Chemical characterization of DPLF before and after TEMPO-mediated oxidation.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3116",leadTitle:null,fullTitle:"Advances in Industrial Design Engineering",title:"Advances in Industrial Design Engineering",subtitle:null,reviewType:"peer-reviewed",abstract:'A fast paced changing world requires dynamic methods and robust theories to enable designers to deal with the new product development landscape successfully and make a difference in an increasingly interconnected world. Designers continue stretching the boundaries of their discipline, and trail new paths in interdisciplinary domains, constantly moving the frontiers of their practice farther. \nThis book, the successor to "Industrial Design - New Frontiers" (2011), develops the concepts present in the previous book further, as well as reaching new areas of theory and practice in industrial design. "Advances in Industrial Design Engineering" assists readers in leaping forward in their own practice and in preparing new design research that is relevant and aligned with the current challenges of this fascinating field.',isbn:null,printIsbn:"978-953-51-1016-3",pdfIsbn:"978-953-51-6319-0",doi:"10.5772/3415",price:119,priceEur:129,priceUsd:155,slug:"advances-in-industrial-design-engineering",numberOfPages:252,isOpenForSubmission:!1,isInWos:1,hash:"9cb2d954a2f9ea36c3d0f915a7fcd8ad",bookSignature:"Denis A. 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Whizar-Lugo and Dr. José Ramón Saucillo-Osuna",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10708.jpg",keywords:"Regional Anesthesia, Ultrasound-Guided Regional Anesthesia, Local Anesthetics, Preventive Analgesia, Peripheral Blocks, Pediatric Regional Anesthesia, Intravenous Regional Anesthesia, Techniques, Complications, Adjuvants in Regional Anesthesia, Opioids, Alfa2 Agonists",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 23rd 2021",dateEndSecondStepPublish:"March 23rd 2021",dateEndThirdStepPublish:"May 22nd 2021",dateEndFourthStepPublish:"August 10th 2021",dateEndFifthStepPublish:"October 9th 2021",remainingDaysToSecondStep:"18 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Whizar-Lugo has published more than 100 publications on Anesthesia, Pain, Critical Care, and Internal Medicine. He works as an anesthesiologist at Lotus Med Group and belongs to the Institutos Nacionales de Salud as an associated researcher.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"169249",title:"Prof.",name:"Víctor M.",middleName:null,surname:"Whizar-Lugo",slug:"victor-m.-whizar-lugo",fullName:"Víctor M. Whizar-Lugo",profilePictureURL:"https://mts.intechopen.com/storage/users/169249/images/system/169249.jpg",biography:"Víctor M. Whizar-Lugo graduated from Universidad Nacional Autónoma de México and completed residencies in Internal Medicine at Hospital General de México and Anaesthesiology and Critical Care Medicine at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in México City. He also completed a fellowship at the Anesthesia Department, Pain Clinic at University of California, Los Angeles, USA. Currently, Dr. Whizar-Lugo works as anesthesiologist at Lotus Med Group, and belongs to the Institutos Nacionales de Salud as associated researcher. He has published many works on anesthesia, pain, internal medicine, and critical care, edited four books, and given countless conferences in congresses and meetings around the world. He has been a member of various editorial committees for anesthesiology journals, is past chief editor of the journal Anestesia en México, and is currently editor-in-chief of the Journal of Anesthesia and Critical Care. Dr. Whizar-Lugo is the founding director and current president of Anestesiología y Medicina del Dolor (www.anestesiologia-dolor.org), a free online medical education program.",institutionString:"Institutos Nacionales de Salud",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],coeditorOne:{id:"345887",title:"Dr.",name:"José Ramón",middleName:null,surname:"Saucillo-Osuna",slug:"jose-ramon-saucillo-osuna",fullName:"José Ramón Saucillo-Osuna",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000033rFXmQAM/Profile_Picture_1611740683590",biography:"Graduated from the Facultad de Medicina de la Universidad Autónoma de Guadalajara, he specialized in anesthesiology at the Centro Médico Nacional de Occidente in Guadalajara, México. He is one of the most important pioneers in Mexico in ultrasound-guided regional anesthesia. Dr. Saucillo-Osuna has lectured at multiple national and international congresses and is an adjunct professor at the Federación Mexicana de Colegios de Anestesiología, AC, former president of the Asociación Mexicana de Anestesia Regional, and active member of the Asociación Latinoamericana de Anestesia Regional.",institutionString:"Centro Médico Nacional de Occidente",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Dr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"38380",title:"TEMPO-Mediated Oxidation of Lignocellulosic Fibers from Date Palm Leaves: Effect of the Oxidation on the Processing by RTM Process and Properties of Epoxy Based Composites",doi:"10.5772/47763",slug:"tempo-mediated-oxidation-of-lignocellulosic-fibers-from-date-palm-leaves-effect-of-the-oxidation-on-",body:'Lignocellulosic fibers display many well-known advantages as compared to their synthetic counterparts, including their being ecologically and toxicologically harmless, biologically degradable, and carbon dioxide (CO2) neutral. Furthermore, natural fibers are characterized by a huge degree of variability and diversity in their properties. As they could be extracted from wood and annual plants, they are available in various forms, give a feeling of warmth to the touch, and have a pleasant appearance. None of these properties are offered by other non-wood engineering fibers.
Over the last two decades, a great deal of work has been dedicated to composites reinforced with natural fibers. Indeed the use of such natural product for the reinforcement of thermoplastic or thermosetting resins, leads to composites with lower density, higher specific stiffness and strength, together with a better biodegradability (Bledzki et al., 1999; Mishra et al., 2004; Zimmermann et al., 2004; Gandini, 2008). However, only few studies have dealt with polymers reinforced with lignocellulosic fibers obtained from palm trees (Abu-Sharkh and Hamid 2004; Wan Rosli et al. 2004; Kaddami et al. 2006; Bendahou et al. 2008 ; Sbiai et al. 2008; Bendahou et al. 2009). In the previous investigations (Kaddami et al. 2006; Bendahou et al. 2008; Sbiai et al. 2008), the reinforcing capability of palm tree fibers in thermoset or thermoplastic polymer matrices was demonstrated. In the case of epoxy-based composites, expected and strong interactions gave rise to enhanced mechanical and thermal characteristics. An increase in the glass transition temperature and an improvement of the thermo-mechanical properties, bending moduli, stress at break values, and maximum absorbed energies were reported for composites based on fibers modified with acetic anhydride (Kaddami et al. 2006). The size of the fibers was also found to have an effect on the properties (Sbiai et al. 2008).
Reinforcement is the physical expression of the microscopic balance at the matrix/filler interface which makes up a filler network. Thus, the adhesion filler/matrix is the most important parameter governing reinforcement. It is required to render possible the transfer of mechanical constraints to the fiber when a load is applied to the composite. This adhesion can be enhanced through chemical or physical modification of the polymer and/or the filler. Such modifications depend on the physico-chemical nature of the matrix.
In most cases, the hydrophilic nature of the lignocellulosic fibers is detrimental for their interface interactions with common resins, which are mostly hydrophobic. Thus, chemical treatments have to be applied to overcome this issue (Reich et al., 2008). For this purpose, various surface modifications have been devised to selectively replace hydroxyl functions with hydrophobic groups (Duanmu et al., 2007; Biagiotti et al., 2004; Goussé et al., 2004; Gandini, 2008). Coupling agents giving rise to covalent junctions between the fibers and the matrix have also been described (Abdelmouleh et al., 2002; Paunikallio et al., 2006; Gonzalez-Sanchez et al., 2008; Bendahou et al., 2008).
Among modifications used to improve interfacial adhesion in natural fiber/polymer composites, oxidative treatments have received much attention during the seventies and eighties. Corona and plasma treatments were found to effectively enhance the interface in epoxy-based composites (Sakata et al 1993a,b), and chemical oxidative treatments have been widely reported in several studies for numerous composites of natural fiber and polymers. Many types of oxidants have been employed, e.g. dichromate/oxalic acid, ozone, potassium ferricyanide, ferric chloride, nitric acid, hydrogen peroxide, dicumyle peroxide, etc. (Sapieha et al 1989; Felix et al 1994; Cousin et al 1989; Kaliński et al. 1981; Raj et al. 1990; Felix and Gatenholm 1991; Flink et al. 1988; Young 1978; Moharana et al. 1990; Gardinera and Cabasso 1987; Zang and Sapieha 1991; Iwakura et al. 1965; Jutier et al. 1988; Michell et al. 1978; Coutts and Campbell 1979; Tzoganakis et al. 1988; Sung et al. 1982; Philippou et al. 1982; Manrich et al. 1989; Sapieha et al. 1991).
