**3. Results and discussion**

## **3.1. FT-IR characterization**

As seen in Figure 3 the cellulose allomorphs showed no major differences in the infrared bands, except for the vibration peak at 3423 cm-1 corresponding to intramolecular OH stretching, including hydrogen bonds and at 2893 cm-1 due to CH and CH2 stretching. It is reasonable that these two bands appear displaced due to the rearrangement of the cellulose chains and hydrogen bonding pattern, which is parallel and antiparallel for MCCI and MCCII, respectively. Other main vibrational peaks with virtually no change due to the polymorphic transformation are: 1642 cm-1 corresponding to OH from absorbed water, 1427 cm-1 due to CH2 symmetric bending, 1375 cm-1 due to CH bending, 1330 cm-1 due to OH in plane bending, 1255 cm-1 corresponding to C-O-H bending, 1161 cm-1 due to C-O-C asymmetric stretching (β-glucosidic linkage), 1063 cm-1 due to C-O/C-C stretching and 895 cm-1 due to the asymmetric (rocking) C-1 (β-glucosidic linkage) out-of-plane stretching vibrations. This band is associated to the cellulose II lattice [28, 29].

## **3.2. P-XRD characterization**

It is well known that the acid hydrolysis of powdered -cellulose I reduces the degree of polymerization and in turn increases slightly the degree of crystallinity, true density, compact tensile strength and fragmentation tendency [30, 31]. In this study, the change in the above properties is only attributed to the polymorphic form, which is evidenced in the powder x-Rays difractograms (Figure 4). MCCI displayed the characteristic diffraction peaks of the cellulose I lattice at 14.8, 16.3 and 22.4° 2, corresponding to the 110, 110 and 200 reflections, respectively. A shoulder at 20.4° 2 has also been also identified in some MCCI excipients [32]. MCCII materials showed crystalline peaks at 12, 20 and 22° 2 corresponding to the 110, 110 and 200 reflections, respectively [2]. The degree of crystallinity of MCCI was larger than that of MCCII. It is plausible that the antiparallel arrangement along with the monoclinic unit cell renders a loose molecular packing and hence causes a lower degree of crystallinity. During the soaking step, the alkali could partially attack the glycosidic bonds located on the less ordered surface of the microfibrils since they are more accessible than the glycosidic bonds located in the ordered regions of the microfibrils of cellulose. This might explain why MCCII has a slightly lower degree of crystallinity than MCCI.

**Figure 3.** FT-IR of microcrystalline cellulose allomorphs

**Figure 4.** Powder XRD of microcrystalline cellulose allomorphs

#### **3.3. Powder properties**

34 Cellulose – Medical, Pharmaceutical and Electronic Applications

Tablets, each weighing ~500 mg, were made on a single punch tablet press (060804, Indumec, Itagui, Columbia) using a 13 mm round, flat-faced punches and die set. Five replicates were tested in distilled water at 37 C employing a Hanson disintegrator (39-133-115, Hanson Research Corporation, Northridge, CA, USA) operating at 30

As seen in Figure 3 the cellulose allomorphs showed no major differences in the infrared bands, except for the vibration peak at 3423 cm-1 corresponding to intramolecular OH stretching, including hydrogen bonds and at 2893 cm-1 due to CH and CH2 stretching. It is reasonable that these two bands appear displaced due to the rearrangement of the cellulose chains and hydrogen bonding pattern, which is parallel and antiparallel for MCCI and MCCII, respectively. Other main vibrational peaks with virtually no change due to the polymorphic transformation are: 1642 cm-1 corresponding to OH from absorbed water, 1427 cm-1 due to CH2 symmetric bending, 1375 cm-1 due to CH bending, 1330 cm-1 due to OH in plane bending, 1255 cm-1 corresponding to C-O-H bending, 1161 cm-1 due to C-O-C asymmetric stretching (β-glucosidic linkage), 1063 cm-1 due to C-O/C-C stretching and 895 cm-1 due to the asymmetric (rocking) C-1 (β-glucosidic linkage) out-of-plane stretching

