NGS‐based methods to profile transcriptome‐wide RNA modifications.
\r\n\t- Traditionally accepted topics related to global health security,
\r\n\t- The impact of human activities and climate change on “planetary health”,
\r\n\t- The impact of global demographic changes and the emergence chronic health conditions as international health security threats.
\r\n\t- A theme dedicated to the COVID-19 Pandemic,
\r\n\t- Novel considerations, including the impact of social media and more recent technological developments on international health security.
\r\n\tThe goal of this book cycle is to provide a comprehensive compendium that will be able to stand on its own as an authoritative source of information on international health security.
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Miller",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10624.jpg",keywords:"Threats, Monitoring, Food Security, Emerging Infections, Transmission, Geopolitics, Climate Change, Cyber Health Security, COVID-19, Novel Coronavirus, Pandemic, Coronavirus",numberOfDownloads:239,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 20th 2020",dateEndSecondStepPublish:"November 5th 2020",dateEndThirdStepPublish:"January 4th 2021",dateEndFourthStepPublish:"March 25th 2021",dateEndFifthStepPublish:"May 24th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"An Associate Professor of Surgery at Temple University School of Medicine and a Chair of the Department of Research and Innovation, St. Luke's University Health Network. A member of multiple editorial boards and co-author of over 550 publications.",coeditorOneBiosketch:"An Associate Professor of Surgery & Integrative Medicine at Northeast Ohio Medical University and Cardiothoracic Surgeon at the Summa Health Care System. A prolific writer and presenter, with multiple books, hundreds of peer-reviewed articles, and innumerable presentations around the world.",coeditorTwoBiosketch:"A CEO of the INDUSEM Health and Medicine Collaborative, Global Executive Director. of the American College of Academic International Medicine (ACAIM) and head of the World Academic Council of Emergency Medicine.",coeditorThreeBiosketch:"A Director of Research in the Department of Emergency Medicine at Nazareth Hospital in Philadelphia, USA, and co-chief editor of the International Journal of Critical Illness and Injury Science. 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He completed residencies in Emergency Medicine and Internal Medicine at the State University of New York (SUNY) Downstate Medical Center (2010) where he served as Chief Resident for Research. He completed fellowships in Pulmonary Medicine at the University of Pittsburgh Medical Center (2013) and Critical Care Medicine at the National Institutes of Health (2014). He is active in the American College of Academic International Medicine, and is co-chief editor of the International Journal of Critical Illness and Injury Science. 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Comparative transcriptomics between mammals has revealed that ∼66% of human genomic DNA is transcribed. Remarkably, only ∼2% of the transcriptional production is protein‐coding messenger RNA (mRNA), while ∼98% encompasses a wide variety of non‐coding RNA (ncRNA) molecules [1, 2]. ncRNAs have been classified functionally as either housekeeping or regulatory. The housekeeping ncRNA genes include ribosomal RNA (rRNA), transfer RNA (tRNA), and small nuclear RNA (snRNA), while examples of regulatory ncRNAs are microRNA (miRNA) and long non‐coding RNA (lncRNA) [3–5]. The complexity of RNA is further complicated by numerous post‐transcriptional modifications which alter the chemical structure of the nucleotides without changing the nucleotide sequence. Similar to the field of epigenetics which investigates the modifications of DNA and histone proteins, the study of chemical modifications of RNA is called epitranscriptomics [6, 7]. More than 140 chemically diverse and distinct modified nucleotides have been identified in both mRNA and ncRNA, including N6‐methyladenosine (m6A), 5‐methyl cytidine (m5C), pseudouridine (Ѱ), adenosine (A) to inosine (I), and N1‐methyladenosine (m1A). These modifications have been identified mostly in the housekeeping ncRNAs [3, 4, 8]; however, chemical modifications have also been detected in mRNA and the regulatory ncRNAs [9–11]. Unfortunately, the knowledge about the occurrence and function of RNA modifications at transcriptome level remains scarce. Recently, the interest in RNA modifications and their functions have gained momentum owing mainly to the application of novel modifications to next‐generation sequencing (NGS) and mass spectrometry technologies, which have allowed transcriptome‐wide detection of distinct RNA modifications [12, 13]. Accurate regulation of the transcriptome is critical for gene expression and its subsequent control of cellular functions, including metabolism, proliferation, differentiation, and development. Thus, alterations in transcriptome regulation can disrupt cellular functions and lead to disease. Accumulating evidence has identified and functionally characterized several distinct types of chemical modifications of RNA nucleotides in both protein‐coding and ncRNAs, further advancing the burgeoning field of epitranscriptomics. In this chapter, we will first provide an overview of RNA modifications and then synopsize several transcriptome‐wide RNA modification mapping techniques such as m6A‐seq, m5C‐seq, pseudouridine‐seq, and NAD captureSeq. Next, we will highlight novel insights into the potential functions of RNA modifications and their disease relevance as revealed and facilitated by epitranscriptomic profiling. Finally, we will offer our perspective on how the field will progress or evolve in the near future.
The process of mRNA maturation involving 5ʹ‐capping, splicing, and polyadenylation has been well studied [14]. However, the more subtle post‐transcriptional modifications of epitranscriptomics, also termed RNA‐epigenetics, are now just fully coming to light. The post‐transcriptional modifications found in RNA are often called marks because they mark a region of RNA that potentially contributes to the regulation of cellular processes, including gene expression, protein translation, or RNA stability. Like mRNA maturation, enzymes are required to catalyze the reactions, which chemically modify RNA nucleotides. The most common post‐transcriptional RNA modification, Ψ, was also the first to be discovered [15]. Originally discovered in rRNA and tRNA, Ψ modifications are also present in mRNA [16, 17]. Site‐specific isomerization of uridine (U) to Ψ (5‐ribosyluracil) is irreversibly catalyzed via Ψ synthases. The family of Ψ synthases (PUS) consists of enzymes which can either function independently or those that require H/ACA ribonucleotide complexes [18]. Compared to U, Ψ contains an extra imino group (>C═NH), which serves as an additional hydrogen bond donor, while the carbon‐carbon (C─C) glycosidic bond linking the sugar to the base is more stable than the carbon‐nitrogen (C─N) found in U. These two chemical changes confer rigidity to the sugar‐phosphate backbone and enhances local base stacking [19].
The most common internal modification in eukaryotic mRNA is m6A [20]. Unlike Ψ, m6A modifications are reversible, suggesting that the modifications are involved in regulatory switches. Methyltransferases (METTL3, METTL14, and WTAP), termed writers, catalyze the methylation of adenosine [21–23], whereas demethylases (FTO and ALKBH5), termed erasers, remove the methyl group [24, 25]. The m6A marks are recognized by YTH domain proteins, termed readers, which regulate mRNA processing and metabolism [26, 27].