More recently, 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation of polysaccharides bearing primary alcohols has been intensively studied. This type of oxidation makes it possible to selectively oxidize, in aqueous medium, primary alcohol groups into carboxyl groups in natural polysaccharides (Isogai, and Kato 1998; Isogai and Saito 2005; Isogai et al. 2005; Davis and Flitsch 1993; De Nooy et al. 1995\n\t\t\t\tFukuzumi et al. 2009; Chang and Robyt 1996; Tahiri and Vignon 2000; Habibi et al. 2006).
Among composite processing techniques, resin transfer molding technique (RTM) has been widely used. This technique was used for high-performance air craft and automotive structures. This process can be divided into four stages: performing, mould filling, curing, and demoulding. First, the dry fiber preform is made and placed in the mould. The mould is filled with liquid resin which is then solidified in the curing stage. Note that the curing stage actually begins as soon as the resin is mixed. However, usually the process is designed such that cure proceeds slowly until the mould has been filled. Once cured, the part is removed from the mould. In some cases, the part is demoulded before complete cure and post-cured in an oven. The purpose of this process was to improve the quality (dry spots, voids) and processability and to minimize the material wastage. In conventional fibers as glass fibers and carbon fibers when these fibers are presented in the form of bundles, the flow of resin through the preform is governed by two mechanisms: bulk flow and fiber wetting. Bulk flow occurs in the space between the fiber tows, whereas fiber wetting occurs within the fiber tows (O’Flynnet al 2007, Octeau 2001, Chu 2003). The interaction between matrix and reinforced fiber was particularly important to the RTM process (Nguen-Thuc et al 2004).
Many studies have been done on the kinetics of the polymerization systems epoxy / amine (Eloundou et al. 1996a and 1996b, Halley et al. 1996, Pichaud 1996, Pascault et al 2002, Nguen-Thuc et al 2004). The chemical reaction between the epoxy prepolymer and diamine hardener can lead, depending on the stoichiometry to formation of a network. It can occur during growth of the macromolecular chains, two structural transformations: gelation and vitrification. At the beginning of the reaction, when the glass transition temperature Tg is less than the reaction temperature, the reaction is controlled by chemical kinetics. At the gel point, the formation of macromolecular chains leads to a gelling phenomenon that characterizes the transition from a liquid to a rubbery state while the vitrification phenomenon reflects a shift from the rubbery state to glassy state (Eloundou et al. 1996a, Halley et al. 1996, Pascault et al 2002). At our knowledge no studies had been dedicated to the effect of the lignocellulosic fibers on the polymerization kinetic.
Leaflets from palm leaves of P. dactylifera were cut into pieces with lengths of 3 to 5 cm. After 24 h soxhlet extraction with acetone/ ethanol (75/25 by vol), the resulting product was slightly discolored. It was then ground and sieved in order to eliminate the fine powder and to keep only the particles with length ranging from 2 to 10 mm and widths from 0.2 to 0.8 mm. this material is hereafter called lignocellulosic fibers from date palm leaflets or DPLF. For XRD analysis, the samples were ground again to obtain a fine powder.
Cellulose, lignin and hemicellulose were extracted from the DPLF according to a previously described procedure (Bendahou et al., 2007). Cellulose whiskers were prepared from the rachis of P. dactylifera leaves (Bendahou et al., 2009).
2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO), sodium bromide, and 10% sodium hypochlorite solution were purchased from Sigma-Aldrich and used as received.
2g of DPLF were stirred in 200 mL distilled water for 1 min. TEMPO (32 mg, 0.065 mmol) and NaBr (0.636 g, 1.9 mmol) were dissolved in the suspension maintained at 4 °C. TEMPO-mediated oxidation was initiated by adding dropwise the sodium hypochlorite solution (10 %, 32 ml, 43 mmol) and adjusting the pH at 10 by addition of a 0.1 M aqueous HCl. The suspension was then maintained at pH 10 ± 0.5 by continuous addition of 0.5 M NaOH and at 4 °C by means of a thermo-controlled bath. When the pH became stable, the reaction was quenched by adding methanol (5 mL). After neutralization of the reaction mixture to pH 7 by addition of 0.1M HCl, the suspension was filtrated and the solid particles were washed with distilled water and dried under vacuum at 30 °C for 18 hours. The soluble part was freeze-dried.
The same oxidation procedure was applied to the other samples, namely the cellulose, the hemicellulose and the lignin extracted from the DPLF, together with the cellulose whiskers extracted from the leave rachis.
The composition of the DPLF before and after oxidation i.e. the weight fraction of their cellulose, hemicellulose, and lignin contents was determined by selective extraction according to the NF T12-011 standard.
The carboxylate content of oxidized cellulose samples was determined by conductometric titrations (Saito & Isogai, 2004).
Infrared spectra were recorded on a FT-IR Perkin-Elmer 1720X spectrometer collecting 20 scans from 400 to 4000 cm-1. Oxidized DPLF was converted to its acid form by ion exchange in order to displace the carboxyl absorption band toward higher wavelengths, thus eliminating any interference with the absorbed water band at 1640 cm-1. Consequently the superposition of the sodium carboxylate peak with those of the hydrogen bonds could be avoided. The samples were dried with acetone and analyzed as KBr.
The XPS spectra were measured using an AXIS ULTRA DLD X-ray photoelectron spectrometer (KRATOS ANALYTICAL). Samples were dried at 50°C under vacuum during 24h, and set with conductive carbon adhesive tabs. The measurements were performed using a monochromatic Al Kα X-ray with a pass energy of 160 eV and a coaxial charge neutralizer. The base pressure in the analysis chamber was smaller than 5×10-8 Pa. XPS spectra of O1s and C1s levels were measured at a normal angle with respect to the plane of the surface. High resolution spectra were corrected for charging effects by assigning a value of 284.6 eV to the C1s peak (adventitious carbon). Binding energies were determined with an accuracy of ±0.2 eV. The spectral decomposition of the C1s and O1s photoelectron peaks was carried out using a Shirley background at positions and FWHMs corresponding to known components, applying a 30% Lorentzian-to-Gaussian peak shape ratio.
The distribution of sodium and calcium ions present in a cross-section of the TEMPO-oxidized fibers was evaluated by the line analysis mode using an energy dispersive X-ray (EDX) device fitted into a scanning electron microscope (SEM) (Hitachi S3500 N). The X-ray detector was a Thermo Noran Superdry II having a resolution of 143eV. The analyses were performed without prior metallization of the samples.
A Philips X’Pert diffractometer equipped with a ceramic X-ray diffraction tube operated at 40 kV and 40 mA with CuKα radiation (wavelength 0.15418 nm) was used to determine the crystalline index of the specimens. The samples were compressed into disks using a cylindrical steel mould (Ø = 15 mm) with an applied pressure of 32 MPa. The diffracted intensity was recorded for 2θ angles in the range of 10 to 40°. Data were treated according to the empirical Segal method (Segal et al., 1959).
DPLF samples were oxidized with TEMPO in aqueous medium. The experiments were performed (i) at low temperature (4 °C) to avoid the formation of side products and (ii) in the presence of a large quantity of sodium hypochlorite, i.e., 21 mmol per gram of the DPLF, in order to reach a high degree of oxidation (Montanari et al., 2005; Okita et al., 2009). The selective oxidation of a hydroxymethyl group to a carboxyl via an aldehyde requires two moles of NaOCl per mole of hydroxyl according to the known TEMPO mechanism (Figure 1) (De Nooy et al., 1995). The kinetic of the reaction was directly followed by addition of an aqueous NaOH solution which neutralizes the carboxylic acid functions resulting from the oxidation. Figure 2 clearly illustrates the efficiency of the reaction with a continuous increase in NaOH consumption over a period of 720 minutes. According to FTIR analysis on the water insoluble fraction (Figure 3), a stretching vibration C=O from the free COOH band near 1737 cm-1 was seen to have a higher intensity in the case of oxidized fibers as opposed to their non-oxidized counterparts, thus providing evidence of the oxidation. Finally, as expected, the degree of oxidation (Do) was found to be 0.71 ± 0.02 (Table 1).
