The growth of nanocellulose has attracted outstanding interest in the last few decades due to its unique and potentially useful features. Novel nanocelluloses improve the strongly expanding field of sustainable materials and nanocomposites.CNCs and CNFs are two kind of nanocelluloses (NCs), and they own various superior properties, such as large specific surface area, high tensile strength and stiffness, low density, and low thermal expansion coefficient.Their application includesnanocellulose in transdermal drug delivery, Hydrogels, Aerogel Systems, Nanocellulose in Tablet Formulations and Nanocellulose in Microparticulate Drug Delivery (1). Different methods of nanocellulose like pretreatment method, mechanical process and chemical hydrolysis used for the synthesis of nanocellulose. Characterization of cellulose includes scanning electron microscopy, x-ray diffraction (XRD) analysis of samples and thermogravimetric analysis.

Cellulose is the main component of the plant cell wall and can be removed from a variety of sources, such as wood, fibers, grasses, seed fibers, marine animals, algae, fungi, invertebrates, and bacteria. Apart from cellulose, the plant cell wall also carries hemicellulose, lignin, and small amount of extractives. Even though wood species are the chief origin of cellulose, nonfood plants are accepting increasing interest due to their low-cost availability and bottom lignin content. Consequently, their fiber purification procedure are uncomplicated and less energy absorbing. For these causes, different agriculturalconsequences are under in-depth study for the manufacturing of various product ranges (2).Derivatizing cellulose obstruct with the orderly crystal-forming hydrogen bonding, so that even hydrophobic derivatives may grow the apparent solubility in water. Methylcellulose, Cellulose acetate, Ethyl cellulose, Carboxymethylcellulose and native cellulose have been used in various industrial applications and these include; barriers films, thickener and emulsifier, lubricant, glue and binder, artificial tears and saliva, optical and biomedical devices, pharmaceutical raw materials, flame retardants, resins and filters, blends and composites. Because of their low cost, toughness, natural feel, transparency, softness, comfort and other favorable aesthetic properties (3). Nanocellulose has obtained growingprofit for a wide range of requesting relevant to the areas of materials science and biomedical engineering due to its renewable nature, anisotropic shape, excellent mechanical properties, better biocompatibility, tailorable surface chemistry, and interesting optical properties. A new scope of nanocellulose application is still under investigation in fields such as photonics, films and foams, surface modifications, nanocomposites (4), flexible optoelectronics, and medical devices like scaffolds for tissue regeneration. The most beneficial property of nanocellulose research is the green nature of the particles, their fascinating physical and chemical properties, and the diversity of applications that can be derived from this material (5).

Cellulose:

Cellulose was first find by Payen. Since then, the physical and chemical properties of cellulose have been considered intensively. It is a well-ordered fibrillar ranging that is primarily answered for the mechanical strength of plants (6). It is considered as one of the most plentiful organic complex obtained from plant biomass. Around 1010 and 1011 t of cellulose biopolymer are produced each year but only about 6 × 109 t are used by various industries such as paper, textile, material and chemical industries, etc. In spit cellulose is a crystalline molecule its crystallinity is faulty; a notablepart of the cellulose building is less commanded and can be mentioned to as amorphous. Thus, the cellulose chain is a two-phase modelholding both crystalline (ordered) and amorphous (less ordered) regions (7). The grade of crystallinity of domestic cellulose usually ranges from 40% to 70

Cellulose nanocrystals:

Cellulose nanocrystals (CNCs) are frequently produced using acid hydrolysis of cellulosic materials dispersed in water. In general, concentrated sulfuric acid is used, which dissolves the amorphous regions of cellulose and the crystalline regions are left alone. Although this procedure produces a rod-like rigid CNC with almost 90% purity, the sulfate groups remain attached at the surface of the fibers as impurities (10). The length and diameter of CNCs commonly vary from a length of 200–500nm to a diameter of 3–35nm.

Cellulose nanofibrils:

CNFs are long entangled fibrils (µm) with a diameter in nanometer range. CNFs are produced by high-pressure grinding of cellulosic pulp suspension and strongly entangled networks of nanofibrils are formed (11). Unlike CNCs, which have near-perfect crystallinity (c.90%), CNFs contain both amorphous as well as crystalline cellulose domains within the single fibers. Typically, CNFs have a diameter of 5–50 nm and a length of a few micrometers. CNF extraction from cellulosic fibers can be obtained by three types of processes: (1) mechanical treatments (e.g., homogenization, grinding, and milling); (2) chemical treatments (e.g., TEMPO oxidation); and (3) a combination of chemical and mechanical treatments.

