by many theories as being related to the free volume of the polymer, i.e., the volume not occupied by the molecules. It is assumed that above the glass transition temperature the free volume is so large that significant chain movement (e.g., rotation of segments) is possible and exists. The true glass transition temperature of cellulose is estimated to be 220° C (Salmen and Back 1977).

The decrease in the glass transition temperature of an amorphous polymer caused by the presence of another component in the polymer, having a lower glass transition temperature, is known as politicisation. In simple words, politicisation is also referred to as the softening of a rigid polymer. Water is an effective softening agent for cellulose and is ubiquitously present in the production process of cellulose materials. The glass transition temperature of water is -137° C, as opposed to 220° C for pure amorphous cellulose (Salmen and Back 1977).

Thus, the presence of water leads to the lowering of the glass transition temperature of amorphous cellulose. However, for native cellulose, which consists of the amorphous regions embedded in the crystalline regions, calculations for the glass transition temperature must account for the weight fraction of amorphous cellulose present in the sample. Salmen and Back (1977) derived theoretical values for the glass transition temperature of cellulose samples, varying in degrees of crystallinity between 35% and 80%, in the presence of moisture content between 0% and 30% w/w. They also reported that viscose cellulose and cotton cellulose, when saturated with water, can have glass transitions at temperatures as low as -25° C and -45° C, respectively.

Batzer et al. (1981) investigated the glass transition temperatures of cellulose-water mixtures using differential scanning calorimetry (DSC). They reported that very small amounts of sorbed water can cause pronounced shifts in the Tg due to breaking of the hydrogen bonds between the cellulose chains, and a reduction of the cohesive energy between the polymer chains. The lowering of TK with increasing moisture has been found to follow an exponential relationship. This is because additional water molecules form clusters with the previously sorbed water. Their results indicated that the Tg can range between -13° C to 102° C, for cellulose having moisture contents between 10% w/w and 2.5% w/w, respectively.

The amount of moisture taken up by a cellulose sample depends on its degree of crystallinity as well as the specific surface area of the sample. Zeronian et al. (1983) obtained water sorption isotherms for several cellulose samples with varying crystalline contents. They calculated the number of molecules of water adsorbed per anhydroglucose unit (agu) when a monomolecular (Wm) layer of water was formed on the samples, using the BET equation. They reported that there was less than 1 molecule of H2O/agu when a monomolecular layer of water was formed on amorphous cellulose. They also proposed an equation for determining the degree of crystallinity of a cellulose sample from the Wm values of the sample and crystalline and amorphous cellulose standards. They observed a good agreement between their calculated values and those obtained by other swelling techniques.

Hatakeyama et al. (1983) proposed that water sorbed by cellulose molecules is of three different types: free water, freezing bound water, and nonfreezing bound water. They defined “free water” as the loosely bound water in cellulose whose transition temperature, enthalpy, and DSC peaks coincide with those of pure water. “Bound water” refers to water restricted by the hydroxyl groups of the cellulose molecules. Therefore, “freezing water” can refer to either or both free and bound water. They also defined “non-freezing water” as bound water. Based on their study, they concluded that strong hydrogen bonding occurs between water molecules and the hydroxyl groups of the anhydroglucose unit of cellulose, and the motion of these water molecules is strongly restricted.

They also indicated that this process continues until the primary sorption sites, i.e., the hydroxyl groups of cellulose, are saturated with water molecules. Longer conditioning at 100% relative humidity (R-H.) causes the formation of multiple layers of water. They also observed recrystallization of amorphous cellulose, which results in some amount of water desorbing from the cellulose-water system. In this intermediate state of crystallization, water seems to act as a catalyst for hydrogen bond formation. With further sorption of water, the amount of free water increases, increasing the heat capacity of the system, indicating that cellulose molecules in the amorphous regions inevitably form a bulky structure containing a greater void volume than that of the original sample. Zografi et al. (1984) observed similar results with respect to the states of water sorbed on microcrystalline cellulose.