Scheme of the catalytic cycle for the oxidation of a primary hydroxyl.
The composition of DPLF was also investigated since a significant amount (30%) of the material became soluble in water during the oxidation. The results presented in Table 1 show that the proportions between components of DPLF have changed before and after the chemical oxidative treatment. Thus cellulose content has increased from 35 to 46 %, whereas lignin and hemicelluloses contents have decreased. Nevertheless both lignin and hemicelluloses were still present in the oxidized DPLF at high concentration respectively 12 and 34 weight percent. Okita et al., have reported on a complete elimination of lignin and hemicelluloses in the case of TEMPO-mediated oxidation of thermomechanical softwood pulp under similar processing conditions (Okita et al., 2009). Pulp used by these authors contained similar percentage of lignin and hemicelluloses but was pried open by the mechanical refining process. One can thus deduce that thermomechanical pulps are much more reactive than lignocellulosic fibers having undergone no activation. On the other hand, a weak increase of the crystalline index is observed. This could be explained by the dissolution of the lignin after oxidation. Actually, this dissolution would induce a weak decrease of the intensity of the amorphous peak Iam at 2θ = 18° (Table 1 and supporting info S1).
Kinetic TEMPO-mediated oxidation of DPLF, the extracted cellulose and lignin from DPLF: Consumption of the NaOH with the reaction time.
In order to compare the reactivity toward oxidation of each component of the DPLF, cellulose, hemicelluloses and lignin were extracted and subjected to the oxidation procedure. Kinetic data were recorded, except for hemicelluloses which presented very fast and uncontrollable kinetic. Data illustrated in Figure 2 clearly show that the extracted lignin reacted faster than the extracted cellulose, whereas the DPLF presented an intermediate rate. The structural characterization of the oxidized lignin and hemicellulose was not undertaken due to the complexity of possible structures. However, a previous study has shown that hemicelluloses extracted from the leaflets and rachis of the P. dactylifera palm consist of arabinoglucuronoxylans, which are either soluble or insoluble in hot water depending on the molar content of 4-O-methyl-glucuronic acid (Bendahou et al., 2007). One can thus deduce that the oxidative treatment under aqueous conditions allowed the conversion of the hydroxymethyl group of the arabinose moieties into carboxylic functions, which further facilitated the hemicellulose extraction in reaction medium maintained at 4°C. For lignin, the conversion of primary hydroxyl functions led to hydrosoluble products as already described (Okita et al., 2009).
Samples | [COOH] mmol/g | Crystalline Index % | Composition Cellulose./ Hemicellulose./Lignin % | Water insoluble fraction % |
Control DPLF | 0 | 49.5+/-0,5 | 35 / 28 / 27 | 100 |
Oxidized DPLF | 0.71 | 52.5+/-0,5 | 46 / 34 / 12 | 70 |
Chemical characterization of DPLF before and after TEMPO-mediated oxidation.
The reason for the moderate reactivity of the cellulose was already described. It originates from the crystalline nature of cellulose and from the difficulty to access to the hydroxyl groups at the surface of the cellulose crystals. In contrast, lignin and hemicelluloses, which are amorphous, react faster. The TEMPO-mediated oxidation of the cellulose sample was confirmed by the appearance of the characteristic carboxylic signal at 176 ppm in the 13C CP-MAS NMR spectrum (Wikberg & Maunu, 2004; Martins et al., 2006) corresponding to a degree of oxidation (Do) equal to 0.07 (See supporting info S2 and S3).
FT-IR spectra for DPLF before (I) and after TEMPO-mediated oxidation (II).
Only few kinetic studies of TEMPO-mediated selective oxidation of cellulosic material have been reported in the literature (De Nooy et al., 1995; Sun et al., 2005; Mao et al., 2010). The authors have observed a first-order kinetic with respect to TEMPO and NaBr as well as a rate constant determined by their concentrations. It has also been claimed that the NaOCl concentration affects mainly the level of the conversion, leading to the possibility of reusing the reaction liquid by addition of more NaOCl. However, although TEMPO-mediated oxidation of cellulose corresponds to a reaction between a solid phase and a liquid phase, the heterogeneous aspect of the reaction was never envisaged.
In fact, cellulose fibers can be represented as accessible porous networks, where reagents can diffuse to the periphery of entities made up of bundles of cellulose microfibrils surrounded with lignin and/or hemicelluloses. This system can be described as a cylinder (Figure 4) with a diameter that becomes decreased when the Tempo-mediated oxidative process progresses.
Schematization of the reactive substrate presented as a cylinder.
The interfacial specific rate ris of an heterogeneous reaction can be expressed by equation 1 where R and H are respectively the radius and the height of the cylinder and k the rate constant for a given temperature and concentration (Levenspiel, 1972).
Considering R0 as the initial radius, the conversion of the reaction at time t, is given by
Since the initial molar concentration of the reactive function is n0, its decrease with time can be described by equation 3:
Where:
Equation 3 can be simplified into:
Which, after integration, gives the following relation:
By expressing the time required for a complete conversion to occurs as:
and rearranging the relation, one obtains:
The conversion X was calculated from the evolution of the NaOH consumption given in Figure 2 and the evolution of (1 – X)1/2 was plotted as a function of t. The results are presented in Figure 5, and as illustrated, the experimental values followed a linear equation as predicted by the model. The value of tFinal calculated from the slope of the curves was 11× 103 minutes.
Additional experiments were attempted, using cellulose whiskers extracted from the rachis of the from P. dactylifera palm. Here, the advantage was to have a pure cellulose substrate with a known length and a squarish cross-section. Consequently, the shape of the cellulose whiskers could be modeled as that of a cylinder (Elazzouzi-Hafraoui et al., 2008). The results presented in Figure 5 are also compatible with a heterogeneous model and clearly highlight that cellulose whiskers behave in a manner analogous to that of DPLF. However for the whiskers, the tFinal was higher (1.1×104 minutes) than for DPLF which caused the specific rate ris of the TEMPO-mediated oxidation to decrease. The difference can be ascribed to high reactivity of DPLF which contain lignin, hemicelluloses and amorphous cellulose being more reactive than cellulose whiskers.
Modeling of the kinetics of TEMPO-mediated oxidation for (♦) DPLF: (1-X)1/2 = 1 – 4,93.10-4t and (ο) cellulose whiskers from data palm rachis: (1-X)1/2 = 1 – 8,71.10-5t.
From the aforementioned model it can be inferred that the oxidation reaction occurs through a heterogeneous process. To characterize the topology of the chemical changes, X-rays photoelectron spectroscopy (XPS) and energy dispersive X-rays analysis were carried out on DPLF before and after oxidative treatment.
XPS revealed the modifications resulting from the oxidation (Figure 6). Indeed the C1s spectrum of the control product (spectrum a) consists of three major peaks at 284.6 (peak 1), 286.2 (peak 2) and 287.8 eV (peak 3), corresponding to C-C + C-H, C-O and O-C-O (and / or C=O) groups respectively. After oxidation (spectrum b), a new peak can be clearly distinguished at 288.8 eV and is attributed to the O=C-O function, typical of carboxylate group. This signal is overlapped with the one of the C=O group and is probably also present in the C1 spectrum of the control product but at lower level. In addition, a quantitative analysis indicates that the atomic concentration of non-oxidized carbon (peak 1) is of 71.2 % and 64.4 % before and after oxidation respectively. Assuming that XPS analysis only characterize a depth of 10 nm, these results clearly highlight that carboxylate functions are present at the top layers of DPLF.
High resolution C1s spectra for DPLF (a) and after (b) TEMPO-mediated oxidation.
The location of carboxylate groups was clearly evidenced by the characterization with SEM/EDX analysis. In Figure 7 are represented typical cross-sections of DPLF showing also the external wall of the fibers before oxidation (Figure 7a), after oxidation (Figure 7b) and after oxidation and calcium ions exchange (Figure 7c). Zones which are colored correspond to the location of the counter-ion of carboxylate functions. The more intense the coloration, the higher is the concentration of the counter-ion and therefore the carboxylate function.