Bacterial cellulose:

 Bacterial cellulose (BC) is also known as microbial cellulose. It is usuallyproduced from bacteria, (e.g., Acetobacterxylinum) as an unrelated molecule and does not need additional handling to remove contaminants like lignin, pectin, and hemicellulose.Furthermore, in disparity to CNC and CNF biosynthesis, BC biosynthesis requires the addition of molecules from tiny units (Å) to small units (nm) (12). In the biosynthesis of BC, the glucose chains are provided inside the bacterial body and discharge out through minor pores present on the cell wall. Ribbon-shaped BC nanofibers are established when glucose is fused with the cell wall. This ribbon-like web-shaped structure build a 20–100 nm long unique nanofiber system.

Preparation of Cellulose Nanocrystals:

 CNCsowngiant crystallinity with diameter less than 100 nm and length less than 500 nm, which are established through intermolecular interaction of cellulose macromolecules in a hydrogen bond way. CNCs are generally obtained through acid hydrolysis or enzymatic hydrolysis of cellulose pulp.  Acid hydrolysis processes need to go through very harsh reaction conditions which usually require concentrated acid, while the enzymatic hydrolysis process requires really long time. There are mainly determined by the inherent stable structure of the materials that have been explained in a related review. During the hydrolysis activity, the amorphous regions of cellulose are more easily invested by acid compared to the crystalline regions, leading to first degradation of amorphous regions, while the crystalline regions are retained. Finally, whisker-like CNCs are obtained. In retrospect, the first successful mixture of CNCs was in 1947 all the time hydrolyzing cellulose with hydrochloric acid and sulfuric acid by Nickerson and Habrle. In 1951, Ranby prepared the stable CNCs colloidal suspensions ˚ through sulfuric acid hydrolysis of wood fiber. In 1953, Mukherjee and Woods proved that the needle particles obtained by sulfuric acid hydrolysis occult nanometer size by X-ray technology and electron microscope and found that their crystal structure was same as that of raw cellulose material. Subsequently, Marchessaults et al. found that the CNCs colloid suspension had birefringence. After that, some new methods to prepare CNCs seemsslowly, such as enzymatic hydrolysis, oxidative degradation, ionic liquid, solid acid hydrolysis, organic acid hydrolysis, and subcritical hydrolysis. 

Mineral Acid Hydrolysis

The mineral acid hydrolysis is the most ordinary method for the preparation of CNCs. Many cellulose sources have been used for the preparation of CNCs by mineral acid hydrolysis, such as tomato peel, oil palm biomass, rice husk, and waste cotton cloth. The classic mechanism is that the hydrogen ions from acid can easily pervade the loose amorphous regions of cellulose to break the 1,4-β-glycoside bonds, resulting in the hydrolysis of amorphous regions, while the crystalline region of cellulose could be keep in the process which is ascribed to the inherent compact structure that averted the permeation of the acid. Hence, the relatively complete crystalline structure of CNCs can be obtained by the hydrolysis of mineral acid. 

Fig:1 Schematic diagram of CNCs prepared by acid hydrolysis: (a) idealized cellulose microfibril showing one of the suggested configurations of the crystalline and amorphous regions and (b) CNCs after acid hydrolysis dissolved the disordered regions.

Figure: 1

The usually used mineral acids are sulfuric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, and their mixed acids. Sulfuric acid is the most usually used as it produces a negative surface charge on the particles which guide to more stable suspension. In general, the hydrolysis process needs the sulfuric acid congregation to be 60–65%, reaction temperature to be 40–50°C, and reaction time to be 30–60 min. However, the yield of CNCs is very low (less than 30 wt.%) due to the intemperate degradation. Fan and Li optimized the sulfuric acid hydrolysis circumstances with cotton pulp as raw material, and the yield of CNCs reached to 63.8%. Chen et al. found that the yield of CNCs could be remarkably improved by decreasing the concentration of sulfuric acid and prolonging reaction time. For example, the yield of CNCs could extend to 75.6% when 58 wt.% sulfuric acid was used at 56°C for 210 min. CNCs from sulfuric acid hydrolysis have poor thermal stability due to the sulfate group which is a remarkable barrier for thermal process in composites. The thermal stability of CNCs can be improved between neutralization with NaOH. The morphology of CNCs can be also changed by controlling the reaction conditions. The spherical CNCs with average dimension of 35 nm could be obtained by using 63.5% H2SO4 to hydrolyse microcrystal cellulose under the ultrasonic ministration combined with mechanical stirring for 3 h. Azrina et al. also reported a commom condition for the preparation of spherical CNCs. This reaction was carried out with 64% (w/v) H2SO4 solution at 45°C for 2 h in an ultrasound bath. In this reaction, the spherical CNCs with an average diameter of 30–40 nm were synthesised from oil palm empty fruit bunch pulp.