From the hydrogen bonding network of cellulose depicted in Figure 2, it can be seen that the carbon-6 hydroxyl (C6-OH) is involved in both intra- and inter-chain hydrogen bonding within the crystalline structure. This hydrogen bonding is absent in the amorphous regions and thus the C6-OH is the most exposed hydroxyl group and the one most likely to be involved in hydrogen bonding with water molecules. Khan et al. (1987) explained that the one water molecule between two anhydroglucose units is actually linked to the two 6-OH groups in the neighboring chains. They also calculated the enthalpy changes that occur with increasing moisture content and found that the enthalpy changes correlated very well with the sorption isotherm data. Thus, it was concluded that the first increase in enthalpy values for moisture uptake up to 6% w/w corresponded to the bonding of water to the C6-OH groups. This was followed by a levelling off as a result of the further sorption of water molecules on to the existing water layer by dipolar hydrogen bonding.

Khan et al. (1988) investigated the effect of moisture on the compaction and tensile strength of microcrystalline cellulose. They observed significant changes in these properties at moisture content values above 3% w/w. They observed an increase of swelling volume, a lowering of the yield pressure, a lowering of the ejection force and an initial increase in tensile strength up to 3% moisture content, followed by a decrease. They postulated that water does not penetrate into the crystalline core, but it does in the amorphous regions of cellulose, and thus disrupts the hydrogen bonds between the cellulose chains, and bonds to the hydroxyls groups on the anhydroglucose units.

This gives rise to the swelling of cellulose in water and also accounts for the reduced rigidity of the polymer, which is reflected in the lowering of the yield pressure. They attributed the initial increase in tensile strength to the greater extent of plastic deformation, bringing a greater amount of area into contact, thereby resulting in a greater extent of bond formation between neighboring particles. However, beyond 3% moisture content, these bonds either weaken or are disrupted, which account for the loss in the tensile strength.

Amidon et al. (1995) investigated the effect of moisture on the mechanical properties of microcrystalline cellulose using Hiestand compaction indices. They observed that the pressure required to cause permanent deformation and an increase in tensile strength of the compacts were independent of the moisture content below 5%w/w, while above 5% w/w a decrease in these properties was noted. The “best case” bonding index was also observed to be independent of moisture content below 5%, and then increased with increasing moisture content.

The brittle fracture index and the “worst case” bonding index, however, did not appear to be affected by changes in the moisture content. They concluded that the changes in the tablet indices seen above 5% moisture were due to the plasticising role of water on microcrystalline cellulose. Amidon et al. (1995) also reported that the inflection in the moisture sorption isotherm for their batch of microcrystalline cellulose occurred approximately between 5% and 7%, which correlated with the moisture content at which the TK was lowered to the experimental temperature (room temperature).


Effect of Applied Pressure on Microcrystalline Cellulose.

Powder Compressibility

Compressibility is a measurement of the ability of a powder to undergo volume reduction with an applied load. Several models of compressibility have been proposed. These are also known as pressure-porosity functions, and they relate the ability of a powder to decrease in volume as a load is applied. Common models include the Cooper-Eaton, Kawakita, and Heckel equations (Banker and Rhodes 2002).

The Cooper-Eaton model assumes that the process of compaction can be described in two steps. The first step is particle rearrangement, with minimal if any plastic deformation, to produce a close packed structure. The second step involves a further reduction in volume as the applied load is increased. The particles attempt to fill the void space as the pressure is increased. This occurs by permanent deformation or brittle fracture. The Cooper-Eaton model fits compaction data over a wide range of volume changes and does especially well when a tablet is formed (Banker and Rhodes 2002).

The most notable and commonly used of the pressure-porosity functions is the Heckel relationship. Heckel assumed the densification of a powder bed follows first order kinetics, where the pores are the reactants, and the densification of the bulk of the product describes the kinetics of the process. Heckel analysis has been used widely in the pharmaceutical industry to characterize the deformation properties of pharmaceutical powders. (Bolhuis and Chowhan 1996) There are two methods of performing the analysis in order to obtain meaningful parameters.

In one method, the tablet dimensions are measured as the force is being applied and the tablet remains in the die. The tablet dimensions are extrapolated from the force displacement transducer. In the second method, the tablet dimensions are physically measured after the tablet is ejected from the die. The first method is known as the “in-die” method and the second method is referred to as the “out-of-die” method. In both methods, the volume of the tablet is calculated from the measured dimensions. The porosity of the tablet is then calculated form the apparent density of the tablet and the true density of the powder.