Figure 7a shows the DPLF before oxidation and the coloration represents the mapping of sodium ions due to the presence of 4-O-methyl-glucuronic acid units within the raw fibers as mentioned above. The density of initial carboxylate is low in comparison to the one observed in the case of oxidized fibers (Figure 7b) indicating the success of the oxidation treatment. TEMPO-oxidized fibers treated within an aqueous calcium chloride solution led to fibers-COOCa+ structures (Saito et al., 2005). As shown in Figure 7c, the density of calcium ion is high and comparable to that obtained with sodium.
It can also be noted that carboxylate groups are found to be slightly more dense at the surface of the fibers than inside, whereas the distribution at the surface is homogeneous and the one inside inhomogeneous. Such difference between the core and the surface which is confirmed with both mapping of calcium and sodium ions was never reported before.
Energy dispersive X-ray analysis on fiber cross-section (a) before oxidation, (b) after oxidation, (c) after oxidation and ion-exchanged with CaCl2.. The colored parts correspond to the presence of the counter-ion of the carboxylate function: sodium in case of 7a and 7b and calcium in case of 7c.
This feature may be ascribed to the presence of hemicelluloses and lignin, which either limit the diffusion of the reagent within the fibers or –which is more probable - migrate to the surfaces after being oxidized. It is also important to underline that the morphology of the fibers remains identical after the TEMPO mediated-oxidation as shown in Figure 7.
3.1.1.1. Polymer matrix
The polyepoxy matrix was obtained through a polymerization reaction of an epoxy prepolymer with an amine curing agent. The selected epoxy resin was di-glycidyl ether of bisphenol A (DGEBA) (Ref.: LY 556 ) supplied by Ciba-Geigy, and the curing agent was isophorone diamine (IPD) supplied by Fluka-Chemika. The characteristics of these components are presented in Table 2. The curing was carried out according to the following setup: 2 h at 80 °C, 2 h at 120 °C, and 2 h at 160 °C.
Component | Chemical structure | Characteristics |
Prepolymer DGEBA | Ciba Geigy LY 556 n = 0.15 M = 380 g/mol d = 1.169 g/cm3 f = 2 | |
isophorone diamine | Fluka–Chemika M = 170 g/mol d = 0.92 g/cm3 g = 4 |
Chemical characteristics
3.1.1.2. Reinforcement fiber preparation
The lignocellulosic fibers were obtained by cutting date palm tree leaves into small pieces of approximately 5 cm long and 10 mm wide. The fibers were then extracted for 24 h in a Soxhlet reflux of a solvent mixture composed of acetone/ethanol (75/25). Subsequently, the discolored fibers were dried at room temperature. The used fibers were denoted as unmodified. The length and width of these fibers ranged from 2 to 10 mm, and 0.2 to 0.8 mm, respectively. They were obtained by grinding and sieving the bleached fibers in a 0.1mm-hole sieve to eliminate particles designated as fines, after which they were further sieved through 0.8 mm holes to eliminate bigger fibers.
Fibers oxidation experiments were made under the following conditions. The following samples were oxidized separately. Samples (fiber, cellulose, lignin, and hemicellulose) (2 g, i.e., 12.35 mmol of anhydroglucose units) were dispersed in distilled water (200 ml) for 1 min with a mechanical agitator. TEMPO (32 mg, 0.065 mmol) and NaBr (0.636 g, 1.9 mmol) were added to the suspension, which was maintained at 4 °C. The sodium hypochlorite solution (10 %, 32.17 ml, 43.21 mmol) with pH adjusted to 10 by addition of a 0.1 M aqueous HCl was set at 4 °C by means a thermocontrolled bath. The mixture was then added to the suspension, which was stirred mechanically. The pH was maintained at 10 during the reaction by addition of a 0.5-M NaOH solution. The temperature of the suspension was maintained at 4 °C by means of a thermocontrolled bath during the oxidation reaction. When the reaction time exceeded 12 h, the kinetics became very slow and the solution turned a yellowish white. The reaction was stopped by adding 5 ml of methanol.
The reaction mixture was neutralized to pH 7 with 0.1 M HCl. The oxidized sample was washed with distilled water, after which it was filtered and dried at room temperature. The fiber oxidation was characterized by various methods (IR, conductimetry, solid-state NMR, XPS, MEB, EDX, X-ray diffraction) (Sbiai and al 2010). In the following, the oxidized fibers are referred to as modified fibers.
3.1.1.3. Composite processing
Composites were processed using the resin transfer molding (RTM) method. This process can be divided into four stages: performing, mould filling, curing, and demoulding. The epoxy resin was stored in container A while container B contained the curing agent IPD. The resin mixtures were preheated at approximately 60 °C to reduce the viscosity. The resin was degassed for 20 min to prevent voids from forming during pumping. In container B, IPD was kept at room temperature under an argon atmosphere in order to avoid evaporation and carboxylation. A good circulation of the resin throughout the pump and pipes was necessary. A mold (100 × 60 × 6 mm3) made of a composite material, was preheated at 80 °C for 2 h before injection. A continuous mat of date palm tree fibers (either unmodified or modified (oxidized)) used as reinforcement was placed in the mold cavity under isothermal conditions. To observe the flow of the resin during the injection process, a transparent mold made of glass was used under equivalent conditions. A camera was employed to observe the process, which was deemed to have come to an end when the resin was seen to exit from the vent at the other side of the mold. Upon completion of the cure cycle, the solid composite parts were ejected and post-cured under the same conditions as the pure matrices.
3.1.2.1. Chemical composition of the fiber
The chemical compositions of the dried date palm tree fibers were determined according to French Standards (NFT12-011). It was thus possible to assess the weight fraction of cellulose, hemicelluloses, and lignin.
3.1.2.2. Scanning Electron Microscopy (SEM)
SEM was used to investigate the morphology of the different types of materials, as well as the filler/matrix interface. The microscope was an ABT-55. The specimens were frozen in liquid nitrogen, fractured, mounted, coated with gold/palladium, and observed using an applied voltage of 10 kV.
3.1.2.3. Differential Scanning Calorimetry (DSC)
A Mettler TA3000 calorimeter was used to measure the glass transition temperature, Tg, which was taken as the onset temperature of the specific heat increment. The heating rate was fixed at 10 °C min-1, and scans were recorded under an argon atmosphere (flowrate10 mL min-1) in a temperature range between -100 and +200 °C.
3.1.2.4. Dynamic Mechanical Analysis (DMA)
DMA experiments were performed with a Rheometrics RDAII, equipped for rectangular samples and working in shear mode. Values of the shear storage, G’, and shear loss, G’’, moduli as well as the tangent of the loss angle, tanδ = G’’/G’, were determined. This apparatus was especially dedicated to the study of films and composite materials. The average typical dimensions of the composite samples were 20x4x1 mm3. The tests were performed under isochronal conditions at 1 Hz, and each sample was heated from -120 to +200 °C at a heating rate of 2K/min. The maximum shear strain was equal to 0.2%.
3.1.2.5. Non-linear mechanical properties
Three-point bending tests were performed according to the international ISO178 standard to determine the flexural strength (MPa), the flexural modulus (GPa), and the total absorbed energy (J) of the composites. The testing machine was a 2/M type supplied by MTS (load cell: 10kN). The samples were parallelepiped bars with dimensions close to 60x10x5 mm3 and the distance between the supports was fixed at 50 mm. Tests were carried out at room temperature, and the data collected on five samples was averaged.
Results of the chemical composition of the different fibers are presented in Table 3. It can be clearly seen that the chemical oxidation induced a significant decrease of the lignin content and an increase of that of the cellulose and hemicelluloses. This was explained by the oxidation followed by the dissolution of lignin during the TEMPO-mediated oxidation.
Constituent | Raw dried palm tree fibers (wt %) | Oxidized fibers (wt %) |
Cellulose Hemicelluloses Lignin | 35 % 28 % 27 % | 46 % 34 % 12 % |
Chemical Composition of Date Palm Tree Fibers Before (raw dried palm tree fibers) and After (modified (oxidized) fibers) the Chemical Oxidative Treatment (Sbiai et al. 2010).
