**3.3 Particle morphology**

Obae et al. suggested that MCC morphology, described by the length of particles (L) and their width (D), was one of the most important factors influencing tabletability [69]. Rod-shaped particles which are fibrous and having higher L/D ratios resulted in higher tablet strengths than round-shaped particles. Other physicochemical properties of MCC including moisture content, bulk density, and specific surface area did not correlate well with tensile strength of obtained tablet. Obae et al. illustrated the reduction of bulk density and flowability and the increase of specific surface area when the L/D ratio increased. This may be due to the property of the particles which is more fibrous. MCC morphology was found to be affecting the drug dissolution which may due to porosity [70].

#### **3.4 Crystallinity**

Modifying the hydrolysis conditions, including temperature, time, and acid concentration, also has a very little impact on the degree of crystallinity, i.e., the regularity of the arrangement of the cellulose polymer chains [2, 50]. This

observation indicates that crystallinity cannot be controlled at the hydrolysis stage. Crystallinity appears to be more dependent on pulp source rather than on processing conditions [4], which is consistent with the method of MCC manufacture where the acid preferentially attacks the (pulp dependent) amorphous regions.

The total amount of sorbed water in MCC is proportional to the fraction of amorphous material [48, 54, 55]. Therefore MCC powders with a lower degree of crystallinity may contain more water than their counterparts with a higher degree. If low-crystallinity MCC preferentially binds more water, moisture-sensitive APIs may exhibit lower rates of degradation [71]. Despite the controversial impact of crystallinity, it may influence the adsorption of water on cellulose microfibrils, which may in turn influence flowability, tabletability, and stability of the drug product.

## **3.5 Bulk density**

Mostly, direct compression excipients are spray-dried; therefore porous structure was produced as a result. This property is characterized by a relatively low bulk density. Increase in porosity (lower density) facilitates higher compressibility, i.e., the densification of a powder bed due to the application of a stress [56]. The improved compressibility of plastically deforming materials, such as MCC, might then result in improved tabletability as a result of the increased bonding surface area [72]. The higher roughness of low density MCC particles may also contribute to particle interlocking [73]. Low bulk density MCC will provide higher dilution potential and hence better counteract the poor tableting properties of APIs. Granulation or drying as preprocesses of tablet formulation will densify MCC hence less tabletable than the original porous MCC [74, 75]. It can therefore be generalized that a decrease in bulk density improves tabletability; however, it will often hinder flowability [62].

#### **3.6 Degree of polymerization**

The degree of polymerization (DP) expresses the number of glucose units (C6H10O5) in the cellulose chain. It decreases exponentially as a function of hydrolysis conditions, including temperature, acid concentration, and time of reaction. The rate of hydrolysis slows down to a certain value which is stated as level-off degree of polymerization (LODP). The LODP value is specific for a particular pulp, and it is usually between the range of 200 and 300 [44, 61], e.g., 180–210 range for hardwood pulps and 210–250 for softwood pulps. Theoretically, to obtain a certain degree of polymerization which is higher than the LODP value, hydrolysis process could be terminated at any time. However, due to the exponential decay of DP, this termination is neither a robust nor a reproducible approach. The degree of polymerization is used as an identity test, as pharmacopoeial MCC is defined by a DP below 350 glucose units, compared to DPs in the order of 10,000 units for the original native cellulose [1].

The correlation between the degree of polymerization (DP) of MCC and its tabletability has not been explored yet. Therefore, it is merely an identity test to distinguish the tabletability of MCC (DP < 350) compared with powdered cellulose (DP > 440). Dybowski showed that the origin of the raw materials and the production method of MCC more decisively influence the physical characteristics than DP. DP value is a criterion used to guide the manufacturer about hydrolysis of MCC, whereas for the user it is a characteristic to distinguish between properties of MCC and powdered cellulose.

**47**

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

cellulose has a higher DP than MCC but is not as tabletable [1].

