**2. Synthesis of MCC**

The MCC can be synthesized by different processes including extrusion and enzyme-mediated process [25]. Other studies reported that it can also be synthesized by steam explosion and acid hydrolysis process [5, 6]. The acid hydrolysis process is more preferable due to shorter duration than others. It also offered the possibility to be applied as a continuous process rather than a batch-type process. Limited quantity of consumed acid is also the advantage of the process, while, despite the lower unit cost from less chemicals used, this process offered more fine particles of the MCC as the final product [5]. Fibrous plant pulp is hydrolyzed by mineral acid under heat and pressure. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which soluble components of cellulose such as beta and gamma celluloses, hemicelluloses, and lignin are dissolved with acid and water, are separated out during washing process by water which continued by filtration. The obtained pure alpha cellulose has then been neutralized and given the slurry final product [3]. This suspension is dried to obtain the insoluble white, odorless, tasteless powder, which has later been characterized as MCC [39]. MCC is hygroscopic in nature, and insoluble in water, but swells when in contact with water.

Another synthesis procedure of the MCC reported by Ohwoavworhua et al. [40] can be concluded as follows: the α-cellulose was hydrolyzed with hydrochloric acid at a boiling temperature of 105° for 15 min. The neutralized slurry obtained from the hydrolysis process was washed, and the fraction passing through 710 μm sieve was stored at room temperature in a desiccator. 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. In order to obtain smaller particle sizes (below 50 μm), further milling MCC can be performed [1].

**43**

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

**Type Conc. Hydrolysis condition MCC-Y** 

**L/C (vol./ wt)**

*yield of microcrystalline cellulose (MCC-Y) hydrolysis reagent.*

**Particle size (micron)**

Less than 50

*Types of the commercial microcrystalline cellulose [1, 51].*

viscoelastic properties [48].

**Table 1.**

**MCC Type**

PH 101

PH 102

PH 103

PH 105

PH 112

PH 113

PH 200

PH 301

**Table 2.**

Other drying techniques may be used, which may require additional screening steps postdrying in order to control particle size distribution [41, 42]. Higher bulk density grades are also available by using specific cellulose pulps (raw material), and median particle sizes below 50 mm can be obtained by further milling MCC [1]. Several studies have compared microcrystalline cellulose with various sources, including different manufacturers and different sites [4, 43–47]. MCC produced by various manufacturers or in various manufacturing sites may have different properties due to the kinds of pulp used as raw materials and their respective manufacturing conditions [2, 4]. A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and

**Temperature (°C)** HCl 2 N 10:1 105 15 n.a [5] HCl 2 N 10:1 45 15 n.a [6] HCl 2.5 N 20:1 85 90 80 [5] HCl 2.5 N 62.5:1 105 15 19 [6] HCl 2 N 10:1 n.a 45–60 n.a [7]

*Hydrolysis reagents (acid type and concentration), liquor to cellulose ratio (L/C), hydrolysis conditions, and* 

**(%)**

**Utilization**

spheronization, and in capsule filling processes

used for moisture-sensitive pharmaceutical active ingredients

It is the most compressible of the PH products owing the smallest particle size. Well known as excipient for direct compression for granular or crystalline materials. When mixed with PH-101 or PH-102, specific flow and compression characteristics will be obtained. It has applications in roller compaction

used for high moisture-sensitive pharmaceutical active ingredients

used for high moisture-sensitive pharmaceutical active ingredients

variation and to improve content uniformity in direct compression formulations and in wet granulation formulations

tablet weight uniformity. Useful for making smaller tablets and in capsule filling excipient

50 It is most widely used for direct compression tableting, for wet granulation, for

100 It is used as the PH-101, but its larger particle size improves the flow of fine powders

50 It has the same particle size as PH-101 with lower moisture content (3%), so it is

100 It has the same particle size as PH-102. It has lower moisture content (1.5%). It is

50 It has the same particle size as PH-101. It has lower moisture content (1.5%). It is

180 It has a large particle size with increased flowability. It is used to reduce weight

50 It has the same particle size as PH-101 but is denser providing more flowability and

**Duration (minute)**

**References**

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

Other drying techniques may be used, which may require additional screening steps postdrying in order to control particle size distribution [41, 42]. Higher bulk density grades are also available by using specific cellulose pulps (raw material), and median particle sizes below 50 mm can be obtained by further milling MCC [1].