With regard to the observation of front displacement in the mat during the RTM experiments, there was a large difference between the two kinds of fibers. In fact, in the case of unmodified fibers, the front displacement was slow and heterogeneous, whereas in the case of the oxidized fibers, it was faster and homogeneous. This difference is portrayed in Fig. 8, presenting the photos of the fronts taken after 15 seconds of resin injection. In fact, the distance covered by the resin front was higher in the case of the oxidized fibers. On the other hand, the mat of oxidized fibers was homogeneously traveled by the resin, as compared to the mat of unmodified fibers.
These differences could be explained by variations in compatibility between the resin and the filler in the two systems, giving rise to a difference of interaction at the resin/fiber interface. In fact, the carboxylic groups at the fiber surface, in addition to the low amount of lignin in the case of the modified fibers, helped increase the affinity of the epoxy resin with the oxidized fibers. These observations were very important for the control of the process. On the other hand, one can predict some effects of the fiber oxidation on the morphologies and the properties.
RTM experiment: the resin front after 15 second of injection (at T° = 25°C and P = 1.5 bar) on a mat of (a) unmodified and (b) TEMPO-mediated oxidized date palm tree fibers
Figures 9 and 10 show SEM micrographs of freshly fractured surfaces of composite materials based on the polyepoxy matrix filled with unmodified and modified fibers, respectively. Reinforced materials were investigated. For each composite material, at least tree magnifications were used to reveal the effect of the fiber treatment on the interfacial adhesion. For the unfilled material, i.e. the thermoset matrix (Fig 9-a), the fracture surface
Scanning electron micrographs of freshly fractured surfaces of polyepoxy /unmodified fiber composites with (a) 0 wt%, and (b, c, d, e) 10 wt % of unmodified date palm tree fibers at various magnifications
was rather smooth, as could be expected for brittle polymers. By comparing these micrographs with those of the composite materials (Fig 9 b, c, d and e), the fibers could be clearly identified. The SEM micrographs in Fig. 9 indicated that the interfacial adhesion between the filler and the matrix was not very strong in the case of composites based on unmodified fibers. In fact, the fibers were pulled out from the matrix and their surface remained practically clean (see Figs 9-b and 9-c). On the other hand, fracturing the samples did not lead to the palm tree fibers breakage (Figs 9-d and 9-e). However, it is worth noting that the interaction between the unmodified fibers and the matrix was superior to that of the composite constituted of a hydrophobic matrix filled with unmodified fibers, such as unsaturated polyesters, polypropylenes or polyethylenes.
In contrast, for the composites containing modified fibers, the micrographs in Fig. 10 are evidence of a better adhesion between the matrix and the filler. One can observe the absence of holes around the fillers on the fractured surface, i.e. no debonding occurred. Nor was there any breakage of fibers during fracture (See Fig. 10-c and 10-d). On the other hand, the area surrounding the cellulosic filler seemed to be continuous with the matrix phase, and the epoxy resin appeared to be polymerized within the fiber lumens (see Figs. 10c and 10-d). This variation in interfacial adhesion between the composites based on unmodified and modified fibers is attributed to difference in the nature of physico-chemical interactions that can be created at the interface. This difference can be explained from the stronger interaction developed by the carboxylic groups created on the modified fibers. On the other hand, the dissolution of lignin after fiber oxidation gave rise to an increase of the hydrophilic character of the fibers. As a consequence, the wettability of the fiber surface with regard to the epoxy resin - a necessary condition for good interfacial adhesion - was superior in the case of the modified fibers. The introduction of the epoxy resin within the lumen was evidence of this higher thermodynamic affinity between the fibers and the polyepoxy matrix.
As mentioned above Section 2, the thermal behavior of date palm tree fiber-based composites was investigated by DSC. The glass transition temperatures, Tg’s, of these materials are listed in Table 4. The Tg of the unfilled epoxy matrix was around 155°C. Table 3 clearly shows that the introduction of the lignocellulosic fibers led to a decrease in Tg. This decrease was more pronounced in the case of composites based on unmodified fibers.
The decrease in Tg could be explained by an unbalance of the stoichiometric ratio in the matrix as well as in the vicinity of the fibers after mixing with fibers. The fibers could have more affinity with one component as opposed to with another. This resulted in a hindering of the cross-linking process of the polyepoxy resin.
These results were completely opposite to those obtained in the case of composites based on an industrial epoxy matrix (DGEAB (AW106)/Jeffamin (HV953U)) supplied by CIBA – GEIGY. For the latter composites, an increase in Tg was observed after the introduction of the lignocellulosic filler (Kaddami et al 2006; Sbiai et al 2008). This difference could be attributed to the difference of resin and polymerization kinetics.
Scanning electron micrographs of freshly fractured surfaces of polyepoxy /modified fiber composites with 10 wt % of modified date palm tree fibers at various magnifications.
Sample | Tg | Tα | G’c | G’c/G’m | |
°C | °C | Mpa | |||
Neat epoxy | 155 | 150 | 9.69 (G\'e) | 1 | |
Composites based on unmodified fibers | 5 wt% | 147 | 148 | 14.4 | 1.49 |
10 wt% | 148 | 148 | 22.2 | 2.29 | |
15 wt% | 145 | 149 | 25.9 | 2.67 | |
Composites based on oxidized fibers | 5 wt% | 147 | 146 | 11.5 | 1.19 |
10 wt% | 137 | 145 | 17.8 | 1.84 | |
15 wt% | 137 | 148 | 16.4 | 1.69 |
The Glass Transition Temperature, Tg, Determined from DSC Measurements, the Main Relaxation Temperature, Tα, the Rubbery Storage Shear Modulus at Tg + 50 °C, the G’c, of the Composite Materials and the Relative Shear Modulus, G’c/G’m (where G’m refers to the rubbery shear storage modulus of the neat epoxy) Determined from DMA Experiments
The mechanical behavior of all specimens was investigated under both linear (DMA measurements), non-linear conditions (three-point bending experiments), and Charpy impact tests.
3.2.5.1. Dynamical mechanical analysis
The dependence of log G’, i.e. the logarithm of the shear storage modulus, and the loss factor tanδ, vs. the temperature at 1Hz are displayed in Figs. 11 and 12, for composite materials based on unmodified and modified fibers, respectively.
All materials exhibited a relaxation process that was associated with the glass-rubber transition of the matrix, displayed as a sharp decrease in modulus and a concomitant maximum of the loss factor. This relaxation process, denoted α, involved the release of cooperative motions of the chains between crosslinks. The relaxation temperature, Tα, corresponding to the maximum of the loss factor is listed in Table 3, and was found to be approximately 150°C for all materials. A slight decrease in Tα was observed for the composites based on modified fibers; however it was less significant than the one observed for theTg, as obtained by DSC.
From the dependence of log G’ vs. temperature, it was clear, for both kinds of fibers (oxidized and not oxidized), that the modulus at the rubbery state increased with the fibers content. However, it was difficult to observe any significant effect of the filler at low temperature, i.e. in the glassy state. A simple mixing rule rendered it possible to account for this fact. As is well known, the exact determination of a sample’s glassy modulus depends on the precise knowledge of the sample dimensions. On the other hand, the water absorption could affect the exact determination of the glassy modulus. Therefore, the reinforcing effect of the filler was estimated in the rubbery region of the polymer matrix. The values of the rubbery shear modulus are reported in Table 4, as are the relative rubbery modulus values corresponding to the ratio of the rubbery modulus of the composites, G’c, divided by that of the neat matrix, G’m. Since the modulus was not perfectly constant as a function of the temperature, the G’ values reported in Table 3 correspond to averages.
For all the composites, the reinforcement effect of the lignocellulosic filler (modified or unmodified) was observed in the rubbery sate. It could be quantified through the values of the relative rubbery modulus, which increased up to 1.84 and 2.67, respectively, for the composites based on the modified and unmodified fibers. The increase in modulus upon filler addition was ascribed to the difference between the modulus of the neat matrix (polyepoxy) and that of the lignocellulosic fibers, as well as to the decent interactions at the interfaces of these composites. No significant effect of the fiber modification was observed on the rubbery modulus despite the fact that TEM microscopy demonstrated the presence of better interactions at the interface in the case of the composites based on modified fibers.
a) The shear storage modulus Go, and (b) the loss factor tanδ vs. temperature at 1 Hz for composites based on unmodified date palm tree fibers with (◊) 0, (▲) 5, (●)10 and (X) 15 wt.-% of filler
a) The shear storage modulus Go, and (b) the loss factor tanδ vs. temperature at 1 Hz for composites based on modified date palm tree fibers with (◊)0, (Δ) 5, (O) 10, and (X) 15 wt.-% of filler.
