**1. Introduction**

Cellulose is the most abundant natural linear polymer. It consists of 1,4-linked-β-D-glucose units and is known to exist in the following distinct allomorphs: I (from algae and bacteria), I (from superior plants), II (the most stable form produced by mercerization), IIII and IIIII (prepared from ammonia at -30 ºC), and IVI and IVII (produced at 260 ºC in glycerol). Each allomorph differs in its physicochemical properties [1,2]. Cellulose III is formed when native cellulose is treated with liquid ammonia at low temperatures, whereas cellulose IV is obtained by treatment of regenerated cellulose at high temperatures (Figure 1) [3]. However, the last two forms have no pharmaceutical applications.

Of these, the cellulose I (MCCI) allomorph is the most prevalent form and cellulose II is the most stable form [4]. MCCI can be converted to MCCII, but not vice versa [5,6]. As shown in Figure 2, in cellulose I (MCCI), the chain orientation is exclusively parallel [3], whereas in cellulose II (MCCII) the chains are arranged in an anti-parallel orientation.

Commercial microcrystalline cellulose (MCCI) contains the cellulose I lattice. It is obtained from wood pulp by treatment with dilute strong mineral acids (HCl, H2SO4, HNO3) at boiling temperatures until the degree of polymerization levels-off [7,8]. The acid hydrolyzes the less ordered regions of the polymer chains, leaving the crystalline regions intact. This MCCI is also called hydrolyzed cellulose or hydrocellulose.

Since the 1970s, microcrystalline cellulose I (MCCI) has been the dominant excipient used for direct compression due to its good diluent and binding properties and low moisture content. The strong binding properties of MCCI are due to hydrogen bonding among the plastically deforming cellulose particles. However, it suffers from sensitivity to lubricants

Effect of Polymorphism on the Particle and Compaction Properties of Microcrystalline Cellulose 29

and poor flow [9,10]. Because of its strong binding properties, it requires the addition of a disintegrant for an effective drug release, making formulations more costly. The compactibility of MCCI is also adversely affected when processed by high shear wet granulation since upon drying part of the water interacts with cellulose through hydrogen bonding and as a result,

Recently, microcrystalline cellulose II (MCCII) was introduced as a new direct compression excipient [12]. It can be produced by soaking MCCI in an aqueous sodium hydroxide solution (> 5 N) at a 1:6 weight-to-volume ratio for 14 h at room temperature, with occasional stirring. The resulting MCCII gel is then precipitated (regenerated) with a 50-60% aqueous ethanolic solution, filtered, washed with distilled water to neutrality by decantation, filtered again, and dried at 40 °C until reaching a moisture content of less than 5 % [13]. During this process, the amorphous regions of the microfibrils are partially eliminated leaving the most crystalline parts intact. The resulting product is usually washed

In most cases, a polymorphic transformation could modify some of the particle properties of a material. One of those properties is related to the water uptake capacity of the powder. In fact, this uptake depends on the crystalline structure of the polymer. Further, the mechanical and disintegrating properties of these materials are related to the degree of crystallinity and water uptake capacity, respectively. Thus, knowledge of the water sorption behavior of the cellulose allomorphs is essential to understand and predict their stability, especially during storage, alone or combined with other materials in a dosage form under variable ambient conditions. In this study, the effect of polymorphic transformation on the microcrystalline cellulose functionality was evaluated. The particle and mechanical properties of MCCII

were assessed and compared with those of commercial MCCI (Novacel® PH-101).

MCCI (Novacel PH-101, lot 6N608C) was donated by FMC Biopolymers, Philadelphia, PA, USA. Sodium hydroxide (lot 58051305C) and concentrated hydrochloric acid (37%, lot k40039517) were obtained from Carlo Erba, and Merck, respectively. Magnesium stearate (lot 2256KXDS) was purchased from Mallinckrodt Baker and acetaminophen (lot GOH0A01)

Approximately, 500 g of MCCI was soaked in 3 L of 7.5 N NaOH for 72 h at room temperature. The cellulose II thus obtained was washed with distilled water until it reached neutral pH. The slurry was sequentially passed through 6 (3350 µm), 10 (2000 µm), 24 (711 µm), 40 (425 µm) and 100 (150 µm) mesh screens using an oscillating granulator (Riddhi

these hydrogen bonds are not available for further particle bonding [11].

and spray-dried to get a powder [14].

**2. Experimental** 

was obtained from Sigma-Aldrich.

*2.2.1. Preparation of Microcrystalline Cellulose II (MCCII)* 

**2.1. Materials** 

**2.2. Methods** 

**Figure 1.** Scheme for the formation of cellulose allomorphs

**Figure 2.** Conformations of MCCI (A) and MCCII (B)

and poor flow [9,10]. Because of its strong binding properties, it requires the addition of a disintegrant for an effective drug release, making formulations more costly. The compactibility of MCCI is also adversely affected when processed by high shear wet granulation since upon drying part of the water interacts with cellulose through hydrogen bonding and as a result, these hydrogen bonds are not available for further particle bonding [11].

Recently, microcrystalline cellulose II (MCCII) was introduced as a new direct compression excipient [12]. It can be produced by soaking MCCI in an aqueous sodium hydroxide solution (> 5 N) at a 1:6 weight-to-volume ratio for 14 h at room temperature, with occasional stirring. The resulting MCCII gel is then precipitated (regenerated) with a 50-60% aqueous ethanolic solution, filtered, washed with distilled water to neutrality by decantation, filtered again, and dried at 40 °C until reaching a moisture content of less than 5 % [13]. During this process, the amorphous regions of the microfibrils are partially eliminated leaving the most crystalline parts intact. The resulting product is usually washed and spray-dried to get a powder [14].

In most cases, a polymorphic transformation could modify some of the particle properties of a material. One of those properties is related to the water uptake capacity of the powder. In fact, this uptake depends on the crystalline structure of the polymer. Further, the mechanical and disintegrating properties of these materials are related to the degree of crystallinity and water uptake capacity, respectively. Thus, knowledge of the water sorption behavior of the cellulose allomorphs is essential to understand and predict their stability, especially during storage, alone or combined with other materials in a dosage form under variable ambient conditions. In this study, the effect of polymorphic transformation on the microcrystalline cellulose functionality was evaluated. The particle and mechanical properties of MCCII were assessed and compared with those of commercial MCCI (Novacel® PH-101).