Paronen (1986) used the in-die and the out-of-die methods of Heckel analysis for microcrystalline cellulose, dicalcium phosphate dihydrate, modified starch, and sodium chloride and demonstrated that reliable conclusions can be drawn about the total elastic recovery using the reciprocal of the difference of the slopes of the Heckel upward plot. The order of the materials to permanent densification, according to Paronen (1986), was: sodium chloride > microcrystalline cellulose > modified starch > dicalcium phosphate dihydrate.

This method of analysis of data from the compression and decompression steps was also used by Duberg and Nystrom (1986) to evaluate the compression behaviour of sodium chloride, dicalcium phosphate dihydrate, aspirin, phenacetin, sodium bicarbonate, lactose, paracetamol and magnesium stearate. From their analyses, they found that sodium chloride and sodium bicarbonate compressed predominantly by plastic deformation and showed very little fragmentation tendency. Dicalcium phosphate dihydrate, on the contrary, showed an extensive fragmentation, and hence, had a very high yield pressure. Lactose showed a fragmentation tendency despite its relatively low yield pressure. The latter has been attributed to the elastic properties of lactose, which overestimate the degree of plastic deformation based on the yield pressure results. An extensive amount of elastic deformation, which was reflected in low yield pressure values, has also been reported for paracetamol, phenacetin and aspirin.

Doelker (1993) reported that MCC exhibits the lowest yield pressure compared to that of sodium chloride, lactose monohydrate, dicalcium phosphate dihydrate and paracetamol. Doelker (1993) also compared the yield pressures of a variety of microcrystalline cellulose materials from various vendors and found the yield pressures to range between 37 MPa and 69 MPa. These differences in the yield pressures have been attributed to the molecular mass, degree of crystallinity, moisture content, and particle size and shape.

Podczeck and Revesz (1993) evaluated the compaction mechanism of a range of microcrystalline celluloses and microfine celluloses from different manufacturers. Heckel analysis performed by these investigators showed that the MCCs deformed mainly by plastic flow, since the mean yield pressures were lower than 80 MPa. Microfine celluloses, which showed yield pressures greater than 90 MPa, a cut-off point for differentiating between a plastic mechanism and a brittle mechanism, have been reported to deform predominantly by fragmentation.

Mechanical Strength Measurements

Nystrom et al. (1993) performed a comparative study of the overall tablet strength of several materials, including sodium chloride, iron, Avicel® PH 101, sodium bicarbonate, and starch. They reported that Avicel® PH 101 had the second highest radial and axial tensile strengths, second only to that of sodium chloride. They postulated that the high tensile strength of Avicel® PH 101 was due to the high surface area taking part in the bonding process. They also proposed the term “surface specific tensile strength,” which is obtained by normalizing the tensile strength values by the surface area of the powder. It was found that the surface specific tensile strength of Avicel® PH101 was also very high, second only to that of the sodium chloride compacts.

Bolhuis et al. (1996) performed a comparative evaluation of various direct compression excipients, including microcrystalline cellulose, microfine cellulose, directly compressible starch, amylose, dicalcium phosphate dihydrate, dextrose monohydrate, spray-crystallized dextrose, anhydrous lactose, and spray dried lactose. They found that the crushing strengths of the Avicel® PH 101 and Avicel® PH 102 tablets, measured by the diametric compression test, were the highest among the materials tested.

Doelker et al. (1993) reported the crushing strength of sixteen types of microcrystalline celluloses obtained from various sources. The tablets were compressed on a single punch machine at 100 MPa compression pressure, and the crushing strength values ranged from as low as 183 N to 460 N. However, in this study the moisture content was not controlled and the samples were evaluated as received. The investigators attributed the differences in the mechanical properties to physicochemical variables, such as particle size, crystallinity, and degree of polymerisation.