3.2.5.2. High strain behavior (three-point bending test)
Storage shear modulus values measured through DMA experiments were determined at room temperature. High strain experiments should provide information on the mechanical properties at the glassy state. Figure 13 gives typical load vs. displacement curves obtained from the three-point bending experiments for the neat polyepoxy matrix and composites filled with 15 wt.-% of modified and unmodified date palm tree fibers. These curves were obtained in the glassy state of the matrix, and the tests were conducted for all materials filled with 5, 10, and 15 wt.-% of modified and unmodified date palm tree fibers. The mechanical properties derived from these experiments are presented in Fig. 14.
Panels a and b of Fig. 14 show the evolution of the shear modulus and the upper yield stress as a function of the filler content. The data were obtained from the three point bending tests. As expected, the composites were more brittle than the neat matrix. The composite material reinforced with the modified filler displayed higher mechanical properties as compared to the composite filled with the unmodified filler. In fact, the composites with modified fibers showed a higher modulus and a higher upper yield stress.
Load versus displacement curves obtained from three-point bending tests performed at room temperature (25 °C) for epoxy-based composites filled with : (Δ) 0, (O)15wt% of non-modified fibers and (◊)15 wt % of oxidized palm tree fibers.
3.2.5.3. Charpy impact tests
Figure 15 shows the results of Charpy impact tests. The absorbed energy at break is presented as a function of the filler content. These tests confirmed that the composites were brittle. In fact, a lower energy was required for breaking the composite materials as compared to the neat matrix. On the other hand, and within the error margins, no significant difference was observed between the composites based on modified and unmodified fibers.
Mechanical properties as functions of the filler content, obtained from three-point bending tests of epoxy based composites filled with (O) modified and (◊) unmodified. a) Shear modulus; b) upper yield stress
The absorbed energy as a function of the filler content, obtained from Charpy impact tests of epoxy based composites filled with (O) modified and (◊) unmodified fibers fibers
A Mettler Thermoanalyser TA3000 operating in the -100°C to 300°C temperature range and equipped with a liquid nitrogen cooling system, was used to determine the enthalpy of reaction, the glass transition temperature Tg, which was taken as the onset temperature of the deflection heat capacity change, and variation of the heat capacity ΔCp through the Tg of the samples. The heating rate was 10 °C min-1 in a nitrogen atmosphere (flowrate10 mL min-1). The Tg0 and the heat capacity of the initial unreacted mixture ΔCp0 were determined during a first scan, the fully cured material glass transition temperature Tg∞ and its corresponding heat capacity change ΔCp∞ were obtained after curing at 160 °C with vaccum.
Isothermal cures were examined at various reaction times. The Conversion, x, can be deduced from DSC Scans and calculated from the following equation:
Where
The gel time was studied by a Couette Rheometer called Rheomat 115 (Cf. Table 5) with a shear rate of 1 s-1 and a period of 30 to 60 minutes. The principle of the apparatus is to measure the viscosity of the mixture as a function of time. The sample in liquid form is placed in a cylindrical tube and the bucket used is the one called D.
Mode | Temperature | Sensors | Frequency | Tools |
- Viscosity versus shear rate - Time study | Tmax = 100°C | - Viscosity from 1 mPa.s to 5. 105 Pa.s - Shear stress from 2 Pa to 35.103 Pa | - N : from 5 to 780 min-1 - N/100 : from 0,05 to 780 min-1 | 2 bucket used C & D. |
Rheometer characteristics
4.2.1.1. Epoxy filled by unmodified fibers
To cure thermoset polymers it’s important to have information about the thermal properties of the starting monomers but also of the fully cured polymer. On the other hand, in order to understand the final morphology and properties, the study of the evolution of the glass transition during the network formation is of great interest. Thus, the glass transition temperature (Tg) of the epoxy networks based on DPLF fibers (from 5 % wt to 15 % wt) epoxy blends was investigated using DSC analysis. Table 6 lists the experimentally obtained values of Tg0, Tg∞, ΔCp0, ΔH0 (relative to the mass of the reactive system), ∆Cp∞ and λ (defined as ratio of ΔCp0 and ∆Cp∞) for each DGEBA/IPD /fibers DPLF blend studied. Not that the ratio is still stoichimetric.
Material | Tg0 (°C) | ∆Cp0 (J.g-1.K-1) | ∆H0 (J/g) | Tg∞ (°C) | ∆Cp∞ (J.g-1.K-1) | |
Neat epoxy | -30 | 0,57 | 463 | 152 | 0,28 | 0,49 |
Epoxy with 5 % wt of unmodified fibers | -29 | 0,47 | 420 | 144 | 0,28 | 0,60 |
Epoxy with 10 % wt of unmodified fibers | -30 | 0,52 | 401 | 135 | 0,32 | 0,62 |
Epoxy with 10 % wt of TEMPO oxidized fibers | -30 | 0,54 | 413 | 119 | 0,29 | 0,54 |
Influence of fibers on thermal properties (DSC analysis)
The thermal characteristics found for the neat epoxy are the same order of magnitude as reported by literature (Pichaud, 1997, Pichaud et al. 1999, Nguyen-Thuc 2004). The initial Tg (Tgo) and final Tg (Tg∞) of the neat epoxy/amine system were −30 °C and 152 °C, respectively. The total exothermic energy of the polymerization reaction ΔH0 was 463 J g−1 K−1.
The enthalpies of reaction ΔH0 decrease by introducing an increasing amount of fiber. This decrease can be explained by the change in amine/epoxy stochiometry resulting from etherification reactions. Indeed, the fibers are rich in hydroxyl function and furthermore have an amount of trapped water. Thus it is then possible to envisage a competition between the following reactions:
Reaction between the oxirane of DGEBA and amine functions of the IPD.
Reaction between the oxirane of DGEBA and water,
Etherification reaction of DGEBA oxirane and the fibers hydroxyl functions.
It was not possible to highlight the presence of ether bonds, by Infrared, because the absorption bands are overlapped by those of the cellulose. But the significant decrease of glass transition temperature Tg∞ observed when DPLF fibers are added could be attributed to the the etherification reactions mentioned above and which have caused the change in local stoichiometry (Garcia-Loera 2002, Pascault et al. 2002). The evolution of the glass transition temperature was also observed in the case of epoxy network modified with thermoplastic (Fernandez et al. 2001). On the other hand, the ratio λ which characterizes the variation of the chain mobility between the crosslinked polymer and initial monomer, varies from 0.49 to 0.62 when the rate of virgin fiber is from 0 to 10 wt% respectively. This is another indication of the evolution of the polymer network stiffness, caused by the introduction of the fibers and indicates that the fibers induce a variation of the stoichiometric ration (oxirane/amine). These evolutions were not observed when epoxy amine system (DGEBA/IPD) was filled by core-shell (probably little or no functionalized) where no/or few reactions were possible between the cross linking polymer and the core-shell (Nguyen-Thuc et al. 2002, 2003 and 2004).
4.2.1.2. Epoxy filled by TEMPO oxidized fibers
In the case of a DGEBA / IPD with modified fibers, we observe similar evolutions of the thermal properties were observed (Tg∞ decreases and the ratio λ increases). The same discussion could be done for these materials, however the decrease of Tg∞ is much more pronounced when compared to unmodified fibers. In this case, the system is more complex compared to the composites of unmodified fibers because the additional reaction between carboxylic acid and oxirane functions. However it’s worthy noticing that the oxidized fibers are more hygroscopic than the unmodified one. Actually, the remaining water fraction after drying (at 105°C overnight) is about 8wt% for the oxidized fibers and 6wt% for the unmodified fibers. This result agrees with this obtained by Trindad et al who compared the moisture in the fibers of sugarcane bagasse before (9.5%) and after modification (11%) by oxidation with sodium periodate (Trindad et al. 2004). This remaining amount of water will induce a variation of the stoichiometry and catalyses the etherification reactions (Sherman et al. 2008). This higher amount of remaining water could explain the more pronounced decrease of Tg∞ in the case of the composites with oxidized fibers.
