**4.4 MCC as binder**

MCC is a self-disintegrating binder [91] with low lubricant requirement with regard to its dry binding properties due to the extreme low coefficient of friction and its very low residual die wall pressure [56, 62, 92]. However these properties do not replace the need for true disintegrants and lubricants as an addition when MCC is used in a tablet formulation. In fact combination of MCC and superdisintegrants

**51**

increase [54, 85].

*Microcrystalline Cellulose as Pharmaceutical Excipient DOI: http://dx.doi.org/10.5772/intechopen.88092*

of handling, and ease of supply for manufacturer [54].

disintegrant when dry compression is employed.

*4.4.1 MCC as a wet binder*

and free flowing.

**4.5 MCC as disintegrant**

or swelling for faster tablet disintegration.

may be complementary to promote fast disintegration [93, 94]. Other advantages of MCC include broad compatibility with various APIs, physiological inertness, ease

Study on the use of MCC with spray-dried lactose as the poorest compressibility

MCC can also be used as a secondary binder in wet granulation tablet preparation either to granulate both soluble and insoluble APIs. This formulation will produce less hard tablets than that without MCC. The fast wicking action of MCC promotes rapid wetting of the powder mix. This is particularly useful in high moisture granulations as it binds the excess moisture and keeps the granules dry

Disintegrants expand and dissolve once it is in contact with water causing the tablet to break apart in the GI tract and release the active ingredients for absorption. It will break a tablet into smaller fragments therefore increasing the surface area of the active drug in the dosage form; hence it will also increase the rate of drug absorption. The mechanism of disintegrants in the tablet disintegration could be as either water uptake facilitators or tablet rupture promoters. MCC has been widely used as a disintegrant in dry compressions and wet granulation method for tablet manufacturing. It enhances drug dissolution by increasing the rate of tablet disintegration. Basically a disintegrant should provide the highest level of disintegration force at low use levels and utilizes dual disintegration mechanisms either in wicking

The Avicel derivate showed the nature in a fast wicking rate of water with small elastic deformation. These properties provide the ability for tablet disintegration. However, Avicel has a tendency to develop static charges with increased moisture content. Sometimes it even can cause striation or separation in the granules. This occurs when the moisture content in Avicel is above 3%, in which the static charges during mixing and compression become more pronounced. The problem can be overcome by drying the Avicel prior the formulation process to reduce the moisture to lower level. Wet granulated Avicel will lose some of its disintegration properties when performing drying and compression during formulation [4]. In contrast with starch, it cannot be wet granulated without losing some of its disintegration properties. Normally, to overcome this problem, Avicel and starch are used in combination

MCC has a very high intraparticle porosity with approximately 90–95% of the surface area being internal [44]. Therefore the surface area is not directly influenced by the nominal particle size [58]. High porosity of MCC promotes swelling and disintegration of formulated tablets, which is attributed to either by the penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores or even by a disruption of the hydrogen bonds. By increasing compaction pressure, water penetration into the tablets will decrease; therefore disintegration time will

in order to facilitate effective and rapid disintegration of tablets.

among all directly compressible fillers showed that a blend of 200 mg of spraydried lactose with appropriate lubricants may not be able to compress unless a correct amount of dry binder is incorporated inside the blend. Incorporation of 2.5% of Avicel to the formulation proved that MCC has served the purpose. A number of Avicel such as PH-113 can act as a dry binder [95]. However, it will also function as a *Microcrystalline Cellulose as Pharmaceutical Excipient DOI: http://dx.doi.org/10.5772/intechopen.88092*

may be complementary to promote fast disintegration [93, 94]. Other advantages of MCC include broad compatibility with various APIs, physiological inertness, ease of handling, and ease of supply for manufacturer [54].

Study on the use of MCC with spray-dried lactose as the poorest compressibility among all directly compressible fillers showed that a blend of 200 mg of spraydried lactose with appropriate lubricants may not be able to compress unless a correct amount of dry binder is incorporated inside the blend. Incorporation of 2.5% of Avicel to the formulation proved that MCC has served the purpose. A number of Avicel such as PH-113 can act as a dry binder [95]. However, it will also function as a disintegrant when dry compression is employed.