Several studies have compared microcrystalline cellulose with various sources, including different manufacturers and different sites [4, 43–47]. MCC produced by various manufacturers or in various manufacturing sites may have different properties due to the kinds of pulp used as raw materials and their respective manufacturing conditions [2, 4]. A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and viscoelastic properties [48].


#### **Table 1.**

*Pharmaceutical Formulation Design - Recent Practices*

ing in shorter and more crystalline fragments.

**2. Synthesis of MCC**

to remove impurities including lignin, pectin, and wax [36].

but also in structural organization, i.e., regions which are relatively more crystalline or amorphous. The amorphous regions are more prone to hydrolysis by acid result-

Non-woody lignocellulosic materials have also been developed as source of MCC such as cotton linters [5], cotton stalks [6], cotton rags [5], cotton fabric waste [7], cotton wool [8], soybean husk [9], corn cob [10], water hyacinth [11], coconut shells [12], oil palm biomass residue [13, 14], oil palm fronds [15], rice husk [6, 16], sugar cane bagasse [6, 16–20], jute [21, 22], ramie [23], fibers and straw of flax [24], wheat straw [25], sorghum stalks [26], sisal fibers [27] and mangosteen [28], alfa grass fibers [29, 30], soybean hulls [31], orange mesocarp [32], Indian bamboo [33], roselle fiber [34], and alfa fiber [35]. Seed flosses from milkweed pods (*Calotropis procera*), shrubs, and kapok (*Ceiba pentandra*) trees are also known as cellulosic resources. Due to its high purity of alpha cellulose, most seed flosses must be treated

Wooden sources contain cellulose chains which are packed as layers held by cross-linking hydrogen bonds [37]. Chemically it consists of polymeric matrix of lignin, hemicelluloses, and pectin [38]. Different woods considerably possessed different chemical composition of cellulose (including allocations of cellulose, hemicelluloses, and lignin in cell wall) and structural organization as well. Relatively different crystallinity in particular regions is observed as more amorphous according to softwoods (evergreen conifer) and hardwoods which are termed as deciduous broadleaf [4, 37]. The amorphous regions of cellulose provide a more susceptible property for depolymerization by acid hydrolysis. At optimum acid concentration, the process gave shorter and more crystalline fragments such as the MCC [2, 37].

The MCC can be synthesized by different processes including extrusion and enzyme-mediated process [25]. Other studies reported that it can also be synthesized by steam explosion and acid hydrolysis process [5, 6]. The acid hydrolysis process is more preferable due to shorter duration than others. It also offered the possibility to be applied as a continuous process rather than a batch-type process. Limited quantity of consumed acid is also the advantage of the process, while, despite the lower unit cost from less chemicals used, this process offered more fine particles of the MCC as the final product [5]. Fibrous plant pulp is hydrolyzed by mineral acid under heat and pressure. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which soluble components of cellulose such as beta and gamma celluloses, hemicelluloses, and lignin are dissolved with acid and water, are separated out during washing process by water which continued by filtration. The obtained pure alpha cellulose has then been neutralized and given the slurry final product [3]. This suspension is dried to obtain the insoluble white, odorless, tasteless powder, which has later been characterized as MCC [39]. MCC is hygroscopic in

nature, and insoluble in water, but swells when in contact with water.

particle sizes (below 50 μm), further milling MCC can be performed [1].

Another synthesis procedure of the MCC reported by Ohwoavworhua et al. [40] can be concluded as follows: the α-cellulose was hydrolyzed with hydrochloric acid at a boiling temperature of 105° for 15 min. The neutralized slurry obtained from the hydrolysis process was washed, and the fraction passing through 710 μm sieve was stored at room temperature in a desiccator. 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. In order to obtain smaller

**42**

*Hydrolysis reagents (acid type and concentration), liquor to cellulose ratio (L/C), hydrolysis conditions, and yield of microcrystalline cellulose (MCC-Y) hydrolysis reagent.*


**Table 2.** *Types of the commercial microcrystalline cellulose [1, 51].*

It was generally recognized that batch-to-batch variability from a sole manufacturing site was less important than differences observed between multiple sources. Only a few studies have tried to correlate the manufacturing conditions of microcrystalline cellulose with its physicochemical properties and its performance in tableting applications [2, 49, 50]. The effect of some parameters on hydrolysis process on yield value of production is shown in **Tables 1** and **2**.