Hydrochloric acid also was frequently used for the preparation of CNCs. The classic acid concentration, reaction temperature, and reaction time are 2.5 N–6.0 N, reflux temperature, and 2–4 h, respectively. Due to the absences of charge on the surface of CNCs, the CNCs prepared by hydrochloric acid are easily flocculation in water. But the thermal stability of CNCs by HCl is more than that by H2SO4. Yu et al. used hydrochloric acid to treat raw cellulose materials under hydrothermal situations. The crystallinity of the resultant CNCs was 88.6% with greater yield of 93.7%. The maximum degradation temperature was 363.9°C which was resolved by TGA analysis. Cheng et al. described an inorganic chloride/hydrochloric acid system for extracting CNCs from microcrystalline cellulose (MCC) under hydrothermal conditions. Four inorganic chlorides including FeCl36H2O, CuCl22H2O, AlCl3, and MnCl24H2O were look over in this work. The research allow that the hydrolysis process was support significantly by inorganic chlorides especially ferric chloride via accelerating degradation of the amorphous region of cellulose. Phosphoric acid, which belongs to middle strong acid (pKa = 2.12), could be used for the preparation of CNCs with high thermal stability and stable suspension. Lu et al. reported a mechanochemical proceed towards to manufacture bamboo cellulose nanocrystals (BCNCs). In this action, the bamboo cellulose pulp was chemically treated by phosphoric acid. Finally, short rod-like BCNCs with the length of 100–200 nm and the width of 15–30 nm was obtained. The crystalline building transformed from cellulose I to cellulose II, and the crystallinity index reduced from 66.44 to 59.62%, while the thermal stability became lower.

Hydrobromic acid (HBr) hydrolysis circumstances assisted with ultrasonication to prepare CNCs were investigated by Sadeghifar et al. When the hydrolysis process was carried out at 2.5 M HBr under 100°C with sonication for 3 h, CNCs could be obtained at a yield of 60%. Moreover, Sucaldito and Camacho used HBr to hydrolyze fresh water green algae to attain the highly crystalline CNCs (crystallinity index of 94.0%). The resultant CNCs have a mean diameter of 20.0 (±4.4) nm, and the rotting temperature reached 381.6°C.

Figure:2 Schematic diagram thermal stability contrast of CNCs from sulfuric acid hydrolysis, hydrochloric caid hydrolysis or phosphoric acid hydrolysis.

Spherical CNCs could be also prepared by using a mixed acid system facilitated with ultrasonication from MCC. The mixed acid system is a mixture of sulfuric acid (98%, w/w), hydrochloride (37%, w/w), and H2O at a ratio of 3: 1: 6 (v/v) which was reported by Zhang et al. The action was carried out at 80°C by ultrasonicator heating for 8 h. The diameters of produced cellulose nanoparticles are in the range of 60–570 nm. The hydrolysis condition provided by Wang et al. was, the ratio of sulfuric acid (98%, w/w), hydrochloride (37%, w/w), and H2O was still 3: 1: 6 (v/v), while the ultrasonic treatment was at 50 Hz for 10 h. The resultant spherical CNCs suspension with the dimension of 10–180 nm showed liquid crystalline quality when the concentration was above 3.9%. A mixed acid system of hydrochloric acid and nitric acid (HCl/HNO3) could be used to developcarboxylated cellulose nanocrystals (CCNCs) from MCC. When the reaction was support out under the mixed acid (HCl/HNO3 = 7: 3 (v/v)) concentration being 4 M at 110°C for 3 h, the resultant CCNCs were rod-like morphology and had good suspension stability and excellent thermal stability.

Generally, mineral acid hydrolysis method to produce CNCs is a simple method and has gone to pilot scale (quite a few around the world) and even exhibition plant (1 tonne/day at CelluForce, Canada). However, there are still some demerits in this method. First, the corrosion problem of the equipment is serious which leads to the arrogant cost of production. Furthermore, a large amount of waste acid and other pollutants will be produced in the procedure of acid hydrolysis, and it is very difficult to dispose and recover. So, it is very necessary to develop green and low-cost CNCs production technologies.