It is well known that the acid hydrolysis of powdered -cellulose I reduces the degree of polymerization and in turn increases slightly the degree of crystallinity, true density, compact tensile strength and fragmentation tendency [30, 31]. In this study, the change in the above properties is only attributed to the polymorphic form, which is evidenced in the powder x-Rays difractograms (Figure 4). MCCI displayed the characteristic diffraction peaks of the cellulose I lattice at 14.8, 16.3 and 22.4° 2, corresponding to the 110, 110 and 200 reflections, respectively. A shoulder at 20.4° 2 has also been also identified in some MCCI excipients [32]. MCCII materials showed crystalline peaks at 12, 20 and 22° 2 corresponding to the 110, 110 and 200 reflections, respectively [2]. The degree of crystallinity of MCCI was larger than that of MCCII. It is plausible that the antiparallel arrangement along with the monoclinic unit cell renders a loose molecular packing and hence causes a lower degree of crystallinity. During the soaking step, the alkali could partially attack the glycosidic bonds located on the less ordered surface of the microfibrils since they are more accessible than the glycosidic bonds located in the ordered regions of the microfibrils of cellulose. This might explain why MCCII has a slightly lower degree of

vibrations. This band is associated to the cellulose II lattice [28, 29].

**2.13. Compact disintegration** 

**3. Results and discussion** 

**3.1. FT-IR characterization** 

**3.2. P-XRD characterization** 

crystallinity than MCCI.

strokes/min.

Figure 5 shows micrographs depicting particle morphologies. It seems to be that the polymorphic transformation had little effect on the morphology of these particles. Both, MCCI and MCCII consisted of aggregated and irregularly-shaped particles with rough surfaces and sharp edges. However, elongated particles were more predominant for MCCI. Table 1 lists the powder properties of these materials. Since the polymorphic transformation did not cause major morphological changes in the particles, the mean particle size of the two polymorphs was comparable. The particle size distribution is depicted in Figure 6. In this case, both materials showed a positively skewed distribution, but MCCII had a slightly larger tendency to have high frequencies in the low particle size region.

MCCI had a larger true density than MCCII. On the other hand, MCCII presented larger bulk and tap densities and consequently lower total powder porosity as compared to MCCI. The great ability of MCCII for particle packing could be due to morphological factors including its lower proportion of elongated particles, lower particle porosity and lower roughness. As a result, upon tapping or application of compression forces, MCCII is more likely to undergo a major volume reduction as indicated by its larger compressibility (52%). All these factors also contributed to an improvement in flow for MCCII. Thus, flowability was 3-fold larger for MCCII than for MCCI.

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 37

The voluminosity of the powder was found by taking the reciprocal of the bulk density and thus, MCCII, due to its large packing ability, presented a lower voluminosity or bulkiness

The degree of polymerization (DP) is an indication of the average polymer length. The lower values of DP obtained for MCCII are probably due to the partial hydrolysis occurring

Property **n MCCI MCCII**  Geometric mean (µm) 1 50.4 ± 7.4 56.5 ± 7.1 Compressibility (%) 1 33 52 Degree of polymerization 3 233.3 ± 0.6 183.6 ± 3.2 Molecular weight (g/mol) 1 37794.6 29743.2 Degree of crystallinity (%) 1 74.3 65.2 Porosity 3 0.78 ± 0.01 0.64 ± 0.01 Bulk density (g/cm3) 3 0.35 ± 0.01 0.55 ± 0.00 Tap density (g/cm3) 3 0.51 ± 0.00 0.76 ± 0.00 Voluminosity (ml/g) 3 2.9 ± 0.1 1.8 ± 0.0 True density (g/cm3) 3 1.578±0.05 1.540 ± 0.03 Flow rate (g/s) 3 1.61 ± 0.43 4.93 ± 0.96 Swelling value (ml/g) 3 0.2 ±0.1 0.8 ±0.0 Specific surface area (m2/g) 3 1.49 ± 0.05 0.53±0.05 Moisture content (%) 1 1.8 2.2

Figure 7 shows the isotherms curves fitted according to the Young-Nelson (YN) model and Table 2 shows the parameters derived from this model. All cellulosic materials exhibited a typical sigmoidal type II isotherm and the sorption and desorption curves showed hysteresis. Hysteresis is defined as the difference between the amount of water desorbed and sorbed. This difference creates a loop in the isotherm and is very common in hydrophilic materials. The amplitude of the loop is observed in Figure 7. This hysteresis was high between 0.2 and 0.7 water activities. Results indicate that hysteresis occurred throughout the sorption range and not just in the capillary condensation region as reported previously [33]. It is well known that the higher moisture content obtained when a polymer is desorbing from a saturated state is due to microcapillary deformation accompanied by the creation of more permanent hydrogen bonds which are no longer attainable in subsequent

re-wetting processes. This phenomenon is known in cellulose as hornification [34].