An additional class of nucleotide modifications, termed RNA editing, creates an irreversible change in the nucleotide sequence. These modifications include insertions, deletions, and base substitutions and occur in all classes of RNA. When they occur in mRNA, the amino acid sequence of the protein will be altered relative to the sequence encoded by genomic DNA. RNA editing by deamination results in adenosine (A) to inosine (I) and cytosine (C) to uridine (U). A‐to‐I editing is an abundant class of RNA modifications found throughout metazoans [28]. The conversion of A‐to‐I residues by base deamination results in the synthesis of distinct proteins, which creates functional diversity and serves to enhance the response to rapid environmental changes [29]. RNA editing by deamination is mediated by two major classes of enzymes; the first class is a group of tissue‐specific and context‐dependent adenosine deaminases called ADARs [30–32]. The ADAR enzyme class (adenosine deaminases acting on RNA) catalyzes hydrolytic deamination of A‐to‐I in double‐stranded regions of RNA secondary structure [33]. The second class of enzymes, the vertebrate‐specific apolipoprotein B mRNA editing catalytic polypeptide‐like (APOBEC) family, promotes C‐to‐U editing by cytosine deamination [34]. APOBEC1, the first‐discovered member of the APOBEC family, was characterized as the zinc‐dependent cytidine deaminase which catalyzed a C‐to‐U modification, resulting in an in‐frame stop codon in APOB mRNA [35].
The first transcriptome‐wide and NGS‐based approach for mapping m6A modifications demonstrated the feasibility of identifying RNA modifications across the entire transcriptome and established the field of epitranscriptomics [6]. The most important aspects of NGS‐based techniques are the ability to map modifications on a global scale at the single nucleotide resolution and that the modified nucleotides are analyzed within the context of the surrounding gene sequence. These features insure that the nucleotide modifications are accurately assigned to the appropriate RNA and not falsely attributed to homologous genes or RNA contaminates [6]. Now, several high‐throughput NGS‐based technologies, including RNA‐seq, have been established to profile and quantitate RNA modifications (m6A, m6Am, m5C, m1A, A‐to‐I, Ѱ, and NAD cap). These RNA‐seq‐based methodologies can be divided into two classes: immunoprecipitation‐based and chemical‐based methods. Table 1 lists six representative NGS‐based detection methods of RNA modifications.
Method | Modification | Strategies |
---|---|---|
m6A‐seq [26], MeRIP‐seq [36], m6A‐LAICIC‐seq [37] | m6A, m6Am | Methyl‐RNA immunoprecipitation and UV cross‐linking |
m1A‐ID‐seq [39] | m1A | Methyl‐RNA immunoprecipitation and the inherent ability of m1A to stall reverse transcription |
Bisulfite sequencing [40] | m5C | Chemical conversion of modified nucleotides |
ICE‐seq [42] | A‐to‐I editing | Cyanoethylation of RNA combined with reverse transcription |
Pseudo‐seq [16], Ѱ‐seq [17] | ѱ | Chemical modification to terminate reverse transcription in the pseudouridylated site |
NAD captureSeq [43] | NAD | Chemoenzymatic capture |
NGS‐based methods to profile transcriptome‐wide RNA modifications.
RNA immunoprecipitation (RIP)‐based methods use an RNA modification‐specific antibody or an enzyme‐specific antibody to capture modified RNA followed by RNA‐seq. m6A‐seq [26], methylated RIP‐seq (MeRIP‐seq) [36] and m6A‐level, and isoform‐characterization sequencing (m6A‐LAIC‐seq) [37] combine RNA‐seq with RIP specific for m6A methylation. Figure 1A displays a typical m6A‐seq workflow. RIP is performed using an anti‐m6A antibody to enrich m6A‐modified RNAs followed by cDNA library preparation and high throughput NGS sequencing and finally analysis to identify the occurrence and consensus motif (RRACU) of global m6A modifications. A modified RIP approach, called m6A individual‐nucleotide‐resolution by cross‐linking and immunoprecipitation (miCLIP), uses ultraviolet light‐induced antibody RNA cross‐linking to induce site‐specific mutations at m6A marks. These mutational signatures block reverse transcription and facilitate the detection of m6A marks at single‐nucleotide resolution [38]. As illustrated in Figure 1B, m1A‐ID‐seq, which combines m1A immunoprecipitation and the m1A residue to cause truncated reverse transcription products, has been applied successfully for the transcriptome‐wide characterizations of m1A [39].
Immunoprecipitation‐based strategies to detect RNA modifications. (A) m6A‐seq workflow: RNA immunoprecipitation is done using anti‐m6A antibody to enrich m6A‐modified RNAs followed by cDNA library preparation and high throughput NGS sequencing before occurrence and consensus motif (RRACU) of global m6A modifications are analyzed. (B) m1A‐ID‐seq workflow: RNA immunoprecipitation is carried out using anti‐m1A antibody to enrich m1A‐modified RNAs, which are then subjected to either the demethylase (−) treatment or the demethylase (+). Reverse transcription is stopped at m1A site in demethylase (−) group while extended in the demethylase (+) group. After NGS, m1A site can be identified by comparing the data of the demethylase (−) group to those of the demethylase (+) group.
Chemical‐based methods rely on the misincorporation of nucleotide or nucleotide conversion to truncate or stop RNA products during reverse transcription. RNA bisulfite conversion followed by high‐throughput sequencing (BS‐seq, Figure 2A) is a chemical conversion method based on converting unmodified cytosine residues to uracil and keeping m5C residues unchanged by bisulfite treatment. BS‐seq is the only method currently available for the detection of site‐specific endogenous m5C [40, 41]. Inosine chemical erasing (ICE) uses nucleotide switching to detect A‐to‐I modifications [42]. Inosine ribonucleotides are cyanoethylated with acrylonitrile to form N1‐cyanoethylinosine (ce1I). Subsequently, the Watson‐Crick base pairing of I with C is inhibited by the newly formed N1‐cyanoethyl group of ce1I. Thus, cyanoethylation of I blocks cDNA synthesis by preventing extension of the cDNA that bears a cytosine (C) corresponding to the editing site during reverse transcription. However, I will be replaced by guanosine (G) [42] (Figure 2B). To detect RNA pseudouridylation, several groups developed Pseudo‐seq (Ѱ‐seq). RNA is treated with N3‐[N‐cyclohexyl‐Nʹ‐β‐(4‐methylmorpholinium) ethylcarbodiimide‐Ѱ (N3‐CMC‐Ѱ)], which binds covalently to U, G, and Ѱ residues and then exposed to alkaline pH to reduce stable U‐CMC and G‐CMC adducts. Reverse transcription will pause at the remaining intact Ѱ‐CMC sites, allowing for the mapping of Ѱ‐modifications [16, 17] (Figure 2C). Comparison of mapping reads from CMC‐treated samples versus non‐treated controls, Ѱ will be detected as the sites with an increased proportion of reads supporting reverse transcription termination. NAD captureSeq (Figure 2D) requires the chemo‐enzymatic modification of NAD which is capping the 5ʹ end of RNA. The first step, the transglycosylation of NAD, is catalyzed by ADP‐ribosyl cyclase (ADPRC) from Aplysia californica in the presence of an alkynyl alcohol. In the second step, the modified NAD is biotinylated by a copper‐catalyzed azide‐alkyne cycloaddition. Thirdly, the biotin‐linked RNA is captured on streptavidin beads and processed further for cDNA library preparation and NGS. The NAD‐biotin‐captured sequences are then identified by comparison with the control samples which were not subjected to the first step of chemo‐enzymatic biotinylation [43].
