Microcrystalline cellulose: Its processing and pharmaceutical specifications

Sherif S. Z. Hindi ^1,*; Abdulmohsin R. Al-Shareef ²

1 Department of Agriculture, Faculty of Environmental Sciences, King Abdullaziz University (KAU), P.O. Box 80208, Jeddah 21589.; ² Deanship of Scientific Research, KAU, Jeddah, 21551, Saudi Arabia

Abstract: Microcrystalline cellulose (MCC) is pure partially depolymerized cellulose synthesized from α-cellulose precursor. The MCC can be synthesized by different processes such as reactive extrusion, enzyme mediated, steam explosion and acid hydrolysis. The later process can be done using mineral acids such as H2SO4, HCl and HBr as well as ionic liquids. The role of these reagents is to destroy the amorphous regions remaining the crystalline domains. The degree of polymerization is typically less than 400. The MCC particles with size lower than 5µm must not be more than 10%. The MCC is a valuable additive in pharmaceutical, food, cosmetic and other industries. Different properties of MCC are measured to qualify its suitability to such utilization, namely particle size, density, compressibility index, angle of repose, powder porosity, hydration swelling capacity, moisture sorption capacity, moisture content, crystallinity index, crystallite size and mechanical properties such as hardness and tensile strength. Thermogravimetric analysis (TGA) and differential thermal analysis (DTA) or differential scanning calorimetry (DSC) are also important to predict the thermal behavior of the MCC upon heat stresses.

Keywords: Microcrystalline cellulose (MCC); XRD, FTIR; XRD;TGA; DTA; MSDS.

* Corresponding Author: shindi@kau.edu.sa

Introduction

Raw Precursor

MCC can be obtained commercially from wood (El-Sakhawy and Hassan, 2007) as well as non-woody lignocellulosic materials such as cotton linters (Chauhan et al., 2009),

cotton stalks (El-Sakhawy and Hassan, 2007), cotton rags (Chauhan et al., 2009), soyabean husk (Uesu et al., 2000), corn cob (Suvachittanont and Ratanapan, 2013), water hyacinth (Gaonkar and Kulkarni, 1987), coconut shells (Gaonkar and Kulkarni, 1989), rice husk (Ilindra and Dhake, 2008; El-Sakhawy and Hassan, 2007), sugar cane bagasse (Paralikar and Bhatawdekar, 1988; Padmadisastra and Gonda, 1989; Shah et al., 1993; Tang et al., 1996; El-Sakhawy and Hassan, 2007; Ilindra and Dhake, 2008), jute (Abdullah, 1991), ramie (Kuga and Brown, 1987), fibers and straw of flax (Bochek et al., 2003), wheat straw (Monschein et al., 2013), sorghum stalks (Ohwoavworhua and Adelakun, 2010), sisal fibers (Bhimte and Tayade, 2007) and coconut shells (Gaonkar and Kulkarni, 1989).

Industrial Applications

The MCC is a valuable additive in pharmaceutical as a binder for tablets by direct compression and in vitamin supplements, in food as an anticaking, thickener, texturizer, emulsifier and bulking agent as well as a fat substitute and in cosmetic as a filler (Chauhan et al., 2009, Ohwoavworhua and Adelakun, 2010). It is one of the most important tableting excipients due to its superior dry binding properties producing high quality of tablets by direct compression (Thoorens et al., 2014). It is also used in plaque assays for counting viruses, as an alternative to carboxymethyl cellulose (Matrosovich et al., 2006). Another applications of the MCC such as paints, paper and nonwoven textiles, oils field services, medicine and composites because of its properties such as high strength, flexibility and aspect ratio (Tubark et al., 1983; Herrick et al., 1983)

Synthesis

The MCC can be synthesized by different processes such as reactive extrusion process, enzyme mediated process (Monschein et al., 2013), the steam explosion process and acid hydrolysis process (El-Sakhawy and Hassan, 2007; Chauhan et al., 2009). The acid hydrolysis process (Table 1) is preferred due to its shorter reaction duration comparing to the other processes. Furthermore, it can be applied by a continuous process

rather than a batch-type process and it consumes limited quantity of acid and produces fine particles of the MCC (Chauhan et al., 2009).