Once cellulose sorbs water it swells slightly because microcapillaries expand due to the thermal motion of incoming water molecules forming new internal surfaces. Once water is removed, relaxation of the matrix to the original state is prevented. As a result, microcapillaries become greater on desorption compared to the adsorption step. In other

than MCCI.

n=replicate

**Table 1.** Powder properties of microcrystalline celluloses

during the NaOH treatment.

**Figure 5.** Optical micropictures of microcrystalline allomorphs

**Figure 6.** Particle size distribution of microcrystalline celluloses

The voluminosity of the powder was found by taking the reciprocal of the bulk density and thus, MCCII, due to its large packing ability, presented a lower voluminosity or bulkiness than MCCI.

The degree of polymerization (DP) is an indication of the average polymer length. The lower values of DP obtained for MCCII are probably due to the partial hydrolysis occurring during the NaOH treatment.


n=replicate

36 Cellulose – Medical, Pharmaceutical and Electronic Applications

was 3-fold larger for MCCII than for MCCI.

**Figure 5.** Optical micropictures of microcrystalline allomorphs

50

40

30

**Frequency (%)**

20

10

0

**Figure 6.** Particle size distribution of microcrystalline celluloses

MCCI had a larger true density than MCCII. On the other hand, MCCII presented larger bulk and tap densities and consequently lower total powder porosity as compared to MCCI. The great ability of MCCII for particle packing could be due to morphological factors including its lower proportion of elongated particles, lower particle porosity and lower roughness. As a result, upon tapping or application of compression forces, MCCII is more likely to undergo a major volume reduction as indicated by its larger compressibility (52%). All these factors also contributed to an improvement in flow for MCCII. Thus, flowability

MCCI MCCII

MCCI MCCII

0 40 80 120 160 200

**Mean particle size (µm)**

**Table 1.** Powder properties of microcrystalline celluloses

Figure 7 shows the isotherms curves fitted according to the Young-Nelson (YN) model and Table 2 shows the parameters derived from this model. All cellulosic materials exhibited a typical sigmoidal type II isotherm and the sorption and desorption curves showed hysteresis. Hysteresis is defined as the difference between the amount of water desorbed and sorbed. This difference creates a loop in the isotherm and is very common in hydrophilic materials. The amplitude of the loop is observed in Figure 7. This hysteresis was high between 0.2 and 0.7 water activities. Results indicate that hysteresis occurred throughout the sorption range and not just in the capillary condensation region as reported previously [33]. It is well known that the higher moisture content obtained when a polymer is desorbing from a saturated state is due to microcapillary deformation accompanied by the creation of more permanent hydrogen bonds which are no longer attainable in subsequent re-wetting processes. This phenomenon is known in cellulose as hornification [34].

Once cellulose sorbs water it swells slightly because microcapillaries expand due to the thermal motion of incoming water molecules forming new internal surfaces. Once water is removed, relaxation of the matrix to the original state is prevented. As a result, microcapillaries become greater on desorption compared to the adsorption step. In other

words, this hysteresis is caused by structural changes due to the disruption of the hydrogen bonding network of the polymer while interacting with water molecules. Therefore, the extra sorbed water showed by hysteresis is related to the structural or conformational changes of cellulose chains, which expose previously inaccessible high affinity sorption sites [35].

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 39

**Figure 8.** Deconvoluted Young-Nelson model for water sorption of microcrystalline celluloses. M, indicates monolayer formation, P, multilayer formation and A, the fraction attributed to the absorption

In the YN model, the absorbed water has diffused through pores into the core of the particle from the adsorbed monolayer. The monolayer water is then the result of the balance between surface binding forces of the multilayer and water in the core. It is possible that water molecules bind as succeeding layers rather than to empty sites on the surface of the solid. Thus, the formation of a second layer probably starts at lower concentrations than those corresponding to the monolayer formation because the completion of the perfect monolayer would lead to a substantial decrease in entropy, which is very unlikely for natural polymers [36]. During the desorption phase vapor pressure is reduced and water molecules at the surface are removed before diffusion forces pull moisture out of the core of