Chemical‐based strategies to detect RNA modification. (A) BS‐seq: Bisulfite selectively converts cytosine, not m5C, into uracil, subsequent to reverse transcription and RNA‐seq processes. After comparison with reference genome or control, m5C residues are identified as cytosine, whereas unmethylated cytosine as thymine. (B) ICE‐seq: The acrylonitrile can cyanoethylate inosine into N1‐cyanoethylinosine (ce1I). Reverse transcription will transcript inosine into cytidine but arrest at the ce1I site after the CE treatment. cDNA library, sequencing, reads mapping, and analysis will detect A‐to‐I sites. (C) Ѱ‐seq: The reagent CMC followed by incubation at alkaline pH leads to hydrolysis of U‐CMC adducts, which are less stable than Ѱ‐CMC. Reverse transcription in Ѱ‐CMC sample will stop at Ѱ site. Following RNA‐seq and reads mapping will detect Ѱ sites with increased transcript termination in the CMC‐treated sample. (D) NAD captureSeq: ADPRC enzyme catalyzes a transglycosylation reaction of NAD with pentynol, which are bound by CuAAC with biotin azide. The RNA with NAD is captured by streptavidin beads before being readied for cDNA library preparation and sequenced for identifying NAD‐capped RNAs.
Although we do not have full knowledge on the effects of RNA modification on physiological function, there is increasing evidence that they play critical roles in the regulation of gene expression, cellular functions, and development. Disruptions of RNA modification mechanisms have also been associated with disease. We present here a few examples, which demonstrate the importance of RNA modification on physiological function.
As stated earlier, m6A modifications are commonly found throughout eukaryotes, as demonstrated by multiple m6A‐seq studies. Human m6A‐seq analyses revealed 12,769 putative m6A sites within 6990 and 250 protein‐coding and non‐coding transcripts, respectively [26], whereas, in mice, 4513 m6A peaks were identified in 3376 and 66 protein‐coding and non‐coding transcripts, respectively [26]. The m6A consensus motif, RRACU, was identified with a median distance from m6A peaks of 24 nucleotides [26]. Interestingly, the majority of m6A sites were conserved between both mouse and human transcriptomes and enriched further within long internal exons and around stop codons, suggesting strong evolutionary selection [26, 36]. m6A‐LAIC‐seq showed that methylated transcripts utilized proximal alternative polyadenylation (APA) sites, which resulted in shorter 3′ untranslated regions, whereas non‐methylated transcripts tended to use distal APA sites [37]. This observation correlated with the finding that m6A‐modified transcripts had both significantly shorter RNA half lives and slightly lower translational efficiencies than unmarked transcripts [44].
In vitro and in vivo genetic depletion of the m6A writer, Mettl3, in both mouse and human, led to the absence of m6A modification within Nanog mRNA which encodes a pluripotency factor. The absence of m6A marks extended Nanog expression throughout differentiation and inhibited embryonic stem cell exit from self‐renewal towards lineage differentiation [44]. m6A‐seq in mouse naïve embryonic stem cells (ESCs), 11‐day‐old embryoid bodies (EBs), and mouse embryonic fibroblasts (MEFs) revealed m6A marks in naïve pluripotency‐promoting genes reduced mRNA stability of key pluripotency‐promoting transcripts and facilitated differentiation [45]. These findings suggest that m6A modification provides the flexibility of the stem cell transcriptome required to differentiate into different lineages [44]. NANOG is also important in both the maintenance and specification of cancer stem cells which can metastasize and form primary tumors. The exposure of breast cancer cells to hypoxia induced the expression of the eraser ALKBH5 which resulted in m6A demethylation in the 3ʹ UTR of NANOG mRNA and the increased half life of NANOG mRNA, thereby promoting the breast cancer stem cell (BCSC) phenotype [46]. The m6A reader YTHDF2 protects the 5′ UTR of stress‐induced transcripts from demethylation. Cap‐independent translation initiation was enhanced by 5′ UTR methylation [47]. m6A modification is critical for the regulation of HIV‐1 replication and HIV‐1\'s effect on the host immune system [48]. HIV‐1 viral infection induced m6A modification in both host and viral mRNAs. HIV‐1 coding, non‐coding, and splicing regulatory regions contained a total of 14 m6A methylation peaks. In addition, methylation of two highly conserved m6A target sites in the HIV‐1 rev response element (RRE) stem loop II region enriched the binding of the HIV‐1 rev protein to the RRE in vivo and enhanced nuclear export of HIV‐1 RNA [48]. The long non‐coding RNA X‐inactive specific transcript (XIST) regulates transcriptional silencing of genes on the X chromosome. XIST is heavily modified with at least 78 m6A sites. Knockdown of METTL3 leads to decreased XIST m6A marks and impairs XIST‐mediated gene silencing [49].
The tRNA T‐loop at position 58 commonly contains a m1A modification [50], along with position 9 of metazoan mitochondrial tRNAs [51] and eukaryotic rRNAs [52]. Initiator tRNAMet contains fully modified m1A 58 which stabilizes its tertiary structure. Hypomodification of tRNA m1A 58 affects the association with polysomes and the subsequent efficiency of translation [53, 54]. m1A modifications in tRNA function in response to environmental stress [55], whereas m1A‐modified rRNA regulates ribosome biogenesis [52]. m1A‐ID‐seq demonstrated that m1A methylation regulated the dynamic response to stimuli and identified 901 m1A peaks enriched within the 5ʹ UTR near the start codons of 600 distinct protein‐coding and non‐coding RNAs [39].
m5C sites have been detected in several eukaryotic tRNA, Rrna, and mRNA. m5C marks stabilize the secondary structure of tRNA, alter aminoacylation and codon recognition [56], and regulate translational fidelity [57]. A low level of internal m5C was found in mRNA cap structures in mammalian‐ and virus‐infected mammalian cells [58, 59]. BS‐seq identified 10,275 sites in protein‐coding and non‐coding RNAs [41]. m5C marks in mRNAs were enriched near argonaute‐binding sites within the 3ʹ UTR [41].