### *4.4.1 MCC as a wet binder*

*Pharmaceutical Formulation Design - Recent Practices*

*4.2.1 Benefits of MCC in wet granulation*

3.Increased drying efficiency

4.Decreased color mottling

**4.3 Filler in dry granulation**

**4.4 MCC as binder**

5.Better drug content uniformity

between 5 and 20% offers the following benefits [51]:

which is observed in incompletely dried granules. This case happened when the granules are dried at a high temperature, from which the inside part of the granules remains wet, while the surface seems dried. The granules are often hard and resist disintegration. When coming to compaction process, the compression forces will break the granules and deform plastically to form soft tablets due to the moisture coming out of the incompletely dried granules. The use of Avicel PH 101 or Avicel PH 302 as filler in wet granulation promotes rapid wetting as a result of the wicking action of MCC. They reduce sensitivity of the wet mass to overwetting and increase the drying process speed. Since there is fewer excess of granulating fluid, screen blockages and case hardenings can be reduced. Homogeneous and uniform granule when MCC is used as wet granulation filler will reduce dye migration. When MCC is employed, faster disintegration from granules and tablets will be obtained.

Basically, using MCC in wet granulation included wetting MCC with water followed by drying and compression. The process resulted in lower hardness tablets than that with dry compression. The wet granulation reduces the density of agglomerated particles thereby decreasing their internal surface area. In contrast, it can also cause adhesion between particle agglomerates, reducing external surface area resulting in less particle interlocking and hydrogen bonding. In general, using Avicel PH-101 or Avicel PH-102 in wet granulation formulations with concentration

1.Rapid adsorption of water by MCC and distribution through the mixture

6.Higher tablet hardness at the same compression force with less friability

Roller compaction is a dry process involving compaction of materials that are then milled to generate a granulation. This granulation is then lubricated and compressed on a tablet machine. This process can be used for moisture-sensitive active pharmaceutical ingredients. The use of Avicel PH grades in roller compaction includes improvement of compaction in the ribbon phase, enhancement of flow of the granules, and preserving of the content uniformity of the Þ nal granulation.

MCC is a self-disintegrating binder [91] with low lubricant requirement with regard to its dry binding properties due to the extreme low coefficient of friction and its very low residual die wall pressure [56, 62, 92]. However these properties do not replace the need for true disintegrants and lubricants as an addition when MCC is used in a tablet formulation. In fact combination of MCC and superdisintegrants

2.Decrease of sensitivity to water content, wet screening, and localized overwetting due to the large surface area of MCC, hence high adsorptive capacity

**50**

MCC can also be used as a secondary binder in wet granulation tablet preparation either to granulate both soluble and insoluble APIs. This formulation will produce less hard tablets than that without MCC. The fast wicking action of MCC promotes rapid wetting of the powder mix. This is particularly useful in high moisture granulations as it binds the excess moisture and keeps the granules dry and free flowing.

#### **4.5 MCC as disintegrant**

Disintegrants expand and dissolve once it is in contact with water causing the tablet to break apart in the GI tract and release the active ingredients for absorption. It will break a tablet into smaller fragments therefore increasing the surface area of the active drug in the dosage form; hence it will also increase the rate of drug absorption. The mechanism of disintegrants in the tablet disintegration could be as either water uptake facilitators or tablet rupture promoters. MCC has been widely used as a disintegrant in dry compressions and wet granulation method for tablet manufacturing. It enhances drug dissolution by increasing the rate of tablet disintegration. Basically a disintegrant should provide the highest level of disintegration force at low use levels and utilizes dual disintegration mechanisms either in wicking or swelling for faster tablet disintegration.

The Avicel derivate showed the nature in a fast wicking rate of water with small elastic deformation. These properties provide the ability for tablet disintegration. However, Avicel has a tendency to develop static charges with increased moisture content. Sometimes it even can cause striation or separation in the granules. This occurs when the moisture content in Avicel is above 3%, in which the static charges during mixing and compression become more pronounced. The problem can be overcome by drying the Avicel prior the formulation process to reduce the moisture to lower level. Wet granulated Avicel will lose some of its disintegration properties when performing drying and compression during formulation [4]. In contrast with starch, it cannot be wet granulated without losing some of its disintegration properties. Normally, to overcome this problem, Avicel and starch are used in combination in order to facilitate effective and rapid disintegration of tablets.

MCC has a very high intraparticle porosity with approximately 90–95% of the surface area being internal [44]. Therefore the surface area is not directly influenced by the nominal particle size [58]. High porosity of MCC promotes swelling and disintegration of formulated tablets, which is attributed to either by the penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores or even by a disruption of the hydrogen bonds. By increasing compaction pressure, water penetration into the tablets will decrease; therefore disintegration time will increase [54, 85].

In intramolecular view, water is only sorbed in the amorphous regions of MCC, which are more hydrophilic than the crystalline regions [3, 54]. Therefore the total amount of sorbed water is proportional to the fraction of amorphous material in the MCC crystallinity and is independent of the surface area [48]. The crystallinity of MCC determined by X-ray diffraction and infrared measurement was found to be in the range of 60–80% [53].