In the sorption phase, the curves of the monolayer formation presented a type I Langmuir isotherm, whereas the curves of the multilayer sorption showed a type II isotherm. The sorption of monolayer water is almost complete at a water activity of 0.1 for MCCII, whereas for MCCI it increased steadily up to 0.9 water activity. On the other hand, both polymers showed a constant increase of the multilayer formation throughout the whole water activity range. This proves that not all the adsorption sites of the first layer were filled when the formation of multilayers started. For this reason, the external moisture component isotherm had a type II shape and its contribution to the total amount of sorbed moisture increased

The parameters derived from the YN model are shown in Table 2. All samples had a good fit to the model (r2 >0.9990). The A (0.04-0.05) parameter confirmed that layering of water molecules either as a monolayer or multilayers was more prevalent than absorption into the core of the particles (B <0.01). Further, this absorption was more predominant for MCCII than for MCCI. The E and H1-HL values indicate that the formation of a monolayer for MCCII was energetically more favorable than the formation of multilayers. Further, H1-HL was positive, indicating the execution of an endothermic process. The E parameter was low

process in the core of the particles.

the material [37].

with increasing water activities.

Since hysteresis took place mostly at a water activity of 0.2-0.7, it cannot be completely attributed to pore effects (ink bottle pores), but to swelling due to specific interactions of water sorbed in the bulk. The lower hysteresis of MCCI might indicate weaker specific interactions of its hydrophilic sites with water, and consequently, smaller structural reorganization of the chains due to cellulose swelling.

Figure 8 shows the deconvoluted curves for the monolayer and multilayer formation, respectively according to the YN model. It assumes that the monolayer and multilayers of water molecules are formed simultaneously at very low water activities. Furthermore, it considers the absorption of water into the core of particles to be the first step, followed by the layering process on the surface. MCCI showed the lowest fraction of water molecules that formed a monolayer and multilayer, respectively. Further, the amount of water absorbed in the core was considered as negligible. Thus, most of the cellulose water uptake can be attributed to adsorption due to layering.

The YN model also demonstrated that the fraction of water absorbed in the particles core was smaller than the fraction adsorbed as a monolayer and multilayer. Also, the H1-HL value for MCCII was very high, indicating the prevalence for layering formation, which is in line with the high hydrophilicity of this material. MCCII always showed higher affinity for water than MCCI as seen by the higher monolayer and multilayer formation at different water activities. This trend proved that the polymorphic transformation of MCCI into MCCII enhanced the water sorption capacity.

**Figure 7.** Water sorption and desorption isotherms according to the Young-Nelson model.

reorganization of the chains due to cellulose swelling.

can be attributed to adsorption due to layering.

MCCII enhanced the water sorption capacity.

[35].

words, this hysteresis is caused by structural changes due to the disruption of the hydrogen bonding network of the polymer while interacting with water molecules. Therefore, the extra sorbed water showed by hysteresis is related to the structural or conformational changes of cellulose chains, which expose previously inaccessible high affinity sorption sites

Since hysteresis took place mostly at a water activity of 0.2-0.7, it cannot be completely attributed to pore effects (ink bottle pores), but to swelling due to specific interactions of water sorbed in the bulk. The lower hysteresis of MCCI might indicate weaker specific interactions of its hydrophilic sites with water, and consequently, smaller structural

Figure 8 shows the deconvoluted curves for the monolayer and multilayer formation, respectively according to the YN model. It assumes that the monolayer and multilayers of water molecules are formed simultaneously at very low water activities. Furthermore, it considers the absorption of water into the core of particles to be the first step, followed by the layering process on the surface. MCCI showed the lowest fraction of water molecules that formed a monolayer and multilayer, respectively. Further, the amount of water absorbed in the core was considered as negligible. Thus, most of the cellulose water uptake

The YN model also demonstrated that the fraction of water absorbed in the particles core was smaller than the fraction adsorbed as a monolayer and multilayer. Also, the H1-HL value for MCCII was very high, indicating the prevalence for layering formation, which is in line with the high hydrophilicity of this material. MCCII always showed higher affinity for water than MCCI as seen by the higher monolayer and multilayer formation at different water activities. This trend proved that the polymorphic transformation of MCCI into

**Figure 7.** Water sorption and desorption isotherms according to the Young-Nelson model.

**Figure 8.** Deconvoluted Young-Nelson model for water sorption of microcrystalline celluloses. M, indicates monolayer formation, P, multilayer formation and A, the fraction attributed to the absorption process in the core of the particles.