The reaction kinetics of the DGEBA / IPD reactive system (r = 1) filled with 0 and 10 wt% unmodified fibers and with oxidized fibers, was studied by DSC. The increase in conversion (the extent of reaction) was monitored as a function of time and curves are plotted in fig. 16.
Evolution of Conversion x versus time of reaction at 80 °C of system DGEBA / IPD (♦) without fiber (■) with 10% wt of unmodified fibers and (Δ) with 10% wt of TEMPO oxidized fibers
Conversion values are higher for systems with PLD fibers. The polymerization kinetics is enhanced through the presence of these fibers. Indeed the introduction of hydroxyl groups (OH, COOH, H2O...) in the reaction medium promotes interactions between the epoxy-amine and other nucleophilic molecules leading to the formation of an intermediate complex (Fig 17.) (Rozenberg 1986, Garcia-Lorea 2002).
Trimolecular complex catalyst formed by hydroxyl functional groups
The formation of this complex makes nucleophilic attack of the primary amine easier and therefore the reaction is accelerated. Indeed, DPLF fibers added to the system contain hydroxyl groups in the case of unmodified fibers, and more acid groups in the case of oxidized fibers. Furthermore a significant amount of water is present (humidity between 6 and 8%wt) which has an additional catalytic effect in the reaction medium. The presence of water seems to be the dominant factor more than acid groups which are presented in small amounts in the oxidized fibers. Garcia-Lorea and al. (Garcia-Lorea 2002) studied the catalytic effect of water on the reaction kinetics of the system DER332 DGEBA / Jeffamine D400. They showed that the kinetics accelerates with the rate of water incorporated into the system epoxy / amine. If we compare the evolution of conversion in our case with the results, we can decide on the strong effect of humidity on the kinetics of fiber. Furthermore the rate of water incorporated studied by Garcia-Lorea (6-10%) is similar to the humidity in DPLF fibers (6-8%) (Garcia-Loera 2002).
The isothermal cure reaction of DGEBA–IPD networks at various cure temperatures was studied. The built-up in Tg and the extent of conversion x, during cure were monitored as the crosslinking reaction progressed under isothermal conditions (Pascault et al. 1990). The Tg –x relationship could be expressed based on Dibenedetto’s formula. Fig 18 presents the Tg vs conversion for the different DGEBA/IPD /DPLF fiber systems. This evolution is predicted by the model based on Dibenedetto’s approach modified by Pascault and William (Pascault et al. 1990) from an extension of the Couchman equation (Couchman 1987).
Dependence of Tg on conversion x of DGEBA/IPD system at 80 °C of system DGEBA / IPD (♦) without fiber (■) with 10% wt of unmodified fibers and (Δ) with 10% wt of TEMPO oxidized fibers.
They showed that the adjustable parameter λ is equal to the ratio ΔCp∞ / ∆Cp0, where ΔCp0 and ∆Cp∞ are respectively the heat capacities of the initial mixture and of the fully cured network.
This curve is very important to understand the kinetics of such systems. The correlation between Tg and X characterizes the structure of the reactive system. Three curves are obtained which correspond to the system DGEBA / IPD without fiber, DGEBA / IPD with 10% DPLF fiber and DGEBA / IPD with 10% TEMPO oxidized fiber. At low conversions the Tg values for the system without fiber are lower than those charged by fiber (modified or unmodified). This is due to the nature of chemical reactions that occur. The kinetics are different and the etherification reaction seems to be favoured by the abundance of reactive species (OH fiber, water, and COOH in the case of modified fibers) that catalyzes the crosslinking reaction. From 50% of conversion Tg values of the system without fibers are superior to those systems with fibers (modified or unmodified). In this interval of Conversion, the decrease of Tg was due to the etherification reactions that change the value of stoichiometric ratio (not equal to unity) (Garcia-Loera 2002).
Comparing the two systems, with 10% DPLF fibers and that with 10% TEMPO oxidized fibers, we note that the Tg values are higher for the system based oxidized fibers. This can be explained by the humidity slightly higher in the oxidized fiber and by the existence of carboxylic acid. These conditions make the interpretation of the kinetics very difficult because of competition between many reactive species. It’s worthy noticing that in composite materials where the filler doesn’t react with the croslinking polymer, Tg-X curves are coincident which indicate that the reaction involved in the croslinking process are the same (Nguyen-Thuc et al. 2003). Thus in our case the fact of the Tg-X curves are not coincident is a proof that the reactions involved in the croslinking process are not the same in the three studied systems and the functional groups of the fibers and water molecules are involved in the croslinking process.
We were interested to determine the gelation time of the crosslinking material and to evaluate the effect of fiber on the gel time. The gelation time of the systems DGEBA / IPD with and without DPLF fibers were studied at different temperatures: 60, 70, 80 and 90 °C (Fig.19). These temperatures were chosen above the Tggel to avoid vitrification (Glass transition) before gelation. According to the work of Pichaud and al (Pichaud et al. 1999) the Tg gel is 32°C for the system DGEBA / IPD.
The gel times determined for the system DGEBA / IPD without fiber are respectively about 30, 14, 9, 5 and 7 minutes at 60, 70, 80 and 90 °C. This result is in parfait agreement with the results found by Pichaud (Pichaud et al. 1999) with the same system. The fibers induce a reduction of the gelation time and this effect is more exacerbated at mow temperature (60°C). The fibers promote the reaction by the presence of various reactive species, including the catalytic effect which promotes the etherification reactions. This effect is less detectable at high temperatures where the reaction kinetics is much faster.
Viscosity vs reaction time for the two systems based DGEBA / IPD without fiber and with unmodified fiber to 5% by weight at 60 °, 70 °, 80 ° and 90 °C
The gelation phenomenon was found to obey an Arrhenius law. The value of the activation energy for the system DGEBA / IPD is about 59 kJ / mol. This value is comparable to that obtained in the literature (Ea = 61kJ/mol by Pichaud and al. (Pichaud et al. 1999)). For the system DGEBA / IPD with DPLF fiber, the activation energy is much lower and equal to 47 kJ / mol. This shows that the mechanisms of crosslinking reactions for the system epoxy / amine are not identical because others reactions are induced by the fibers.
4.2.3.1. Effect of TEMPO oxidized fibers on the gel time
The fig. 20 below shows the evolution of viscosity versus time for the three systems DGEBA / IPD without fibers (EP), DGEBA / IPD with 5 wt% DPLF fiber and DGEBA / IPD with 5 wt % TEMPO oxidized fibers.
DPLF Fibers into system DGEBA / IPD promotes the reaction kinetics. Nevertheless, viscosity versus time curve of epoxy DGEBA/IPD with oxidized fibers exhibit similar behavior as that with unmodified fibers and the gelation time is the same for both systems (27 min).
Evolution of the viscosity vs reaction time of DGEBA/IPD system at 60 °C (♦) without fiber (■) with 10% wt of unmodified fibers and (Δ) with 10% wt of TEMPO oxidized fibers.
The results presented in this study show that date palm lignocellulosic fibers with high lignin and hemicelluloses contents have been successively modified by a classical TEMPO-mediated oxidation process. Despite the composite character of the fibers substrate, kinetic results have proved that oxidation has occurred in a heterogeneous manner. In contrast to previous studies, it was possible to perform this efficient and aqueous chemoselective reaction without destruction of the fibers structure, while keeping a large amount of residual lignin and hemicelluloses. It was further demonstrated that the distribution of the carboxylate group was unconventional, with an inhomogeneity between the core and the surface of the fibers probably due to a migration of the oxidized and partially hydrosoluble product.
The kinetic study by DSC enables to determine the evolution of conversion degree as function of the reaction time. It was also shown that the polymerization kinetics were accelerated in the presence of the fibers. This catalytic effect is more important in the case of the oxidized fibers. This was explained by the presence of water adsorbed by the fibers but also the catalytic effect of the carboxyl groups in the case of the oxidized fibers. However, even the presence of the fibers acceleration the gelation of the system, no effect of the oxidation of the fibers on the gelation time was detected.