A‐to‐I editing sites are distributed through human mRNA, including exons, introns. and 5ʹ and 3ʹ UTRs [60]. Alu repeat elements contain the highest frequency of A‐to‐I editing sites among the untranslated regions of the genome [61]. Intronic editing mediated by ADAR1 contributes to the maintenance of mature mRNA by protecting it against unfavorable processing of the Alu sequence and by degradation of aberrant transcripts by nonsense‐mediated decay (NMD) [42]. A‐to‐I RNA editing is diminished in brain tissue from patients with Alzheimer\'s disease relative to controls [62]. The reduction occurs predominantly in the hippocampus and to a lesser extent in the temporal and frontal lobes. These alterations result in decreased levels of protein recoding, the process of changing the amino acid sequence by A‐to‐I editing, in Alzheimer\'s disease [62]. The APOBEC3 family of cytidine deaminases has been associated with mutations in cancer genomes in several types of cancer. Accumulated data linking mutations in oncogenes and tumor suppressor genes with APOBEC3B activity are providing evidence that cytidine deaminase‐induced mutagenesis is activated in tumorigenesis, thus providing novel therapeutic targets [63].
Pseudo‐seq revealed that mRNA Ψ marks mRNA are regulated in response to stimuli, such as serum starvation in human cells and nutrient deprivation in yeast. The observations indicate that Ψ triggers a rapid regulatory mechanism to rewire the genetic code through inducible mRNA [16]. Pseudouridylation of rRNA and telomerase RNA component (TERC) were also found to be reduced in dyskeratosis congenita patients [17]. Furthermore, missense mutations in pseudouridine synthase 1 (PUS1) may lead to deficient pseudouridylation of mitochondrial tRNAs in mitochondrial myopathy and sideroblastic anemia (MLASA) patients [64].
NAD captureSeq identified NAD as a 5ʹ RNA cap in a subset of regulatory RNAs in bacteria [43] and subsequently proposed that this type of capping may be common across all of life [65]. It is safe to predict that investigation of the roles and mechanisms of 5ʹ NAD caps in eukaryotes will draw increasing attention in the biomedical field. This is due to mainly two reasons. First, the chemical modification of the 5ʹ end of RNA is critical for RNA processing, localization, stability, translational efficiency, and epitranscriptomic regulation of gene expression [66]. Second, NAD is both a co‐substrate for enzymes, such as the sirtuins and poly(adenosine diphosphate‐ribose) polymerases, and a critical electron‐carrying coenzyme for enzymes that catalyze oxidation‐reduction reactions. NAD is involved in nearly all physiological processes. For example, cellular NAD+ levels are modulated during aging, and the use and production of NAD+ usage has been associated with prolonged health and life spans [67]. Regulation of NAD‐mediated RNA capping and hence gene expression will undoubtedly enrich our understanding of NAD\'s expanding roles in normal physiology and disease pathogenesis.
Although rapid advances have been made in the past few years in epitranscriptomics, more work is needed in this field. To date, more than 140 different RNA modifications have been identified. However, there are only a few reliable high‐throughput techniques available to determine the global occurrence of a particular RNA modification. Thus, there is a need for the development of more high‐throughput techniques to characterize the full spectra of RNA modifications. It is also important to pursue the comprehensive identification and characterization of the enzymes responsible for RNA modification since several of these enzymes have been shown to play important roles in development and disease. It is essential to decipher all functions and disease involvements of all RNA modifications. Development of additional technologies to alter RNA modifications, including the engineering of RNA‐modifying enzymes with modified substrate specificity and activity via the CRISPR‐Cas 9 system, will open the door to new types of detection and analysis pipelines. With further technological development, we will be able to elucidate the sequence‐specific signatures in RNA that direct modifications and then better relate these RNA marks to their corresponding biological functions. Finally, the advancement of current approaches, coupled with new technologies, will allow for the development of new therapies and therapeutic targets for human diseases associated with deficient RNA modification.
Cellulose, a fibrous carbohydrate found in all plants, is the most abundant natural polymer with biomass production of 50 billion tons per year [1]. Cellulose is a linear polymer of glucose. Based on solubility in alkaline, cellulose is divided into three groups which are alpha, beta, and gamma celluloses. Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose having the formula (C6H10O5)n. It is prepared by treating alpha cellulose with mineral acids (type Ib). This polysaccharide polymer consists of a linear chain of several hundred to over ten thousand β(1 → 4) linked D-glucose units, consisting of linear chains of β-1,4-
Non-woody lignocellulosic materials have also been developed as source of MCC such as cotton linters [5], cotton stalks [6], cotton rags [5], cotton fabric waste [7], cotton wool [8], soybean husk [9], corn cob [10], water hyacinth [11], coconut shells [12], oil palm biomass residue [13, 14], oil palm fronds [15], rice husk [6, 16], sugar cane bagasse [6, 16, 17, 18, 19, 20], jute [21, 22], ramie [23], fibers and straw of flax [24], wheat straw [25], sorghum stalks [26], sisal fibers [27] and mangosteen [28], alfa grass fibers [29, 30], soybean hulls [31], orange mesocarp [32], Indian bamboo [33], roselle fiber [34], and alfa fiber [35]. Seed flosses from milkweed pods (Calotropis procera), shrubs, and kapok (Ceiba pentandra) trees are also known as cellulosic resources. Due to its high purity of alpha cellulose, most seed flosses must be treated to remove impurities including lignin, pectin, and wax [36].
Wooden sources contain cellulose chains which are packed as layers held by cross-linking hydrogen bonds [37]. Chemically it consists of polymeric matrix of lignin, hemicelluloses, and pectin [38]. Different woods considerably possessed different chemical composition of cellulose (including allocations of cellulose, hemicelluloses, and lignin in cell wall) and structural organization as well. Relatively different crystallinity in particular regions is observed as more amorphous according to softwoods (evergreen conifer) and hardwoods which are termed as deciduous broadleaf [4, 37]. The amorphous regions of cellulose provide a more susceptible property for depolymerization by acid hydrolysis. At optimum acid concentration, the process gave shorter and more crystalline fragments such as the MCC [2, 37].