In the YN model, the absorbed water has diffused through pores into the core of the particle from the adsorbed monolayer. The monolayer water is then the result of the balance between surface binding forces of the multilayer and water in the core. It is possible that water molecules bind as succeeding layers rather than to empty sites on the surface of the solid. Thus, the formation of a second layer probably starts at lower concentrations than those corresponding to the monolayer formation because the completion of the perfect monolayer would lead to a substantial decrease in entropy, which is very unlikely for natural polymers [36]. During the desorption phase vapor pressure is reduced and water molecules at the surface are removed before diffusion forces pull moisture out of the core of the material [37].

In the sorption phase, the curves of the monolayer formation presented a type I Langmuir isotherm, whereas the curves of the multilayer sorption showed a type II isotherm. The sorption of monolayer water is almost complete at a water activity of 0.1 for MCCII, whereas for MCCI it increased steadily up to 0.9 water activity. On the other hand, both polymers showed a constant increase of the multilayer formation throughout the whole water activity range. This proves that not all the adsorption sites of the first layer were filled when the formation of multilayers started. For this reason, the external moisture component isotherm had a type II shape and its contribution to the total amount of sorbed moisture increased with increasing water activities.

The parameters derived from the YN model are shown in Table 2. All samples had a good fit to the model (r2 >0.9990). The A (0.04-0.05) parameter confirmed that layering of water molecules either as a monolayer or multilayers was more prevalent than absorption into the core of the particles (B <0.01). Further, this absorption was more predominant for MCCII than for MCCI. The E and H1-HL values indicate that the formation of a monolayer for MCCII was energetically more favorable than the formation of multilayers. Further, H1-HL was positive, indicating the execution of an endothermic process. The E parameter was low

for MCCII indicating that the driving force for water sorption was higher than that of MCCI during the sorption phase. The first water molecule could bind to the 6-hydroxyl group because it is the most exposed hydroxyl group in cellulose [38]. Then, more incoming water molecules could bind to hydroxyl groups located in carbons 2 and 3 of the cellulose monomers.

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 41

Another widely used model for assessing compressibility of powders is the one proposed by Kawakita [17,18]. The "a" parameter indicates that MCCII was more compressible than MCCI. In other words, this material had a larger ability to reduce in volume upon compression. Likewise, the large "b" value for MCCII indicates that a tight packing arrangement in the powder bed generates a large resistant force for volume reduction. However, once consolidation starts, it is easier for MCCII to have a larger compressibility

Figure 9 shows the relationship between compact tensile strength and compression pressure. MCCI formed stronger compacts than MCCII. The magnitude of this difference appears to increase with increasing compression forces. The area under the curve of the tensile strength is an indication of the material compactibility. This compactibility was 4 times larger for MCCI than for MCCII suggesting this polymorphic transformation had a negative effect on the tensile strength of MCCI compacts. The small compact tensile strength values of MCCII are due to its low plastic deforming ability. These results indicate that the tight molecular arrangement of the chains and the higher plastic deforming ability of MCCI facilitate the formation of hydrogen bonding upon compression resulting in the formation

Model **Parameter MCCI MCCII**

Py (MPa) 92.6 144 D0 0.22 0.36 Da 0.48 0.45 Db 0.22 0.10 r2 0.9910 0.9850

> A 0.33 0.52 B 0.03 0.12 r2 0.9980 0.9999

AUCTS 885.1 180.6 Friability (%) 0.11 0.23 SRS (%) 7.3 15.6 D. Pot. (%) 24 20

LSR 0.38 0.36

Py, powder yield pressure; D0, initial rearrangement as a result of die filling; Da, total packing at low pressures; Particle rearrangement/fragmentation at early compression stages; a, Compressibility parameter; b, Indicates ease of compression; LSR, lubricant sensitivity ratio; SRS, strain rate sensitivity; D. Pot, dilution potential for acetaminophen;

**Table 3.** Parameters obtained from the Heckel and Kawakita models and other tableting tests

than MCCI.

of strong compacts.

Heckel

Kawakita

Test

AUCTS, area under the tensile strength curve.

**5. Compactibility studies** 


SD, standard deviation, A, fraction of adsorbed water; B, fraction of absorbed water;

E, equilibrium constant between the monolayer and liquid water; H1-Hl, heat difference between absorption and condensation of water; r2 coefficient of determination.

**Table 2.** Parameters obtained from the Young-Nelson model

The degree of crystallinity of MCCI was higher than that of MCCII. Therefore, as expected the less crystalline MCCII presented more water sorption sites due to its large amorphous component as compared to MCCI.