Recently, Avicel has been used as a disintegrant in orally disintegrating tablets. Besides being a disintegrant, it also acts as a dissolution enhancer. US Patent No 6350470 explains the use of Avicel as a disintegrating agent in effervescent drug delivery system for oral administration. In this system, by performing dry granulation, Avicel acts as disintegrant in a concentration of 5.20% [96]. Avicel acts as an effervescent penetration enhancer.

#### **4.6 MCC as lubricant**

Lubricants ensure that tablet formation and ejection can occur with low friction between the solid and die wall.

Avicel has an extremely low coefficient of friction, both static and dynamic, so that it has no lubricant requirement itself. However, when more than 20% of the drug and other excipients are added, lubrication is necessary.

#### **4.7 MCC as glidant**

In tablet formulation, glidant is used to promote powder flow by reducing interparticle friction and cohesion. Glidants can be used in combination with lubricants as they have no ability to reduce die wall friction. Normally, silica-based glidants like silicon dioxide, hydrated sodium silicoaluminate, silica hydrogel, etc. are used in tablet compression to promote good flow property. Proslov as a marketed product of coprocess excipient containing MCC is available which imparts superior flow, good compactibility, and dispersion to tablet formulation [97].

When used as excipient in direct compression, Prosolv SMCC® (JRS Pharma, Patterson, NY) can replace granulation step and significantly reduce excipient numbers and levels. Prosolv SMCC® formulations produce distinctive, uniform, and cost-effective tablets. It is available in three grades: Prosolv SMCC 50, Prosolv SMCC 90, and Prosolv SMCC HD 90. The products differ in average of particle size and bulk density [98]. They offer many benefits including enhanced mixing characteristics, enhanced flow properties, lower unit cost of production due to less excipients needed, and shorter disintegration time. Due to improvement in powder compactibility and dust-free handling during production, Prosolv facilitates less loss in production hence a higher manufacturing efficiency.

In a more recent study, it is reported that silicified MCC and MCC were found to be good plug formers in hard gelatin capsule shells. The study was conducted in a compaction simulator at tamping forces and piston speeds similar to those found in some filling machines. Several grades of silicified MCC and a particular grade of MCC having particle size of 90 μm produced plugs with a higher maximum breaking force than anhydrous lactose and Starch 1500 under similar compression conditions [99].

#### **4.8 MCC as a spheronizing agent**

MCC is an excipient of choice in a multiparticulate delivery of pellets prepared by extrusion spheronization. The extrusion-spheronization process aims to produce drugs into sphere-shaped tablets. Extrusion-spheronization process offers an

**53**

binders.

**5. Conclusions**

*Microcrystalline Cellulose as Pharmaceutical Excipient DOI: http://dx.doi.org/10.5772/intechopen.88092*

discrete

through autoadhesion.

can be lessened to the lower level.

**4.9 Sustained release applications**

in order to obtain particular particle sizes.

alternative to traditional drug layering on pellets. This highly specialized process results in unique spherical, drug-loaded spherical pellets. Higher drug loading can be employed with this approach over that which looks impossible with conventional drug layering. The product, initially called as extrudates, is plastic without rigidity, which tends to agglomerate into very large spherical balls. The formulation mixture which will be manufactured by extrusion method must fulfill the requirements:

1.Cohesive and deformable in order to have good flow through the die without

2.Plastic, so that it can proceed rolling process into spheres in the spheronizer but possesses non-cohesive property so that the final sphere form can remain

MCC, especially Avicel PH-101, can act as an excellent extrusion-spheronization aid excipient that absorbs the water added to the formulation more as a molecular sponge. This ability alters the rheological properties of the wet mass, therefore enhancing the tensile strength of the wet mass during spheronization process

Avicel® PH-101 or Avicel PH-102 is highly recommended to be used for this method because it can reduce spheroid friability, prevent overwetting of spheres, and improve sphericity of pellets. Process sensitivity during the whole manufacture

Recently, MCC has been widely used in the formulation of multiparticulate and matrix tablet dosage forms for sustained release drug delivery system. In general, hydrophilic polymers in matrix tablet formulation are included to form a viscous, gelling layer which can retard water penetration and acts as a barrier to drug release. Drug release is accomplished by diffusion through the gel layer and at the same time through erosion of this layer. Some studies proved that zero-order release profiles can be achieved by selection of appropriate polymers in addition of Avicel as fillers/

Microcrystalline cellulose is a pure partially depolymerized cellulose synthesized

from α-cellulose precursor with hydrolysis by mineral acids, usually in forms of a pulp from a fibrous plant. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which more soluble, such as beta and gamma celluloses, hemicelluloses and lignin are dissolved with acid and water, are separated out during washing. MCC is commonly dried from the slurry by spray-drying method. By varying spray-drying conditions, the degree of agglomeration and moisture content can be manipulated,