The MCC can be synthesized by different processes including extrusion and enzyme-mediated process [25]. Other studies reported that it can also be synthesized by steam explosion and acid hydrolysis process [5, 6]. The acid hydrolysis process is more preferable due to shorter duration than others. It also offered the possibility to be applied as a continuous process rather than a batch-type process. Limited quantity of consumed acid is also the advantage of the process, while, despite the lower unit cost from less chemicals used, this process offered more fine particles of the MCC as the final product [5]. Fibrous plant pulp is hydrolyzed by mineral acid under heat and pressure. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which soluble components of cellulose such as beta and gamma celluloses, hemicelluloses, and lignin are dissolved with acid and water, are separated out during washing process by water which continued by filtration. The obtained pure alpha cellulose has then been neutralized and given the slurry final product [3]. This suspension is dried to obtain the insoluble white, odorless, tasteless powder, which has later been characterized as MCC [39]. MCC is hygroscopic in nature, and insoluble in water, but swells when in contact with water.
Another synthesis procedure of the MCC reported by Ohwoavworhua et al. [40] can be concluded as follows: the α-cellulose was hydrolyzed with hydrochloric acid at a boiling temperature of 105° for 15 min. The neutralized slurry obtained from the hydrolysis process was washed, and the fraction passing through 710 μm sieve was stored at room temperature in a desiccator. MCC is commonly dried from the slurry by spray-drying method. By varying spray-drying conditions, the degree of agglomeration and moisture content can be manipulated. In order to obtain smaller particle sizes (below 50 μm), further milling MCC can be performed [1].
Other drying techniques may be used, which may require additional screening steps postdrying in order to control particle size distribution [41, 42]. Higher bulk density grades are also available by using specific cellulose pulps (raw material), and median particle sizes below 50 mm can be obtained by further milling MCC [1].
Several studies have compared microcrystalline cellulose with various sources, including different manufacturers and different sites [4, 43, 44, 45, 46, 47]. MCC produced by various manufacturers or in various manufacturing sites may have different properties due to the kinds of pulp used as raw materials and their respective manufacturing conditions [2, 4]. A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and viscoelastic properties [48].
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 process on yield value of production is shown in Tables 1 and 2.
Type | Conc. | Hydrolysis condition | MCC-Y (%) | Duration (minute) | References | |
---|---|---|---|---|---|---|
L/C (vol./wt) | Temperature (°C) | |||||
HCl | 2 N | 10:1 | 105 | 15 | n.a | [5] |
HCl | 2 N | 10:1 | 45 | 15 | n.a | [6] |
HCl | 2.5 N | 20:1 | 85 | 90 | 80 | [5] |
HCl | 2.5 N | 62.5:1 | 105 | 15 | 19 | [6] |
HCl | 2 N | 10:1 | n.a | 45–60 | n.a | [7] |
Hydrolysis reagents (acid type and concentration), liquor to cellulose ratio (L/C), hydrolysis conditions, and yield of microcrystalline cellulose (MCC-Y) hydrolysis reagent.
MCC Type | Particle size (micron) | Utilization |
---|---|---|
PH 101 | 50 | It is most widely used for direct compression tableting, for wet granulation, for spheronization, and in capsule filling processes |
PH 102 | 100 | It is used as the PH-101, but its larger particle size improves the flow of fine powders |
PH 103 | 50 | It has the same particle size as PH-101 with lower moisture content (3%), so it is used for moisture-sensitive pharmaceutical active ingredients |
PH 105 | Less than 50 | It is the most compressible of the PH products owing the smallest particle size. Well known as excipient for direct compression for granular or crystalline materials. When mixed with PH-101 or PH-102, specific flow and compression characteristics will be obtained. It has applications in roller compaction |
PH 112 | 100 | It has the same particle size as PH-102. It has lower moisture content (1.5%). It is used for high moisture-sensitive pharmaceutical active ingredients |
PH 113 | 50 | It has the same particle size as PH-101. It has lower moisture content (1.5%). It is used for high moisture-sensitive pharmaceutical active ingredients |
PH 200 | 180 | It has a large particle size with increased flowability. It is used to reduce weight variation and to improve content uniformity in direct compression formulations and in wet granulation formulations |
PH 301 | 50 | It has the same particle size as PH-101 but is denser providing more flowability and tablet weight uniformity. Useful for making smaller tablets and in capsule filling excipient |
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].
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, 58, 59, 60]. MCC particle size and moisture content are often considered as the most important CMAs for tableting performance [61]. Considering that the brittle-ductile 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 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].
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 the drug dissolution which may due to porosity [70].
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 observation indicates that crystallinity cannot be controlled at the hydrolysis stage. Crystallinity appears to be more dependent on pulp source rather than on processing conditions [4], which is consistent with the method of MCC manufacture where the acid preferentially attacks the (pulp dependent) amorphous regions.
The total amount of sorbed water in MCC is proportional to the fraction of amorphous material [48, 54, 55]. Therefore MCC powders with a lower degree of crystallinity may contain more water than their counterparts with a higher degree. If low-crystallinity MCC preferentially binds more water, moisture-sensitive APIs may exhibit lower rates of degradation [71]. Despite the controversial impact of crystallinity, it may influence the adsorption of water on cellulose microfibrils, which may in turn influence flowability, tabletability, and stability of the drug product.
Mostly, direct compression excipients are spray-dried; therefore porous structure was produced as a result. This property is characterized by a relatively low bulk density. Increase in porosity (lower density) facilitates higher compressibility, i.e., the densification of a powder bed due to the application of a stress [56]. The improved compressibility of plastically deforming materials, such as MCC, might then result in improved tabletability as a result of the increased bonding surface area [72]. The higher roughness of low density MCC particles may also contribute to particle interlocking [73]. Low bulk density MCC will provide higher dilution potential and hence better counteract the poor tableting properties of APIs. Granulation or drying as preprocesses of tablet formulation will densify MCC hence less tabletable than the original porous MCC [74, 75]. It can therefore be generalized that a decrease in bulk density improves tabletability; however, it will often hinder flowability [62].
The degree of polymerization (DP) expresses the number of glucose units (C6H10O5) in the cellulose chain. It decreases exponentially as a function of hydrolysis conditions, including temperature, acid concentration, and time of reaction. The rate of hydrolysis slows down to a certain value which is stated as level-off degree of polymerization (LODP). The LODP value is specific for a particular pulp, and it is usually between the range of 200 and 300 [44, 61], e.g., 180–210 range for hardwood pulps and 210–250 for softwood pulps. Theoretically, to obtain a certain degree of polymerization which is higher than the LODP value, hydrolysis process could be terminated at any time. However, due to the exponential decay of DP, this termination is neither a robust nor a reproducible approach. The degree of polymerization is used as an identity test, as pharmacopoeial MCC is defined by a DP below 350 glucose units, compared to DPs in the order of 10,000 units for the original native cellulose [1].