## **4. Compression studies**

Although initially developed for metals, the Heckel analysis is widely used to assess the compressibility of pharmaceutical powders. Table 3 lists the Heckel analysis results. The yield pressure value, Py, which is obtained from the inverse of the slope of the linear portion of the Heckel curve, refers to the pressure at which the material begins to deform plastically. A plastic deformation implies deformation and sliding of the crystals planes that consolidate the particles. Usually, a plastic deformation causes a minimum change in the surface area available for particle binding. On the other hand, brittle materials require extensive fragmentation for the formation of available surfaces for particle binding. In this case, large particles brake down into smaller particles upon compression. In general, the lower the Py value, the higher the ductility of the material. In the present study, MCCI showed a low value, whereas MCCII exhibited a high Py value (∼93 MPa and 144 MPa, respectively). Therefore, MCCII is considered as less ductile than MCCI.

The D0, Da and Db parameters, calculated from the Heckel plots, represent the initial packing of the material upon die filling, total packing at low pressures, and the degree of powder bed arrangement due to fragmentation at low pressures, respectively. The D0 values follow the same trend than the bulk density values suggesting that the polymorphic transformation of MCCI into MCCII increased the ability of this material for packing. On the contrary, the total powder packing at low compression pressures remained unchanged. The Db value as expected was higher for MCCI due to the less tendency to pack in the powder bed and thus, its particles were more able to rearrange at low compression forces.

Another widely used model for assessing compressibility of powders is the one proposed by Kawakita [17,18]. The "a" parameter indicates that MCCII was more compressible than MCCI. In other words, this material had a larger ability to reduce in volume upon compression. Likewise, the large "b" value for MCCII indicates that a tight packing arrangement in the powder bed generates a large resistant force for volume reduction. However, once consolidation starts, it is easier for MCCII to have a larger compressibility than MCCI.

## **5. Compactibility studies**

40 Cellulose – Medical, Pharmaceutical and Electronic Applications

condensation of water; r2 coefficient of determination.

component as compared to MCCI.

**4. Compression studies** 

**Table 2.** Parameters obtained from the Young-Nelson model

Therefore, MCCII is considered as less ductile than MCCI.

its particles were more able to rearrange at low compression forces.

monomers.

for MCCII indicating that the driving force for water sorption was higher than that of MCCI during the sorption phase. The first water molecule could bind to the 6-hydroxyl group because it is the most exposed hydroxyl group in cellulose [38]. Then, more incoming water molecules could bind to hydroxyl groups located in carbons 2 and 3 of the cellulose

**A B EH1-HL** 

MCCI 0.04 ± 0.00 0.00 ± 0.00 0.26 ± 0.02 3.3 0.9990 MCCII 0.05 ± 0.01 0.01 ± 0.00 0.07 ± 0.05 7.4 0.9997

The degree of crystallinity of MCCI was higher than that of MCCII. Therefore, as expected the less crystalline MCCII presented more water sorption sites due to its large amorphous

Although initially developed for metals, the Heckel analysis is widely used to assess the compressibility of pharmaceutical powders. Table 3 lists the Heckel analysis results. The yield pressure value, Py, which is obtained from the inverse of the slope of the linear portion of the Heckel curve, refers to the pressure at which the material begins to deform plastically. A plastic deformation implies deformation and sliding of the crystals planes that consolidate the particles. Usually, a plastic deformation causes a minimum change in the surface area available for particle binding. On the other hand, brittle materials require extensive fragmentation for the formation of available surfaces for particle binding. In this case, large particles brake down into smaller particles upon compression. In general, the lower the Py value, the higher the ductility of the material. In the present study, MCCI showed a low value, whereas MCCII exhibited a high Py value (∼93 MPa and 144 MPa, respectively).