**3.7 Effect of lignin**

hence drug release rate.

differences still exist among them [44].

**4. MCC as pharmaceutical excipients**

lubricants, antiadhesives, glidants

Excipients classified as:

Wood pulps with high bulk density grades which can be characterized by lower level-off DP should not be directly compared with standard grades. This parameter reflects the lack of distinction between the degree of polymerization (DP) and level-off degree of polymerization (LODP). LODP is typical of a particular raw material, with a common value between the range of 200 and 300 [44]. Cellulose having LODP value at this range usually difficult for further hydrolysis. In contrast, cellulose materials with DP values higher than the level-off degree of polymerization plateau are more difficult to control due to their greater sensitivity to hydrolysis. Owing LODP above 200–300, the MCC remains to be more fibrous, which would result in a lower bulk density, with improved tabletability, but would hinder powder flow [49, 50]. Below the LODP MCC is less fibrous, denser, and less tabletable. Tabletability is not related to a particular DP value; as an example powdered

Landín et al. compared four brands of MCC [45]. Different woods used as raw materials, i.e., hardwood versus softwood, suggested differences in lignin and hemicelluloses composition. The non-cellulose component has also significantly different manufacturing process intensities which resulted in variable suggestive composition and potentially varying qualities of product. Landín et al. found that lignin content increased the dissolution rate of prednisone [46]. Lignin being hydrophobic may alter cellulose–cellulose and/or cellulose–API interactions and

Thoorens et al. [37] studied that differences in packing and flow properties which are shown by scanning electron micrographs from Avicel PH-101 and Avicel PH-102 were attributed to differences in moisture content, particle shape, and particle size distribution. Tabletability which also varied among the MCC samples were attributed to the differences in moisture content and the internal structure of the particles. These are mostly caused by different processing conditions which are specific to each manufacturer. However, the impacts of crystallinity and particle morphology are negligible. Significant differences in lubricant sensitivity, compressibility, and tablet disintegration were also noted between MCCs due to various manufacturing processes by different manufacturers. Variability between lots from the same manufacturer was found to give a smaller effect on properties of MCC product. A current study from Doelker concluded that even if all of various MCCs comply with compendial specifications, large

According to the International Pharmaceutical Excipient Council (IPEC), excipients are the process aids or any substances other than the active pharmaceutical ingredient that are included in pharmaceutical dosage forms. The functionalities of excipient are to impart weight, consistency, and volume which allow accuracy of dose, improve solubility, and in the end increase stability. It can also be proposed to enhance bioavailability, modifying drug release and used in product quick identifi-

1.Primary excipients: diluents (filler), binders (adhesives), disintegrants,

cation, increase patient acceptability, and facilitate dosage form design.

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

Wood pulps with high bulk density grades which can be characterized by lower level-off DP should not be directly compared with standard grades. This parameter reflects the lack of distinction between the degree of polymerization (DP) and level-off degree of polymerization (LODP). LODP is typical of a particular raw material, with a common value between the range of 200 and 300 [44]. Cellulose having LODP value at this range usually difficult for further hydrolysis. In contrast, cellulose materials with DP values higher than the level-off degree of polymerization plateau are more difficult to control due to their greater sensitivity to hydrolysis. Owing LODP above 200–300, the MCC remains to be more fibrous, which would result in a lower bulk density, with improved tabletability, but would hinder powder flow [49, 50]. Below the LODP MCC is less fibrous, denser, and less tabletable. Tabletability is not related to a particular DP value; as an example powdered cellulose has a higher DP than MCC but is not as tabletable [1].

## **3.7 Effect of lignin**

*Pharmaceutical Formulation Design - Recent Practices*

regions.

product.

**3.5 Bulk density**

flowability [62].

native cellulose [1].

and powdered cellulose.