The synthesis procedure of the MCC reported by (Ohwoavworhua et al., 2004) and applied with slight modification by Ohwoavworhua et al., 2010 can be concluded as follow: A 50 g quantity of the α-cellulose was hydrolyzed with 0.8 l of 2.5 N hydrochloric acid at a boiling temperature of 105° for 15 min. The fraction passing through 710 µm sieve was obtained and stored at room temperature in a desiccator.

Table 1. Hydrolysis reagents (acid type and concentration), liquor to cellulose ratio (L/C)

, hydrolysis conditions (HC) and yield of microcrystalline cellulose (MCC-Y)

¹Not defined

Characterization

There are many different techniques are available to characterize the MCC such as infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), atomic force spectroscopy (AFM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), hi-resolution transmission electron microscopy (Hi-TEM).

Physicochemical properties of MCC

The organoleptic characteristic, identification tests, solubility and presence of organic impurities such as starch, dextrin and water-soluble substances can be done according to credit procedures such as the British Pharmacopoeia (BP) specifications (Ejikeme, 2008). The pH determination of the supernant obtained by shaking 2 g of the MCC powder with 100 ml of deionized water for 5 minutes (Ohwoavworhua et al., 2004). Total ash content in the MCC can be determined by weighing the residue remained after combustion at 550° until all the carbon is eliminated (Ohwoavworhua et al., 2004).

Different properties of MCC synthesized from many cellulosic precursors were evaluated by several investigators. The MCC of sugar cane and Avicel powders were evaluated for particle size analysis (Ansel et al., 2005) , density and compressibility index (Ohwoavworhua et al., 2004 and 2005 and Bhimte and Tayade, 2007) , angle of repose (Train, 1958) , powder porosity (Ohwoavworhua et al., 2004) , hydration ( (Kornblum and Stoopak, 1973) and swelling capacity (Ohwoavworhua et al., 2004), moisture sorption capacity and moisture content (Ohwoavworhua et al., 2005) .

For particle size analysis, it can be determined using a sieve shaker, containing standard sieves arranged in a descending order according to their opening size. About 20 grams of the MCC powder is placed on the top sieve and shaking for 5 min. The weight of MCC retained on each sieve is determined. The average diameter can be calculated as reported by Ansel et al. (2005) using the following equation: Average diameter of the MCC particles = [∑ (% retained)×(mean aperture)]/100. The real density (Dr) of cellulose powders can be determined by the xylene displacement method (Ohwoavworhua et al., 2005) and computed according to the following Equation: Dr = [w/{(a+w)-b}×SG], where w represents weight of powder, SG represents specific gravity of xylene, a represents sum weights of bottle and solvent and b represents the sum weights of bottle, solvent and the MCC powder (Ohwoavworhua and Adelakun, 2010).

For the moisture content (MC) determination, about 2 g of the MCC sample was weighed

• and oven-dried at 105-C for 8 hours, and then weighed again (B). The MC was calculated using the following formula: [(A-B)/A]×100 (Annonymous, 2006). Spectroscopic Studies

The optical microscope (10X, 40X or 100 X magnifications) can be used for speculating advancing hydrolysis as well as preliminary assessment of the MCC particles. Scanning electron microscopy (SEM) and/or transmission electron microscopy (TEM) study (Table 2) is widely used to character the MCC particles. The samples are placed on the double side carbon tape on Al-stub and dried in air. Before examination, all samples are sputtered with a 15 nm thick gold layer (JEOL JFC- 1600 Auto Fine Coater) in a vacuum chamber. For the SEM imaging, it can be done by Field Emmision SEM device such as JEOL, JSM-7600F (Bhimte and Tayade, 2007), while TEM imaging can

be applied by such TEM-1011 JEOL, Japan.