The correlation between the degree of polymerization (DP) of MCC and its tabletability has not been explored yet. Therefore, it is merely an identity test to distinguish the tabletability of MCC (DP < 350) compared with powdered cellulose (DP > 440). Dybowski showed that the origin of the raw materials and the production method of MCC more decisively influence the physical characteristics than DP. DP value is a criterion used to guide the manufacturer about hydrolysis of MCC, whereas for the user it is a characteristic to distinguish between properties of MCC and powdered cellulose.
Wood pulps with high bulk density grades which can be characterized by lower level-off DP should not be directly compared with standard grades. This parameter reflects the lack of distinction between the degree of polymerization (DP) and level-off degree of polymerization (LODP). LODP is typical of a particular raw material, with a common value between the range of 200 and 300 [44]. Cellulose having LODP value at this range usually difficult for further hydrolysis. In contrast, cellulose materials with DP values higher than the level-off degree of polymerization plateau are more difficult to control due to their greater sensitivity to hydrolysis. Owing LODP above 200–300, the MCC remains to be more fibrous, which would result in a lower bulk density, with improved tabletability, but would hinder powder flow [49, 50]. Below the LODP MCC is less fibrous, denser, and less tabletable. Tabletability is not related to a particular DP value; as an example powdered cellulose has a higher DP than MCC but is not as tabletable [1].
Landín et al. compared four brands of MCC [45]. Different woods used as raw materials, i.e., hardwood versus softwood, suggested differences in lignin and hemicelluloses composition. The non-cellulose component has also significantly different manufacturing process intensities which resulted in variable suggestive composition and potentially varying qualities of product. Landín et al. found that lignin content increased the dissolution rate of prednisone [46]. Lignin being hydrophobic may alter cellulose–cellulose and/or cellulose–API interactions and hence drug release rate.
Thoorens et al. [37] studied that differences in packing and flow properties which are shown by scanning electron micrographs from Avicel PH-101 and Avicel PH-102 were attributed to differences in moisture content, particle shape, and particle size distribution. Tabletability which also varied among the MCC samples were attributed to the differences in moisture content and the internal structure of the particles. These are mostly caused by different processing conditions which are specific to each manufacturer. However, the impacts of crystallinity and particle morphology are negligible. Significant differences in lubricant sensitivity, compressibility, and tablet disintegration were also noted between MCCs due to various manufacturing processes by different manufacturers. Variability between lots from the same manufacturer was found to give a smaller effect on properties of MCC product. A current study from Doelker concluded that even if all of various MCCs comply with compendial specifications, large differences still exist among them [44].
According to the International Pharmaceutical Excipient Council (IPEC), excipients are the process aids or any substances other than the active pharmaceutical ingredient that are included in pharmaceutical dosage forms. The functionalities of excipient are to impart weight, consistency, and volume which allow accuracy of dose, improve solubility, and in the end increase stability. It can also be proposed to enhance bioavailability, modifying drug release and used in product quick identification, increase patient acceptability, and facilitate dosage form design.
Excipients classified as:
Primary excipients: diluents (filler), binders (adhesives), disintegrants, lubricants, antiadhesives, glidants
Secondary excipients: coloring agents, flavors, sweeteners, coating agents, plasticizers wetting agents, buffers, and adsorbents
Diluents are incorporated into tablet or capsule dosage forms to increase dosage form volume or weight and can also be referred as fillers. Direct compression binders are functional even at low use levels and offer superior tabletability [1]. Some diluents, such as microcrystalline cellulose, can also be considered as dry binders since they improve the compactibility or tabletability of the compression mix.
Microcrystalline cellulose, according to many publications, is an excipient of outstanding merit and remains the most widely used direct compression excipient serving as a strong dry binder, tablet disintegrant, an absorbent, filler or diluent, a lubricant, and anti-adherent.
MCC is generally considered as the diluent having the best binding properties and is recognized as one of the preferred DC binders [44, 76]. It is used as a binder/diluent in oral tablet and capsule formulations including both wet granulation and direct compression processes. It also has some lubricant and disintegrant properties which is useful in direct tableting. Small amounts of MCCs are able to efficiently bind other materials, especially poorly tabletable active pharmaceutical ingredients. MCC exhibits a high dilution potential, whereas the broad particle size range provides optimum packing density and coverage of other materials [44, 54].
MCC has been the most favorite diluent among others due to its low bulk density. Excipient having low bulk density and large particle size distribution will exhibit a high dilution potential on a weight basis, optimum packing density, and coverage of drug and other excipient materials [77].
MCC is commercially available in different particle sizes, density, and moisture grades that have different properties and applications. The most widely pronounced grades are Avicel PH 101 and Avicel PH 102 (FMC Corporation, Princeton, NJ, USA). PH stands for the pharmaceutical grade of MCC. Avicel PH 101 is the original grade of MCC, while PH 102 is available as a partially agglomerated product with a larger particle size distribution and slightly better fluidity. Both grades show no significant difference in the compressibility [78].
MCC has been very well known as the most compressible of all direct compression fillers which has the highest dilution potential and capacity. It is defined as the amount of active ingredient that a diluent can successfully carry in the direct compression method. This property can be explained by the basis of the physicochemical nature of MCC particles, which are held together by hydrogen bonds. MCC particles are deformed plastically under compaction forces to yield an extremely large number of clean surfaces brought in contact during this deformation, forming a strong compact even under low compression forces [78].
Direct compression (DC) is the tableting process of a blend of ingredients without a preliminary granulation or agglomeration process. Despite involving only few process steps, product design in DC can be challenging because of the numerous competing objectives [79]. Direct compression requires increased performance, quality, and consistency from the starting ingredients including excipients [44, 56, 80, 81]. The use of poorly controlled or inadequately specified raw materials may lead to several challenges in DC, such as poor flowability and inconsistent tablet weight, unsatisfactory tablet strength, lack of content uniformity or segregation, and dissolution failure [56, 82, 83]. Among several requirements, the compression mix has to flow to ensure a consistent tablet weight; it has to compress and compact into robust tablets. Overall, as a direct compression filler, Avicel promotes efficient dry blending of ingredients and produces tablets with high hardness levels and low friability levels with excellent compression. It produces tablets of superior whiteness and color stability.
Lately, MCC can be considered as the most widely used diluent in the direct compression and wet granulated tablet making procedures. MCC type 102, having a median particle size of about 100 mm (D50 value measured by laser diffraction), presents acceptable flow properties required for successful high-speed tableting [2, 84]. However due to the low bulk density of MCC, its mass flow is less than that of other common and denser excipients such as direct compression grades of lactose or dibasic calcium phosphates [43, 44, 59, 82]. Avicel grades (Avicel PH-102 SCG, Avicel HFE-102, Avicel PH-200, Avicel PH-302) provide excipient solutions to many challenges of direct compression formulations including improved flow, better compressibility, and accommodation of moisture-sensitive actives [78]. The larger particle size grades generally provide better flow properties, while low-moisture grades are used for moisture-sensitive materials. Higher-density grades have improved flowability. Flowability may be improved by selecting coarser grades of MCC with a larger number of aggregates, such as MCC type 200 with a median particle size approximating 200 mm [58, 85].