Mostly, a raw material for MMC is a cellulose pulp from fibrous plant such as conifer wood. Another source is from cotton either its linters, stalks, rags, fabric waste, or wool. Another study reported a potential source for MCC such as soybean, corn cob, water hyacinth, coconut shells, oil palm biomass residue, oil palm fronds, rice husk, sugar cane bagasse, jute, ramie, fibers and straw of flax, wheat straw, sorghum stalks, sisal fibers, mangosteen, alfa grass fibers, soybean

sticking and able to retain its shape after extrusion process

### *Microcrystalline Cellulose as Pharmaceutical Excipient DOI: http://dx.doi.org/10.5772/intechopen.88092*

*Pharmaceutical Formulation Design - Recent Practices*

in the range of 60–80% [53].

effervescent penetration enhancer.

between the solid and die wall.

**4.6 MCC as lubricant**

**4.7 MCC as glidant**

In intramolecular view, water is only sorbed in the amorphous regions of MCC, which are more hydrophilic than the crystalline regions [3, 54]. Therefore the total amount of sorbed water is proportional to the fraction of amorphous material in the MCC crystallinity and is independent of the surface area [48]. The crystallinity of MCC determined by X-ray diffraction and infrared measurement was found to be

Recently, Avicel has been used as a disintegrant in orally disintegrating tablets. Besides being a disintegrant, it also acts as a dissolution enhancer. US Patent No 6350470 explains the use of Avicel as a disintegrating agent in effervescent drug delivery system for oral administration. In this system, by performing dry granulation, Avicel acts as disintegrant in a concentration of 5.20% [96]. Avicel acts as an

Lubricants ensure that tablet formation and ejection can occur with low friction

Avicel has an extremely low coefficient of friction, both static and dynamic, so that it has no lubricant requirement itself. However, when more than 20% of the

In tablet formulation, glidant is used to promote powder flow by reducing interparticle friction and cohesion. Glidants can be used in combination with lubricants as they have no ability to reduce die wall friction. Normally, silica-based glidants like silicon dioxide, hydrated sodium silicoaluminate, silica hydrogel, etc. are used in tablet compression to promote good flow property. Proslov as a marketed product of coprocess excipient containing MCC is available which imparts superior flow,

When used as excipient in direct compression, Prosolv SMCC® (JRS Pharma, Patterson, NY) can replace granulation step and significantly reduce excipient numbers and levels. Prosolv SMCC® formulations produce distinctive, uniform, and cost-effective tablets. It is available in three grades: Prosolv SMCC 50, Prosolv SMCC 90, and Prosolv SMCC HD 90. The products differ in average of particle size and bulk density [98]. They offer many benefits including enhanced mixing characteristics, enhanced flow properties, lower unit cost of production due to less excipients needed, and shorter disintegration time. Due to improvement in powder compactibility and dust-free handling during production, Prosolv facilitates less

In a more recent study, it is reported that silicified MCC and MCC were found to be good plug formers in hard gelatin capsule shells. The study was conducted in a compaction simulator at tamping forces and piston speeds similar to those found in some filling machines. Several grades of silicified MCC and a particular grade of MCC having particle size of 90 μm produced plugs with a higher maximum breaking force than anhydrous lactose and Starch 1500 under similar compression

MCC is an excipient of choice in a multiparticulate delivery of pellets prepared by extrusion spheronization. The extrusion-spheronization process aims to produce drugs into sphere-shaped tablets. Extrusion-spheronization process offers an

drug and other excipients are added, lubrication is necessary.

good compactibility, and dispersion to tablet formulation [97].

loss in production hence a higher manufacturing efficiency.

**52**

conditions [99].

**4.8 MCC as a spheronizing agent**

alternative to traditional drug layering on pellets. This highly specialized process results in unique spherical, drug-loaded spherical pellets. Higher drug loading can be employed with this approach over that which looks impossible with conventional drug layering. The product, initially called as extrudates, is plastic without rigidity, which tends to agglomerate into very large spherical balls. The formulation mixture which will be manufactured by extrusion method must fulfill the requirements:


MCC, especially Avicel PH-101, can act as an excellent extrusion-spheronization aid excipient that absorbs the water added to the formulation more as a molecular sponge. This ability alters the rheological properties of the wet mass, therefore enhancing the tensile strength of the wet mass during spheronization process through autoadhesion.

Avicel® PH-101 or Avicel PH-102 is highly recommended to be used for this method because it can reduce spheroid friability, prevent overwetting of spheres, and improve sphericity of pellets. Process sensitivity during the whole manufacture can be lessened to the lower level.
