**3. Physicochemical properties of MCC**

#### **3.1 Moisture content**

A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and *viscoelastic* properties [48, 52, 53]. Moisture within the pores of MCC may act as an internal lubricant, reduce frictional forces, and facilitate slippage and plastic flow within the individual microcrystals [54, 55]. The lubricating properties of water may also reduce tablet density variation by providing a better transmission of the compression force through the compact and by decreasing the adhesion of the tablet to the die wall [55, 56]. Compressibility of MCC depends on moisture content, which means that when MCC having different moisture content is compressed with the same pressure, it may not result in the same compact porosity. It is very well known that compaction pressure required to produce certain porosity (or solid fraction) decreases with increasing moisture content. Sun reported that below 3% water content, the compaction properties of MCC were insensitive to variation of moisture [53]. However up to an optimum level, an increase of moisture will increase the tablet strength of most excipients. This can be explained by the fact that molecular binding in water vapor layers reduces interparticular surface distances, hence increasing intermolecular attraction forces [56].

The storage conditions of the MCC compacts also play an important role, as an increase in relative humidity will negatively impact tablet strength [47]. However this softening is often reversible when tablets are removed from the humid environment [1]. Fundamental forces affecting powder flow are cohesion and friction [55]. Frictional forces and electrostatic charges between particles during the compression process will decrease as moisture content increases. Moisture may also play a role in increasing cohesion forces inside particles due to the creation of liquid or even solid bridges. In the case of MCC as excipient, significant changes in flowability were observed when increasing moisture contents were applied which resulted in changes in powder cohesiveness. This phenomenon was described by the increase in compressibility index and the shear cell [48].

#### **3.2 Particle size**

Particle size has a very little effect on the tabletability of neat MCC, i.e., not lubricated nor blended with other excipients or active pharmaceutical ingredients (APIs) [57–60]. MCC particle size and moisture content are often considered as the most important CMAs for tableting performance [61]. Considering that the brittleductile transition diameter (Dcrit) of MCC is 1949 mm, standard MCC grades, having particle sizes below Dcrit, should all deform plastically when compression pressure exceeds yield pressure. Coarser grades of MCC, characterized by a smaller envelope surface area, have been reported to be more lubricant sensitive than finer MCC [52, 58, 62, 63]. In complete formulations finer MCCs would therefore promote tablet (compact) strength [64, 65]. Reducing the particle size of MCC

**45**

**3.4 Crystallinity**

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

drug products [68].

exceed 4.

MCC [51].

compactable properties [51].

the drug dissolution which may due to porosity [70].

**3.3 Particle morphology**

will increase cohesiveness and hence as a consequence surely affect its flowability. Kushner et al. reported that different particle sizes of excipient may impact tablet characteristics including hardness, friability, disintegration, and content uniformity [66]. Improved flowability will be obtained when coarser MCCs are employed as well as reduction in tablet weight variation [67]. Hlinak et al. suggested that particle size may also impact wetting properties, dissolution of the API, and stability of

Albers et al. evaluated the tableting properties of three batches from five different brands MCC type 101 [43]. Batches using single manufacturer source produced more similar tablet characteristic than those using samples from various sources. Statistically significant differences were also observed within single brands of MCC. From a different batch of MCC studied, the greatest differences in powder properties were observed in the median particle size and specific surface area. Despite the lower median particle size of Avicel PH-101 (FMC), this MCC was described as easy flowing powder compared to other brands as illustrated by its low compressibility index and high values of shear cell flow functions (FFc) which

Williams et al. used tableting indices to investigate the compaction properties of MCC types 101 and 102 (median particle size of about 50 and 100 mm, respectively), each type being represented by two batches from five different sources [47]. The lubricant sensitivity of MCC expressed as its compressibility decreased when this excipient was mixed with other materials such as magnesium stearate. Another factor affecting lubricant sensitivity of MCC is the particle size. A higher particle size of MCC, Avicel PH-200 (180 microns), is more sensitive to lubricant than Avicel PH-101 (50 microns). At the same concentration, the lubricant covers more efficiently a larger particle size of MCC (PH-200) than that of the smaller particle size of MCC (PH-101) due to a larger particle surface area of smaller particles of

Compactability of the MCC particles is affected by the porosity. Avicel PH-101, Avicel PH-102, and Avicel PH-200 as marketed products of MCC owing almost the same density showed the same compressibility despite their mean particle size which varies from 50 to 180 microns. Avicel PH-301 (50 microns) and Avicel PH-302 (90 microns) which physically are more dense revealed less compressible or