Solid Acid Hydrolysis

Tang et al. reported a cation interchange resin hydrolysis method for the preparation of CNCs. By hydrolyzing MCC with cation trading resin (NKC-9), an optimum yield (50.04%) was achieved with a ratio of resin to MCC (w/w) being 10 and at 48°C for 189 min. The results showed that the diameter of CNCs was about 10–40 nm and the length was 100–400 nm. The crystallinity of resin-CNCs was excessive than that of H2SO4-CNCs. In counting to the recoverable capacity of cation exchange resin, the cation exchange resin-catalysed hydrolysis is a favourable approach for manufacturing of CNCs. Liu and co-workers reported the phosphotungstic acid (HPW) catalysed-hydrolysis procedure with bleached hardwood pulp as raw material. CNCs with the diameter of 15–40 nm were given, which had high thermal solidity and stable dispersion in watery phase. The reaction was support out with 75 wt.% phosphotungstic acid at 90°C for 30 h; the yield of CNCs was up to 60%. Phosphotungstic acid could be retrieve through extraction with available ethyl ether. Since this method is a solid/liquid/solid three-phase reaction, the reaction efficiency is low and the reaction time is comparatively long compared with the mineral acid hydrolysis method. Further research results showed that the response time was notably shortened under the optimal conditions, and the obtained CNCs had a high crystallinity index (79.6%) with a 84% yield. Torlopov et al. also reported a CNCs preparation procedure using phosphotungstic acid/acetic acid method to destruct cotton cellulose. The resulting CNCs have high-crystalline method and rod-like morphology.Contrast with the typical mineral acid hydrolysis method, solid acid hydrolysis method has mild surrounding and low corrosion to equipment, and the solid acid can be recycled. Moreover, the yield of CNCs is higher. However, the reaction order is low and the reaction time is pretty long. Allocate physical approach (such as microwave and ultrasound assisted) or suitable catalyst could be used to better the reaction efficiency. At present, solid acid hydrolysis method to prepare CNCs is still in the phase of laboratory research.

Figure:3 The overall procedure for manufacturing CNCs by using HPG

   Organic Acid Hydrolysis

Recently, organic acid hydrolysis was introduce to produce NCs due to the fact that the organic acid is mild, recyclable, and environment-friendly and of low corrosiveness. However, in order to improve the efficiency of hydrolysis, higher temperature and prolonged reaction time are necessary because of the weak acidity of organic acid. Li and co-workers reported a two-step master plan to produce CNCs from bleached chemical pulp under mild conditions. In the first stage, formic acid (FA) was used to hydrolyse the amorphous region of cellulose and free CNCs. In the second stage, the cause CNCs were further oxidized by TEMPO in order to grow the surface charge. The results manifested that the crystallinity index of resultant CNCs could reach 75% when 0.015 M FeCl3 was used. Moreover, up to 90

Scanning Electron Microscopy:

 The surface morphology of the samples was carried out using Phenom World ProX desktop scanning electron microscope with fully integrated and specifically designed EDS detector made in Eindhoven Netherlands (22). 

FT-IR results of Cellulose, Methylcellulose and Cellulose acetate nanoparticles:

The FT-IR spectra of samples were recorded FT-IR-8400S Fourier Transform Infrared Spectrophotometer in the spectra range of 4000-400 cm-1. Samples were run as (Kbr) pellets.

X-Ray Diffraction (XRD) Analysis of samples:

X-ray diffractometry in reflection mode was carried out using a diffractometer (DLMAX-2550, Japan), with monochromatic Cu Kα radiation (λ = 0.154 nm), with a divergence and scatter at 1.00o, and a receiving slit at 0.30 mm, generated at 40 kV and 30 mA, at room temperature. The samples were scanned within 2.00 - 70.00˚ 2θ in continuous scan mode with a step of 0.02˚ and a rate of 0.10 sec. The crystallite index of cellulose was calculated using the Kim’s empirical method.

CI = (I002-Iam)/I002 x 100 Where CI is the crystallinity index, I002 is the maximum intensity and represents crystalline material, while Iam represents maximum intensity of the amorphous material. 

Thermogravimetric Analysis (TGA):

Thermal behavior of the prepared samples was examined by Thermogravimetric Analyzer model Schimadzu TGA-50H (Kyoto, Japan) from 28 °C to 900 °C. A heating rate of the analysis was 10 °C / min under nitrogen atmosphere and at a flow rate of 20 mL / min. 

BET Analysis:

 The surface area of the prepared samples was examined by BET analysis using Quanta chrome NovaWin-Data Acquisition and Reduction for NOVA instruments version 11.03.