For X-ray differaction (XRD), the wide angle X-ray diffraction spectra of the MCC can be recorded on a proper X-ray differactometer such as a XRD 7000 Shimadzu diffractometer (Japan). The system has a rotating anode generator with a copper target and wide angle powder goniometer. The generator must be operated at 30 KV and 30 mA. All the experiments should be performed in the reflection mode at a scan speed of 4° /min in steps of 0.05°. All samples are scanned in 2θ range varying from 4° to 30°.

The crystallinity index of the fiber is determined by using the following equation: Ic=[(I002-Iam)/( I002)]x100 (Bhimte and Tayade, 2007), where I002 represents the intensity of crystalline peak arising from and alpha-cellulose while Iam is the crystallographic plane arising from remained amorphous cellulose plus amorphous impurities (lignin and pectin.

The crystal and molecular structure together with the hydrogen-bonding system in cellulose Iβ can be determined using synchrotron and neutron diffraction data recorded from oriented fibrous samples prepared by aligning cellulose microcrystals (Nishiyama et al., 2002).

Thermal Analyses

There are different types of the thermal analyses of the MCC (Table 2), namely thermogravimetric analysis (TGA) which measures weight changes, differential thermal analysis (DTA) that measures exothermic and endothermic reactions, differential scanning calorimetry (DSC) which measures the heat required to raiuse the sample temperature. In addition, thermal conductivity (TC) is frequently used to measure ability to transmit heat across the MCC sample. Furthermore, thermo-mechanical analysis (TMA) is useful to measure dimensional changes due to altering temperature. For the composites reinforced by the MCC, dynamic mechanical thermal analysis (DMTA) is used to investigate viscoelastic properties of polymers. The thermal behavior of the MCC can be predicted by TGA, DTA or DSC using a Seiko &star 6300 analyzer. Heating scans from 30 up to 550

°C at 20 °C/min in nitrogen atmosphere are performed for each sample (Fortunati et al., 2013)

Table 2. Parameters and techniques used to characterize microcrystalline cellulose (MCC), namely crystallinity index (CI) and crystallite size (CS) determined by X-ray differaction (XRD), Fourier transform infrared (FTIR) spectrometry, thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), viscosity measurement (VM), particle size and particle size distribution (PZ&PZD), true density (TD), tensile strength (TS), hardness (H), wet granulation (WG), hydration capacity (HC), swelling capacity (SC), moisture sorption capacity (MSC) and compressibility (Co).

The material safety data sheet (MSDS) of the MCC is presented in appendices 1-7.

Conclusions

• The Microcrystalline cellulose is a valuable additive in pharmaceutical, food, composites and cosmetic industries.
• The Microcrystalline cellulose can be synthesized by reactive extrusion, enzyme mediated, the steam explosion and acid hydrolysis.
• The acid hydrolysis process is preferred due to its shorter reaction duration, can be applied by a continuous process rather than a batch-type, it consumes limited quantity of acid and produces fine particles.
• Different techniques are used to characterize the microcrystalline cellulose such as infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, nuclear magnetic resonance, atomic force spectroscopy, scanning electron microscopy, transmission electron microscopy, hi-resolution transmission electron microscopy.
• The organoleptic characteristic, identification tests, solubility and presence of organic impurities such as starch, dextrin and water-soluble substances are important to characterize the microcrystalline cellulose.

• The pH, moisture content, total ash content, particle size analysis, true density, compressibility index, angle of repose, porosity, hydration, swelling capacity, moisture sorption capacity and moisture content.

Appendices

Appendix 1. Product and commercial identification of the microcrystalline cellulose

Appendix 2. Physical and chemical properties

Appendix 3. Hazards and toxicological information of microcrystalline cellulose

Appendix 4. First aid treatments to confront any health hazards due to the microcrystalline cellulose (MCC)

Appendix 5. Ecological and eco-toxicological information

Appendix 6. Permissible exposure limits (PEL) of dust in some countries:

1 TWA: Time-weighted average, ² STEL: Short-term exposure limits and ³ PEL: Permissible exposure limit.

Appendix 7. Considerations on fighting fires occurred due to microcrystalline cellulose

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