Podczeck and Revesz (1993) used the equation to evaluate the strength of tablets made from various brands of microcrystalline and microfine cellulose. The equation is given as:

στ = m. ln P + n,

where στ is the tablet strength and P is the compaction pressure. Here, the dependence of the strength on the compaction pressure is considered to be exponential. The slope m is a measure of the increase in strength with increasing pressure used. The greater the value of m the more sensitive the powder is the fluctuations in the consolidation pressure. The slopes m, for microcrystalline cellulose materials were distinctly steeper than those for microfine cellulose materials.  Among the microcrystalline cellulose types, there were two distinct groups with respect to the slopes seen for the Higuchi plots. The investigators attributed these differences to the differences in the sources of the raw materials (Podczeck and Revesz 1993).

Hiestand Compaction Indices

During compaction, contacts are at all stages of development. The formation of a tablet bond occurs as a result of physical interactions between particle surfaces when they are brought into sufficiently close contact. New contacts are formed, while older ones continue plastic deformation. Plastic deformation of a material under compression is a mechanism by which surface accommodation is accomplished either at a bulk level or at a molecular level. Brittle fracture can also result in surface accommodation. The formation of true contact areas during compression and the survival of these contact areas during decompression and ejection result in a tablet. The contacts formed during unloading or during tensile loading can undergo ductile extension or brittle fracture (Hiestand 1997).

Hiestand (1997) made several assumptions regarding the various processes that occur during tableting and, on the basis of these assumptions, they formulated the “tablet indices”. These tablet indices, namely, the bonding index, brittle fracture index, and strain index, provide quantitative information of a more fundamental nature than traditional methods. They are useful in the analysis of compacts of individual materials or a mixture of materials (Hiestand 1997). The indices are dimensionless numbers. Experienced operators can also find useful information from tensile strength, compaction pressures and hardness values used in the calculation of these indices. The analysis of compacts by Hiestand indices requires a large amount of powder. However, the use of Hiestand indices is justified in that the lot-to-lot variation seen with individual ingredients in a given formulation directly affects the measured indices.

Williams and McGinity (1989) used Hiestand indices to study the effect of varying concentrations of magnesium stearate and talc on the compaction properties of microcrystalline cellulose. Both lubricants in a concentration range from 0% to 9% w/w in blends with Avicel® PH 101 lowered the tensile strength, dynamic indentation hardness, bonding index and brittle fracture index. Magnesium stearate had a greater effect on the tensile strength reduction than did talc at equivalent concentrations. The tensile strength as a function of solid fraction was also investigated.

It was found that tensile strength was related to solid fraction by a log-linear relationship. Dynamic indentation hardness showed an exponential increase with increasing solid fraction. This study also investigated the compaction properties of a binary mixture of microcrystalline cellulose and sodium sulfathiazole. It was assumed, a priori, that changes in the indices as a result of variations in the composition of the mixtures would follow a linear function. The experimental results showed a negative deviation from linearity for the bonding and brittle fracture indices. The tensile strength also showed a negative deviation from linearity, while the dynamic indentation hardness measurements exhibited positive deviation.

Majuru and Wurster (1997) also evaluated binary powder mixtures using the Hiestand compaction indices. Their research demonstrated that a quantitative predictive capability could be derived for the indices for mixtures of powders. The binary mixtures were classified according to the mechanism of consolidation of each of the components (plastic-plastic, brittle-brittle, or plastic-brittle). In this study, microcrystalline cellulose, Avicel® PH 101, was used as the plastic material for preparing the mixtures. The composition of the mixtures was varied systematically and was reported as a weight percentage of each component used.

The study revealed that the bonding indices of compacts made from binary mixtures were related to composition in a quantitative and systematic manner. The bonding indices were linearly related to the composition of compacts prepared using mixtures of materials, which consolidated by the same mechanism. In the case of compacts prepared from a plastic-brittle mixture, the bonding indices varied with composition of the mixture according to a second-degree polynomial relationship. A single equation was derived which allowed a reasonable prediction of the bonding indices of all plastic-brittle combinations from the bonding indices of the pure materials.

Roberts and Rowe (1986) determined the brittle fracture indices of cylindrical compacts of Avicel PH 101 (microcrystalline cellulose). The compacts were 15 mm in diameter and were compressed at various relative densities using a high-speed compaction simulator fitted with specially designed flat-faced “F-type” tooling. This method was chosen to produce tablets at strain rates approaching those normally used in tableting. The brittle fracture indices were found to be independent of punch velocity but showed dependence on the tablet porosity.