Nanocellulose in Microparticulate Drug Delivery:

The importance of encapsulating drugs, food actives, flavors, or even cell for improved performance and preservation has been well appreciated across different scientific fields. A broad range of natural and synthetic polymeric materials are available for encapsulation, the choice of which mainly rested upon the desired performance of the end products. Nanocellulose is an emerging natural polymer that has received considerable interest in recent years as the encapsulating polymer for drug delivery (23). It has also been widely investigated to enhance the mechanical properties and influence drug delivery behavior of microcapsules prepared with other natural polymers. A study was conducted to estimate the influence of three polysaccharide nanocrystals (PNs) such as CNCs, starch nanocrystals, and chitin whiskers on the mechanical and drug release properties of sodium alginate microspheres. All the three PNs resulted in ameliorated mechanical properties and pH sensitivity of the microspheres. All the PNs were found to restrict the motion of the sodium alginate polymer chains and inhibit diffusion of the drug, resulting in the slow dissolution of theophylline from the microspheres, and diffusion transport was found to be the drug release mechanism from the systems.

Nanocellulose in Tablet Formulations:

Cellulose and its derivatives in different forms have been indispensable components in the preparation of tablets for a long time. Cellulose derivatives such as MCC, hydroxypropyl methylcellulose, ethyl cellulose, carboxymethylcellulose, and others are extensively used in conventional as well as controlled‐release tablet formulations. With the practical edge supplied by nanocellulose in numerous functional properties being realized and appreciated, a few investigations have explored its potential as functional excipients in tablet formulations. The potential of spray‐dried cellulose nanofibers as novel tablet excipients was evaluated and compared against two commercial MCC, Avicel PH‐101 and Avicel PH‐102, which are the two most commonly used direct compression excipients (24). Cellulose nanofibers were found to possess better compressibility and were amendable to both wet granulation and direct compression methods of tablet preparations. Cellulose nanofibers formulated through direct compression method showed faster disintegration and drug release showing its potential as direct compression excipients. Freeze‐dried CNC prepared from water sugarcane bagasse was also shown to increase the dissolution of diltiazem hydrochloride tablets prepared with the nanocellulose.

Aerogel Systems:

Aerogels are insubstantial materials with excellent surface area and open porosity, suitable for high loading of active compounds. They are nano porous systems procured from the wet gels or hydrogels through an acceptable drying technology that keeps the porous texture of the wet material intact. Due to their web like structure, high porosity, and high surface reactivity, aerogels prepared from nanocelluloses possess a high mechanical flexibility and ductility with ability for water uptake, which makes them an excellent applicant for the removal of dye pollutants, thermal insulation materials, and drug delivery system (25). As a result, different types of nanocelluloses, due to their outstanding and acceptable properties, have become the subject of keen interest in the preparation of aerogels for drug delivery.

Hydrogels:         

 Hydrogels are produced by cross‐linking of polymer chains through the interactivity that may be of ionic, physical, or covalent, having the capacity to absorb water (26).Hydrogels expand in water but do not dissolve in it. Due to their ability to display sol–gel transitions that can be induced by a slight changes in the environmental conditions such as temperature, pH, ionic strength, phase separation, wavelength of light, crystallinity, and others, bright polymeric hydrogels are extensively used in biomedical fields such as in the growth of controlled‐release drug delivery systems, tissue engineering, and regenerative medicine(27). Several smart hydrogels such as injectable hydrogels, shape‐memory bacterial nanocellulose hydrogels, supramolecular hydrogels, double‐membrane hydrogels, temperature‐sensitive hydrogels, and many others with possibilities for drug delivery have been developed, which were based on nanocellulose.

Nanocellulose in Transdermal Drug Delivery:

Delivery of drugs through the skin offers several leads over other routes as well as elimination of first‐pass metabolism, minimization of pain, prolonged release of the drug, and the potential to terminate drug absorption by removing the patch from the skin (28). Nanocellulose, mainly bacterial cellulosic sources, has entice a great deal of interest in the development of controlled transdermal drug delivery and woundalleviate preparations.

Nanocellulose prepared from wood cellulose has unique and promising properties, such as high crystallinity, aspect ratio, Young’s moduli, and tensile strengths, which originate from the properties of natural wood cellulose microfibrils. A change in processing technique changes the properties of the resulting nanocellulose, which is reflected in the final product. Besides the conventional mechanical methods traditionally used to prepare CNFs, such as grinding or homogenization, other promising methods are discussed, which can be instrumental to further research and industrialization of these materials.This review explains the preparation methods of CNCs and CNFs. For the preparation of CNCs, promising abilities were discussed besides the conventional mineral acid hydrolysis, such as organic acid hydrolysis, subcritical hydrolysis, AVAP method, and ionic liquid hydrolysis. Most of them have great feasibility for further industrialization.Different methods of nanocellulose like pretreatment method, mechanical process and chemical hydrolysis used for the synthesis of nanocellulose. Characterization of cellulose includes scanning electron microscopy, x-ray diffraction (xrd) analysis of samples, thermogravimetric analysis (TGA).