The D0, Da and Db parameters, calculated from the Heckel plots, represent the initial packing of the material upon die filling, total packing at low pressures, and the degree of powder bed arrangement due to fragmentation at low pressures, respectively. The D0 values follow the same trend than the bulk density values suggesting that the polymorphic transformation of MCCI into MCCII increased the ability of this material for packing. On the contrary, the total powder packing at low compression pressures remained unchanged. The Db value as expected was higher for MCCI due to the less tendency to pack in the powder bed and thus,

E, equilibrium constant between the monolayer and liquid water; H1-Hl, heat difference between absorption and

**Sample Mean ± SD Mean ± SD Mean ± SD kJ/mol**

SD, standard deviation, A, fraction of adsorbed water; B, fraction of absorbed water;

**r2** 

Figure 9 shows the relationship between compact tensile strength and compression pressure. MCCI formed stronger compacts than MCCII. The magnitude of this difference appears to increase with increasing compression forces. The area under the curve of the tensile strength is an indication of the material compactibility. This compactibility was 4 times larger for MCCI than for MCCII suggesting this polymorphic transformation had a negative effect on the tensile strength of MCCI compacts. The small compact tensile strength values of MCCII are due to its low plastic deforming ability. These results indicate that the tight molecular arrangement of the chains and the higher plastic deforming ability of MCCI facilitate the formation of hydrogen bonding upon compression resulting in the formation of strong compacts.


Py, powder yield pressure; D0, initial rearrangement as a result of die filling; Da, total packing at low pressures; Particle rearrangement/fragmentation at early compression stages; a, Compressibility parameter; b, Indicates ease of compression; LSR, lubricant sensitivity ratio; SRS, strain rate sensitivity; D. Pot, dilution potential for acetaminophen; AUCTS, area under the tensile strength curve.

**Table 3.** Parameters obtained from the Heckel and Kawakita models and other tableting tests

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 43

most highly deforming material. Therefore, MCCI compactibility was reduced to a value comparable to that of MCCII. Moreover, the more fragmenting character of MCCII makes it able to create a large number of binding surfaces which counteract the coating effect exerted by magnesium stearate. In other words, magnesium stearate coats easily the surface of MCCI particles and thereby restricts the contact points between particles resulting in compacts of low strength. Thus, the lubricant film around particles in more fragmenting

Independent of compact porosity, compact disintegration time was less than 20 s for MCCII (Fig. 10). Only compacts of MCCI made at ~40 MPa passed the test requiring disintegration times of less than 30 min. The rapid disintegration times of MCCII are due to its larger swelling value and larger affinity for water as compared to MCCI. Further, it is possible that the low degree of crystallinity of MCCII played an important role in its rapid disintegration. The effect of compact porosity was considered as negligible since all compacts were made at 10-20% porosity. These results indicate that when MCCI is employed as excipient for making tablets, it always requires the addition of a superdisintegrant, which is a material with a large affinity for water that enhances compact disintegration. On the contrary, MCCII

The polymorphic transformation had a major effect on the degree of polymerization, degree of crystallinity, packing tendency, bulk and tap densities, voluminosity, swelling ability and water sorption rate of microcrystalline cellulose. MCCII exhibited a faster disintegration ability, but lower compactibility than MCCI due to its large amorphous component. However, when MCCII was mixed and compressed with acetaminophen it was as

materials such as MCCII is not complete easing the formation of hard compacts.

does not require that ingredient due to its intrinsic disintegrating properties.

**Figure 10.** Compact disintegration time of the cellulosic materials.

**6. Conclusions** 

**5.4. Compact disintegration** 

**Figure 9.** Compact tensile strength of the cellulose allomorphs

## **5.1. Dilution potential**

To assess the effect of a poorly compressible substance on the compactibility of cellulose, compacts containing different weight ratios of the test material and acetaminophen were prepared and their crushing strength was determined. In this case, the crushing strength of the powder mixtures were plotted against the mass fraction of excipient and the resulting straight lines were interpolated to the X-axis to find the dilution potential. The dilution potential of MCCII (20%) was comparable to that of MCCI (24%). These results clearly suggest that MCCII and MCCI serve as effective binders and offer potential to produce tablets with poorly compressible drugs by direct compression. In fact, MCCI showed the highest compactibility but presented a comparable dilution potential for acetaminophen. This indicates that the presence of a poorly compressible drug affected the compactibility of MCCI much more than that of MCCII since a larger dilution potential was expected for MCCI.

## **5.2. Compact friability**

Tablets prepared using 150 MPa compression pressures were tested for friability. All tablets had less than 1% friability indicating an optimum strength for handling and shipping. These results correlate well with the tensile strength results shown in Fig. 7. These findings clearly suggest that MCCI and MCCII serve as effective binders and offer potential to produce compacts with poorly compressible drugs by direct compression.