**3.6 Degree of polymerization**

observation indicates that crystallinity cannot be controlled at the hydrolysis stage. Crystallinity appears to be more dependent on pulp source rather than on processing conditions [4], which is consistent with the method of MCC manufacture where the acid preferentially attacks the (pulp dependent) amorphous

The total amount of sorbed water in MCC is proportional to the fraction of amorphous material [48, 54, 55]. Therefore MCC powders with a lower degree of crystallinity may contain more water than their counterparts with a higher degree. If low-crystallinity MCC preferentially binds more water, moisture-sensitive APIs may exhibit lower rates of degradation [71]. Despite the controversial impact of crystallinity, it may influence the adsorption of water on cellulose microfibrils, which may in turn influence flowability, tabletability, and stability of the drug

Mostly, direct compression excipients are spray-dried; therefore porous structure was produced as a result. This property is characterized by a relatively low bulk density. Increase in porosity (lower density) facilitates higher compressibility, i.e., the densification of a powder bed due to the application of a stress [56]. The improved compressibility of plastically deforming materials, such as MCC, might then result in improved tabletability as a result of the increased bonding surface area [72]. The higher roughness of low density MCC particles may also contribute to particle interlocking [73]. Low bulk density MCC will provide higher dilution potential and hence better counteract the poor tableting properties of APIs. Granulation or drying as preprocesses of tablet formulation will densify MCC hence less tabletable than the original porous MCC [74, 75]. It can therefore be generalized that a decrease in bulk density improves tabletability; however, it will often hinder

The degree of polymerization (DP) expresses the number of glucose units (C6H10O5) in the cellulose chain. It decreases exponentially as a function of hydrolysis conditions, including temperature, acid concentration, and time of reaction. The rate of hydrolysis slows down to a certain value which is stated as level-off degree of polymerization (LODP). The LODP value is specific for a particular pulp, and it is usually between the range of 200 and 300 [44, 61], e.g., 180–210 range for hardwood pulps and 210–250 for softwood pulps. Theoretically, to obtain a certain degree of polymerization which is higher than the LODP value, hydrolysis process could be terminated at any time. However, due to the exponential decay of DP, this termination is neither a robust nor a reproducible approach. The degree of polymerization is used as an identity test, as pharmacopoeial MCC is defined by a DP below 350 glucose units, compared to DPs in the order of 10,000 units for the original

The correlation between the degree of polymerization (DP) of MCC and its tabletability has not been explored yet. Therefore, it is merely an identity test to distinguish the tabletability of MCC (DP < 350) compared with powdered cellulose (DP > 440). Dybowski showed that the origin of the raw materials and the production method of MCC more decisively influence the physical characteristics than DP. DP value is a criterion used to guide the manufacturer about hydrolysis of MCC, whereas for the user it is a characteristic to distinguish between properties of MCC

**46**

Landín et al. compared four brands of MCC [45]. Different woods used as raw materials, i.e., hardwood versus softwood, suggested differences in lignin and hemicelluloses composition. The non-cellulose component has also significantly different manufacturing process intensities which resulted in variable suggestive composition and potentially varying qualities of product. Landín et al. found that lignin content increased the dissolution rate of prednisone [46]. Lignin being hydrophobic may alter cellulose–cellulose and/or cellulose–API interactions and hence drug release rate.

Thoorens et al. [37] studied that differences in packing and flow properties which are shown by scanning electron micrographs from Avicel PH-101 and Avicel PH-102 were attributed to differences in moisture content, particle shape, and particle size distribution. Tabletability which also varied among the MCC samples were attributed to the differences in moisture content and the internal structure of the particles. These are mostly caused by different processing conditions which are specific to each manufacturer. However, the impacts of crystallinity and particle morphology are negligible. Significant differences in lubricant sensitivity, compressibility, and tablet disintegration were also noted between MCCs due to various manufacturing processes by different manufacturers. Variability between lots from the same manufacturer was found to give a smaller effect on properties of MCC product. A current study from Doelker concluded that even if all of various MCCs comply with compendial specifications, large differences still exist among them [44].