The difference between these common excipients is less pronounced on a volumetric basis [86], which determines die fill. Another approach may be to combine MCC with other free flowing excipients or glidants [59, 62, 87]. Gamble et al. observed that the particle size distributions of coarser grades of MCC do not scale up proportionally [58]. MCC types 101, 102, and 200 all have primary particles of about 50 mm but differ in the number of larger aggregated particles. These aggregates, accounting for a large volume/mass fraction but a low number fraction, enable improved flow.
During compression, MCC plastically deforms and therefore maximizes the area of interparticle bonding [88]. Mechanical interlocking of irregularly shaped and elongated MCC particles has also been suggested to enhance tabletability [44, 60, 75]. The plasticity of MCC is the main reason of its exceptional binding properties. However, compared to brittle excipients, MCC is more lubricant sensitive. For a constant number of revolutions, tabletability may also decrease with increasing blender sizes and decreasing loadings in the blender [89]. The viscoelastic behavior of MCC also explains its strain rate sensitivity (SRS), which refers to the greater elastic effects at higher tableting speeds where there is insufficient compaction time for plastic deformation [90]. The strain rate sensitivity of viscoelastic excipients has to be taken into account by the formulation scientists in order to design robust formulations.
MCC is one of the types of filler which is water insoluble having swelling tendencies and excellent water imbibing or wicking action. Other filler examples with the same property are calcium pectinate and sodium alginate. This property makes MCC as also an excipient of choice for wet granulation. Both Avicel PH 101 and Avicel PH 102 can be used advantageously as fillers in wet granulation in a concentration of 5.15%. When used as filler in wet granulation method, the wicking action of MCC promotes rapid wetting of the powder mix. Another advantage offfered by using MCC as wet granulation filler is the ability to retain water, which makes the wet mass less sensitive to overwetting due to an excess of granulating fluid. The milling of the wet mass will be much easier due to less clogging of the screen; hence it will produce a more uniform granules. Drying process also will be more homogeneous, and the case of hardening can be reduced. Case hardening is a phenomenon which is observed in incompletely dried granules. This case happened when the granules are dried at a high temperature, from which the inside part of the granules remains wet, while the surface seems dried. The granules are often hard and resist disintegration. When coming to compaction process, the compression forces will break the granules and deform plastically to form soft tablets due to the moisture coming out of the incompletely dried granules. The use of Avicel PH 101 or Avicel PH 302 as filler in wet granulation promotes rapid wetting as a result of the wicking action of MCC. They reduce sensitivity of the wet mass to overwetting and increase the drying process speed. Since there is fewer excess of granulating fluid, screen blockages and case hardenings can be reduced. Homogeneous and uniform granule when MCC is used as wet granulation filler will reduce dye migration. When MCC is employed, faster disintegration from granules and tablets will be obtained.
Basically, using MCC in wet granulation included wetting MCC with water followed by drying and compression. The process resulted in lower hardness tablets than that with dry compression. The wet granulation reduces the density of agglomerated particles thereby decreasing their internal surface area. In contrast, it can also cause adhesion between particle agglomerates, reducing external surface area resulting in less particle interlocking and hydrogen bonding. In general, using Avicel PH-101 or Avicel PH-102 in wet granulation formulations with concentration between 5 and 20% offers the following benefits [51]:
Rapid adsorption of water by MCC and distribution through the mixture
Decrease of sensitivity to water content, wet screening, and localized overwetting due to the large surface area of MCC, hence high adsorptive capacity
Increased drying efficiency
Decreased color mottling
Better drug content uniformity
Higher tablet hardness at the same compression force with less friability
Roller compaction is a dry process involving compaction of materials that are then milled to generate a granulation. This granulation is then lubricated and compressed on a tablet machine. This process can be used for moisture-sensitive active pharmaceutical ingredients. The use of Avicel PH grades in roller compaction includes improvement of compaction in the ribbon phase, enhancement of flow of the granules, and preserving of the content uniformity of the Þ nal granulation.
MCC is a self-disintegrating binder [91] with low lubricant requirement with regard to its dry binding properties due to the extreme low coefficient of friction and its very low residual die wall pressure [56, 62, 92]. However these properties do not replace the need for true disintegrants and lubricants as an addition when MCC is used in a tablet formulation. In fact combination of MCC and superdisintegrants may be complementary to promote fast disintegration [93, 94]. Other advantages of MCC include broad compatibility with various APIs, physiological inertness, ease of handling, and ease of supply for manufacturer [54].
Study on the use of MCC with spray-dried lactose as the poorest compressibility among all directly compressible fillers showed that a blend of 200 mg of spray-dried lactose with appropriate lubricants may not be able to compress unless a correct amount of dry binder is incorporated inside the blend. Incorporation of 2.5% of Avicel to the formulation proved that MCC has served the purpose. A number of Avicel such as PH-113 can act as a dry binder [95]. However, it will also function as a disintegrant when dry compression is employed.
MCC can also be used as a secondary binder in wet granulation tablet preparation either to granulate both soluble and insoluble APIs. This formulation will produce less hard tablets than that without MCC. The fast wicking action of MCC promotes rapid wetting of the powder mix. This is particularly useful in high moisture granulations as it binds the excess moisture and keeps the granules dry and free flowing.
Disintegrants expand and dissolve once it is in contact with water causing the tablet to break apart in the GI tract and release the active ingredients for absorption. It will break a tablet into smaller fragments therefore increasing the surface area of the active drug in the dosage form; hence it will also increase the rate of drug absorption. The mechanism of disintegrants in the tablet disintegration could be as either water uptake facilitators or tablet rupture promoters. MCC has been widely used as a disintegrant in dry compressions and wet granulation method for tablet manufacturing. It enhances drug dissolution by increasing the rate of tablet disintegration. Basically a disintegrant should provide the highest level of disintegration force at low use levels and utilizes dual disintegration mechanisms either in wicking or swelling for faster tablet disintegration.
The Avicel derivate showed the nature in a fast wicking rate of water with small elastic deformation. These properties provide the ability for tablet disintegration. However, Avicel has a tendency to develop static charges with increased moisture content. Sometimes it even can cause striation or separation in the granules. This occurs when the moisture content in Avicel is above 3%, in which the static charges during mixing and compression become more pronounced. The problem can be overcome by drying the Avicel prior the formulation process to reduce the moisture to lower level. Wet granulated Avicel will lose some of its disintegration properties when performing drying and compression during formulation [4]. In contrast with starch, it cannot be wet granulated without losing some of its disintegration properties. Normally, to overcome this problem, Avicel and starch are used in combination in order to facilitate effective and rapid disintegration of tablets.