Effects of Degrees of Crystallinity and Polymerization

Many investigators analysed the differences in the compression properties of various types of celluloses, however, so far, no effort has been successful to quantitatively correlate these differences to the degree of crystallinity or the degree of polymerisation of various celluloses (Podczeck and Revesz 1993).  Only speculation has been proposed, that the differences may be due to variability in morphological characteristics, as well as to variations in crystallinity and molecular weights. In one study, Doelker (1993) evaluated the effect of crystallinity of various celluloses on their compression properties and found no correlation. Since the degree of polymerisation of the materials, the porosity of the particles, and the moisture contents of the samples were not reported, this study may understandably have been inconclusive.

Effect of Particle Size on the Mechanical Properties

It is generally believed that a change in particle size affects the external surface area of the particles as well as their mechanical properties. The underlying reason for the change in the particle strength can be explained on the basis of Griffith’s theory of crack propagation  (Alderborn 1996). As the particle size gets smaller, the probability of the existence of defects in the crystal structure is reduced greatly. Thus, the mechanical strength of the particles increases with a reduction in particle size. It has also been reported that when the particle size is reduced, a change in the volume reduction mechanism can also occur, which is termed the “brittle to ductile transition”. However, this generalization does not hold for all pharmaceutical materials.

Alderborn (1996), in a literature review, has reported on particle size effects on the mechanical properties of pharmaceutical materials. Differences exist in literature reports for the particle size effects of the same materials, such as sodium chloride and starch. These different observations may be due to differences in the experimental conditions, technique and material variables not accounted for. In general, significant differences in mechanical properties with changes in particle size have been reported for lactose, sodium chloride, sodium bicarbonate and starch (Alderborn 1996).

The effect of particle size on the mechanical properties of cellulose excipients has been investigated by several investigators. Interestingly, all studies have concluded that changes in particle size showed no significant effects on either the volume reduction mechanism or the mechanical strength of tablets of microcrystalline cellulose (Alderborn 1996). Also, it was found that the bonding index for microcrystalline cellulose was constant with a change in particle size, the brittle fracture index increased as the particle size decreased and the strain index remained constant over the particle size range tested.


Effect of Particle Porosity on the Mechanical Properties

Very few investigators have recognized the role of particle porosity on the mechanical characteristics of excipients. Zuurman et al. (1994) studied the relationship between the bulk density and the compactability of lactose granulations. They observed an increase in the compactability of the granulations with an increasing porosity of the granules. They explained this dependence to be due to a greater amount of space available for deformation in the more porous granules. Plastic deformation can also be viewed on a bulk (macroscopic) scale as rearrangement of the primary particles to accommodate the stress and produce an altered shape or arrangement of the particles. Thus, more intimate contacts are formed between the particles giving the higher tensile strengths.

Similar results were observed by Johansson et al. (1995) using spherical pellets of microcrystalline cellulose having varying degrees of porosity. They observed that the degree of deformation and the compactability of the pellets were directly related to the original pellet porosity. This preferential deformation of the pellets, over fragmentation, was explained on the basis that the repositioning of the primary particles within the pellets by shearing would require less energy than the separation of the primary particles by the formation of a fracture plane.


Microcrystalline cellulose, currently commonly and widely used as direct compression excipients in the design of a tablet dosage form, are obtained by mechanical and chemical disintegration of native cellulose, respectively. Microcrystalline cellulose is among the top ten excipients and is among the first three excipient monographs selected by the U.S. Pharmacopeia, along with the powdered cellulose, for harmonization of excipient standards and test methods with European Pharmacopeia and Japanese Pharmacopeia.  Microcrystalline cellulose is widely used as a direct compression excipient. It possesses excellent compaction properties that have been attributed to its relatively high particle surface area, plastic deformation, and semicrystalline composition, among others. It, however, has some limitations, such as poor flowability, inconsistent disintegration properties, capping problems, loss of mechanical strength during wet granulation, etc.


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