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

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

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

*Pharmaceutical Formulation Design - Recent Practices*

**3. Physicochemical properties of MCC**

**3.1 Moisture content**

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

A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and *viscoelastic* properties [48, 52, 53]. Moisture within the pores of MCC may act as an internal lubricant, reduce frictional forces, and facilitate slippage and plastic flow within the individual microcrystals [54, 55]. The lubricating properties of water may also reduce tablet density variation by providing a better transmission of the compression force through the compact and by decreasing the adhesion of the tablet to the die wall [55, 56]. Compressibility of MCC depends on moisture content, which means that when MCC having different moisture content is compressed with the same pressure, it may not result in the same compact porosity. It is very well known that compaction pressure required to produce certain porosity (or solid fraction) decreases with increasing moisture content. Sun reported that below 3% water content, the compaction properties of MCC were insensitive to variation of moisture [53]. However up to an optimum level, an increase of moisture will increase the tablet strength of most excipients. This can be explained by the fact that molecular binding in water vapor layers reduces interparticular surface distances, hence increasing intermolecular attraction forces [56]. The storage conditions of the MCC compacts also play an important role, as an increase in relative humidity will negatively impact tablet strength [47]. However this softening is often reversible when tablets are removed from the humid environment [1]. Fundamental forces affecting powder flow are cohesion and friction [55]. Frictional forces and electrostatic charges between particles during the compression process will decrease as moisture content increases. Moisture may also play a role in increasing cohesion forces inside particles due to the creation of liquid or even solid bridges. In the case of MCC as excipient, significant changes in flowability were observed when increasing moisture contents were applied which resulted in changes in powder cohesiveness. This phenomenon was described by the increase in compressibility index and the

Particle size has a very little effect on the tabletability of neat MCC, i.e., not lubricated nor blended with other excipients or active pharmaceutical ingredients (APIs) [57–60]. MCC particle size and moisture content are often considered as the most important CMAs for tableting performance [61]. Considering that the brittleductile transition diameter (Dcrit) of MCC is 1949 mm, standard MCC grades, having particle sizes below Dcrit, should all deform plastically when compression pressure exceeds yield pressure. Coarser grades of MCC, characterized by a smaller envelope surface area, have been reported to be more lubricant sensitive than finer MCC [52, 58, 62, 63]. In complete formulations finer MCCs would therefore promote tablet (compact) strength [64, 65]. Reducing the particle size of MCC

process on yield value of production is shown in **Tables 1** and **2**.

**44**

shear cell [48].

**3.2 Particle size**

will increase cohesiveness and hence as a consequence surely affect its flowability. Kushner et al. reported that different particle sizes of excipient may impact tablet characteristics including hardness, friability, disintegration, and content uniformity [66]. Improved flowability will be obtained when coarser MCCs are employed as well as reduction in tablet weight variation [67]. Hlinak et al. suggested that particle size may also impact wetting properties, dissolution of the API, and stability of drug products [68].

Albers et al. evaluated the tableting properties of three batches from five different brands MCC type 101 [43]. Batches using single manufacturer source produced more similar tablet characteristic than those using samples from various sources. Statistically significant differences were also observed within single brands of MCC. From a different batch of MCC studied, the greatest differences in powder properties were observed in the median particle size and specific surface area. Despite the lower median particle size of Avicel PH-101 (FMC), this MCC was described as easy flowing powder compared to other brands as illustrated by its low compressibility index and high values of shear cell flow functions (FFc) which exceed 4.

Williams et al. used tableting indices to investigate the compaction properties of MCC types 101 and 102 (median particle size of about 50 and 100 mm, respectively), each type being represented by two batches from five different sources [47]. The lubricant sensitivity of MCC expressed as its compressibility decreased when this excipient was mixed with other materials such as magnesium stearate. Another factor affecting lubricant sensitivity of MCC is the particle size. A higher particle size of MCC, Avicel PH-200 (180 microns), is more sensitive to lubricant than Avicel PH-101 (50 microns). At the same concentration, the lubricant covers more efficiently a larger particle size of MCC (PH-200) than that of the smaller particle size of MCC (PH-101) due to a larger particle surface area of smaller particles of MCC [51].

Compactability of the MCC particles is affected by the porosity. Avicel PH-101, Avicel PH-102, and Avicel PH-200 as marketed products of MCC owing almost the same density showed the same compressibility despite their mean particle size which varies from 50 to 180 microns. Avicel PH-301 (50 microns) and Avicel PH-302 (90 microns) which physically are more dense revealed less compressible or compactable properties [51].