MCC has a very high intraparticle porosity with approximately 90–95% of the surface area being internal [44]. Therefore the surface area is not directly influenced by the nominal particle size [58]. High porosity of MCC promotes swelling and disintegration of formulated tablets, which is attributed to either by the penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores or even by a disruption of the hydrogen bonds. By increasing compaction pressure, water penetration into the tablets will decrease; therefore disintegration time will increase [54, 85].
In intramolecular view, water is only sorbed in the amorphous regions of MCC, which are more hydrophilic than the crystalline regions [3, 54]. Therefore the total amount of sorbed water is proportional to the fraction of amorphous material in the MCC crystallinity and is independent of the surface area [48]. The crystallinity of MCC determined by X-ray diffraction and infrared measurement was found to be in the range of 60–80% [53].
Recently, Avicel has been used as a disintegrant in orally disintegrating tablets. Besides being a disintegrant, it also acts as a dissolution enhancer. US Patent No 6350470 explains the use of Avicel as a disintegrating agent in effervescent drug delivery system for oral administration. In this system, by performing dry granulation, Avicel acts as disintegrant in a concentration of 5.20% [96]. Avicel acts as an effervescent penetration enhancer.
Lubricants ensure that tablet formation and ejection can occur with low friction between the solid and die wall.
Avicel has an extremely low coefficient of friction, both static and dynamic, so that it has no lubricant requirement itself. However, when more than 20% of the drug and other excipients are added, lubrication is necessary.
In tablet formulation, glidant is used to promote powder flow by reducing interparticle friction and cohesion. Glidants can be used in combination with lubricants as they have no ability to reduce die wall friction. Normally, silica-based glidants like silicon dioxide, hydrated sodium silicoaluminate, silica hydrogel, etc. are used in tablet compression to promote good flow property. Proslov as a marketed product of coprocess excipient containing MCC is available which imparts superior flow, good compactibility, and dispersion to tablet formulation [97].
When used as excipient in direct compression, Prosolv SMCC® (JRS Pharma, Patterson, NY) can replace granulation step and significantly reduce excipient numbers and levels. Prosolv SMCC® formulations produce distinctive, uniform, and cost-effective tablets. It is available in three grades: Prosolv SMCC 50, Prosolv SMCC 90, and Prosolv SMCC HD 90. The products differ in average of particle size and bulk density [98]. They offer many benefits including enhanced mixing characteristics, enhanced flow properties, lower unit cost of production due to less excipients needed, and shorter disintegration time. Due to improvement in powder compactibility and dust-free handling during production, Prosolv facilitates less loss in production hence a higher manufacturing efficiency.
In a more recent study, it is reported that silicified MCC and MCC were found to be good plug formers in hard gelatin capsule shells. The study was conducted in a compaction simulator at tamping forces and piston speeds similar to those found in some filling machines. Several grades of silicified MCC and a particular grade of MCC having particle size of 90 μm produced plugs with a higher maximum breaking force than anhydrous lactose and Starch 1500 under similar compression conditions [99].
MCC is an excipient of choice in a multiparticulate delivery of pellets prepared by extrusion spheronization. The extrusion-spheronization process aims to produce drugs into sphere-shaped tablets. Extrusion-spheronization process offers an alternative to traditional drug layering on pellets. This highly specialized process results in unique spherical, drug-loaded spherical pellets. Higher drug loading can be employed with this approach over that which looks impossible with conventional drug layering. The product, initially called as extrudates, is plastic without rigidity, which tends to agglomerate into very large spherical balls. The formulation mixture which will be manufactured by extrusion method must fulfill the requirements:
Cohesive and deformable in order to have good flow through the die without sticking and able to retain its shape after extrusion process
Plastic, so that it can proceed rolling process into spheres in the spheronizer but possesses non-cohesive property so that the final sphere form can remain discrete
MCC, especially Avicel PH-101, can act as an excellent extrusion-spheronization aid excipient that absorbs the water added to the formulation more as a molecular sponge. This ability alters the rheological properties of the wet mass, therefore enhancing the tensile strength of the wet mass during spheronization process through autoadhesion.
Avicel® PH-101 or Avicel PH-102 is highly recommended to be used for this method because it can reduce spheroid friability, prevent overwetting of spheres, and improve sphericity of pellets. Process sensitivity during the whole manufacture can be lessened to the lower level.
Recently, MCC has been widely used in the formulation of multiparticulate and matrix tablet dosage forms for sustained release drug delivery system. In general, hydrophilic polymers in matrix tablet formulation are included to form a viscous, gelling layer which can retard water penetration and acts as a barrier to drug release. Drug release is accomplished by diffusion through the gel layer and at the same time through erosion of this layer. Some studies proved that zero-order release profiles can be achieved by selection of appropriate polymers in addition of Avicel as fillers/binders.
Microcrystalline cellulose is a pure partially depolymerized cellulose synthesized from α-cellulose precursor with hydrolysis by mineral acids, usually in forms of a pulp from a fibrous plant. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which more soluble, such as beta and gamma celluloses, hemicelluloses and lignin are dissolved with acid and water, are separated out during washing. MCC is commonly dried from the slurry by spray-drying method. By varying spray-drying conditions, the degree of agglomeration and moisture content can be manipulated, in order to obtain particular particle sizes.
Mostly, a raw material for MMC is a cellulose pulp from fibrous plant such as conifer wood. Another source is from cotton either its linters, stalks, rags, fabric waste, or wool. Another study reported a potential source for MCC such as soybean, corn cob, water hyacinth, coconut shells, oil palm biomass residue, oil palm fronds, rice husk, sugar cane bagasse, jute, ramie, fibers and straw of flax, wheat straw, sorghum stalks, sisal fibers, mangosteen, alfa grass fibers, soybean hulls, orange mesocarp, Indian bamboo, roselle fiber, and alfa fiber. Seed flosses from milkweed pods, shrubs, and kapok (Ceiba pentandra) trees are also known as sources of cellulose.
A different manufacture will produce variability in properties of MCC due to the kinds of pulp used as raw materials and applied process parameters. This can be characterized from the physicochemical properties of product including moisture content, particle size, particle morphology, crystallinity, bulk density, and degree of polymerization.
Microcrystalline cellulose, according to many publications, is an excipient most widely used for direct compression. Besides, it also serves as a strong dry binder, tablet disintegrant, absorbent, filler or diluent, a lubricant, and anti-adherent.
Authors are listed below with their open access chapters linked via author name:
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\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
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\\n\\nXin-She Yang 2017, 2018
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\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
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\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
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\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
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\n\nXin-She Yang 2017, 2018
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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