## **5.3. Lubricant sensitivity**

Lubricant sensitivity was tested with magnesium stearate at a 1.0% w/w level in compacts made at 60 MPa of compression pressure. The presence of a surrounding layer of this hydrophobic lubricant had a large detrimental effect on MCCI since this material was the most highly deforming material. Therefore, MCCI compactibility was reduced to a value comparable to that of MCCII. Moreover, the more fragmenting character of MCCII makes it able to create a large number of binding surfaces which counteract the coating effect exerted by magnesium stearate. In other words, magnesium stearate coats easily the surface of MCCI particles and thereby restricts the contact points between particles resulting in compacts of low strength. Thus, the lubricant film around particles in more fragmenting materials such as MCCII is not complete easing the formation of hard compacts.

## **5.4. Compact disintegration**

42 Cellulose – Medical, Pharmaceutical and Electronic Applications

**Figure 9.** Compact tensile strength of the cellulose allomorphs

To assess the effect of a poorly compressible substance on the compactibility of cellulose, compacts containing different weight ratios of the test material and acetaminophen were prepared and their crushing strength was determined. In this case, the crushing strength of the powder mixtures were plotted against the mass fraction of excipient and the resulting straight lines were interpolated to the X-axis to find the dilution potential. The dilution potential of MCCII (20%) was comparable to that of MCCI (24%). These results clearly suggest that MCCII and MCCI serve as effective binders and offer potential to produce tablets with poorly compressible drugs by direct compression. In fact, MCCI showed the highest compactibility but presented a comparable dilution potential for acetaminophen. This indicates that the presence of a poorly compressible drug affected the compactibility of MCCI much more than that of MCCII since a larger dilution potential was expected for

Tablets prepared using 150 MPa compression pressures were tested for friability. All tablets had less than 1% friability indicating an optimum strength for handling and shipping. These results correlate well with the tensile strength results shown in Fig. 7. These findings clearly suggest that MCCI and MCCII serve as effective binders and offer potential to produce

Lubricant sensitivity was tested with magnesium stearate at a 1.0% w/w level in compacts made at 60 MPa of compression pressure. The presence of a surrounding layer of this hydrophobic lubricant had a large detrimental effect on MCCI since this material was the

compacts with poorly compressible drugs by direct compression.

**5.1. Dilution potential** 

**5.2. Compact friability** 

**5.3. Lubricant sensitivity** 

MCCI.

Independent of compact porosity, compact disintegration time was less than 20 s for MCCII (Fig. 10). Only compacts of MCCI made at ~40 MPa passed the test requiring disintegration times of less than 30 min. The rapid disintegration times of MCCII are due to its larger swelling value and larger affinity for water as compared to MCCI. Further, it is possible that the low degree of crystallinity of MCCII played an important role in its rapid disintegration. The effect of compact porosity was considered as negligible since all compacts were made at 10-20% porosity. These results indicate that when MCCI is employed as excipient for making tablets, it always requires the addition of a superdisintegrant, which is a material with a large affinity for water that enhances compact disintegration. On the contrary, MCCII does not require that ingredient due to its intrinsic disintegrating properties.

**Figure 10.** Compact disintegration time of the cellulosic materials.

#### **6. Conclusions**

The polymorphic transformation had a major effect on the degree of polymerization, degree of crystallinity, packing tendency, bulk and tap densities, voluminosity, swelling ability and water sorption rate of microcrystalline cellulose. MCCII exhibited a faster disintegration ability, but lower compactibility than MCCI due to its large amorphous component. However, when MCCII was mixed and compressed with acetaminophen it was as compactable as MCCI and possessed a comparable acetaminophen loading capacity and lubricant sensitivity as those of MCCI.

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 45

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Particle morphology and particle size were not affected, but compact tensile strength was highly affected by the polymorphic transformation. Most of the resulting particle and tableting properties depended on the polymorphic form of MCC. For this reason, it is important to select the right crystalline form of MCC before formulating a drug in a solid dosage form since it could affect the overall particle and tableting properties of the mixture.

Cellulosic excipients are hydrophilic materials and the polymorphic transformation caused differences in the hydrophilic properties of cellulose. Most of the water sorption isotherms exhibited a type II sigmoid shape and MCCII presented the largest water uptake by absorption into the core of the particles.

Cellulosic materials showed a hysteresis loops which were caused by capillary shrinking during the desorption step. The YN model assume sorption and desorption as a dynamic process, in which the primary sorption sites are filled up throughout the whole water activity range and do not require the formation of a complete monolayer to form a multilayer.