When studying the effect of the oxidation on the processing of the composites, it was shown that the preparation of composites using RTM process was facilitated in the case of composites based on oxidized fibers. During the process, the front displacement of injected resin was regular, homogeneous and faster in the case of oxidized fibers. The morphology, thermal and mechanical properties of polyepoxy reinforced with lignocellulosic fibers extracted from date palm trees were also investigated. Thermal properties from DSC measurements showed that the glass transition temperature of the composites, mainly those based on oxidized fibers, was lower than that of the neat matrix. Dynamic mechanical analysis showed a significant increase of the rubbery modulus when lignocellulosic, unmodified and oxidized fibers were introduced into the polymer. No significant difference of the rubbery modulus between the two families of composites was observed. Analysis of the high strain mechanical proprieties (three-point bending tests) demonstrated some reinforcement of the oxidized fibers as compared to their unmodified counterparts. This confirmed the microscopic analysis which pointed at a better adhesion at the fiber/matrix interface in the case of the composites comprising the oxidized fibers.
The authors thank for their financial support the Hassan II Academy of Sciences and Technologies - Morocco and and the French Ministry ofForeign Affairs (Corus program 6046).
This chapter deals with regulatory considerations related to radiopharmaceutical precursors within Europe. Outside, different aspects may apply, with the exception of certain harmonized documents. Radiopharmaceuticals are considered a safe class of medicinal products. Due to the small chemical quantities administered they are not expected to exhibit any measurable pharmacological effect [1]. However, since they are radioactive, the rules for minimizing the risk associated with the use of ionizing radiation to the patients and to the personnel must be observed. Depending on the chemical and physical properties, radiopharmaceuticals are used in major clinical areas for diagnostics and/or therapy [2]. As defined by the European Pharmacopeia (Ph. Eur.) general monograph (0125) radiopharmaceutical preparations or radiopharmaceuticals are medicinal products which, when ready for use, contain one or more radionuclides (radioactive isotopes) included for a medicinal purpose [3]. Importantly, they can also have the form of kits for radiopharmaceutical preparation, radionuclide generators and radionuclide precursors. For the latter it is understood that they are not used in patients as such but only after attaching them to the suitable pharmaceutical vector. Although according to Ph. Eur. monograph (0125) radionuclide precursor is any radionuclide produced for radiolabeling of another substance prior to administration, and according to Ph. Eur. general monograph (2902) the substance, which is used as such vector, is defined as a chemical precursor for radiopharmaceutical preparations [4], the term radiopharmaceutical precursor is used interchangeably for either of the two above defined precursors (Figure 1).
Radiopharmaceutical precursors according to Ph. Eur.
Given the complex nomenclature used in various regulations and guidance documents, the understanding of radiopharmaceutical precursor’s definition might be challenging. Depending on the context it could be interpreted as the substance which becomes a radiopharmaceutical after radiolabeling with a radionuclide of choice or a radionuclide which is used for radiolabeling of that substance. Therefore, the quality requirements and test methods specifications of precursors for use in preparation of theranostic radiopharmaceuticals can be discussed only in the light of current regulatory framework.
The preparation and use of radiopharmaceuticals are regulated by number of directives, regulations and rules. These documents may be classified with respect to the status of radiopharmaceutical preparation:
radiopharmaceuticals with marketing authorization (MA), regulated by:
radiopharmaceuticals to be used in clinical trials (CT), regulated by:
unlicensed radiopharmaceuticals extemporaneously (just before use) prepared, not for CT [12, 13].
Radiopharmaceuticals with marketing authorization (MA) meet the requirements of GMP Annex 3 (Manufacture of Radiopharmaceuticals) [8] and EMA Guideline on Radiopharmaceuticals [12]. For the small scale preparation of radiopharmaceuticals outside the marketing authorization the guide of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) [14], the Guidelines on Good Radiopharmacy Practice (CRPP) issued by the Radiopharmacy Committee of European Association of Nuclear Medicine (EANM) [13] and the Chapter 5.19. Extemporaneous preparation of radiopharmaceutical preparations of the Ph. Eur. [15] are setting standards for good practices.
The translation of new radiopharmaceuticals from the preclinical stage into clinical trials requires appropriate quality assessment essential to ensure efficacy and safety of both drug substance and drug product [16, 17]. The specific regulatory framework for the use of radiopharmaceuticals in clinical trials has been established in Europe [9, 11, 18]. From the radiopharmaceutical development perspective, the essential step is the preparation of an Investigational Medicinal Product Dossier (IMPD). This document includes information related to the chemical and pharmaceutical quality of the drug substance and drug product, as well as non-clinical data related to pharmacology, pharmacokinetics, radiation dosimetry and toxicology [19]. IMPD contains two main sections related to the production and quality control of the radiopharmaceutical: the drug substance (the active pharmaceutical ingredient, or API) and the drug product.
An active pharmaceutical ingredient (API) is defined as any substance or mixture of substances intended to be used in the manufacture of a drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis as well as treatment of disease or to affect the structure and function of the body. Radiopharmaceutical preparations are often formulated using predefined radionuclide precursors and chemical precursors. If such a preparation does not need a purification step prior to its administration to the patient, both precursors used in the synthesis are considered to be an API in the drug substance part of IMPD. This in particular applies to precursors for theranostic applications where a radiometal is used to radiolabel a vector targeting the receptor, e.g. peptide. On the other hand, chemical precursors used in the manufacture of radiopharmaceuticals, which are purified after the radiolabeling process, are defined as API starting material (e.g. chemical precursors for most F-18 and C-11 PET radiopharmaceuticals).
The manufacture of APIs should be carried out following general GMP requirements. In a GMP-based system, all processes are defined, systematically reviewed, and shown to be capable of consistently providing medicinal products of the required quality and complying with their specifications [20]. Written and approved protocols specifying critical steps, acceptance criteria, must be in place. Process validation is a crucial part of GMP, meaning that all critical steps of manufacturing processes as well as significant changes to these processes are validated. It should be noted that the requirements for validations differ depending whether marketing authorization, clinical trials or in-house preparation of radiopharmaceuticals are planned (see also Figure 2.) [21]. The qualification and validation aspects related to the small-scale “in house” preparation of radiopharmaceuticals are covered in the EANM guidance [22].
Requirements for chemical precursors used in preparation of radiopharmaceuticals depending on their regulatory status.
In the process of IMPD preparation the prime challenge is to establish quality specifications for radiopharmaceutical precursors. They are supposed to comprise a set of tests that are necessary to confirm identity, purity and strength of the drug substance. Issues under consideration are the definition of release criteria, analytical procedures and especially their validation. Main references to address these issues are the European Pharmacopeia and guidance provided by the International Conference on Harmonization (ICH). Ph. Eur. provides general requirements for quality control of radiopharmaceutical precursors, in addition, a number of monographs for individual radiopharmaceuticals and chemical precursors are available in the Ph. Eur.
The use of analytical methods described in the pharmacopeia allows to reduce the work load related to analytical method validation. This does not mean that a pharmacopeia method may be implemented without any preliminary testing and verification. As a minimum, the most critical parameters should be verified, depending on the intended method. If no pharmacopeia monograph exists, analytical methods need to be fully validated. As stated by the general reference document issued by ICH the objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose [23]. To validate an analytical method, the following characteristics may be considered: specificity, accuracy, linearity range, precision (repeatability and intermediate precision), limit of detection (LOD), limit of quantitation (LOQ) and robustness. Recently, recommendations for the validation of analytical methods which are specific for radiopharmaceuticals has been published by EANM [24].
Chemical precursors for radiopharmaceutical preparations, are non-radioactive substances obtained by chemical synthesis for combination with a radionuclide in contrast to precursors manufactured using substances of human or animal origin [4].
The quality specification for chemical precursors is built upon three elements: exact methods, test limits and selection of reference standard. Pharmacopeia monographs comprise a set of critical attributes categorized into three subdivisions: identity, tests (related substances, residual solvents, metal catalyst or metal reagent residues, microbial contamination, bacterial endotoxin) and assay of the active substance. To ensure the appropriate quality, reference substances (like primary standards e.g. Ph. Eur. Chemical Reference Substance, CRS, or Pharmaceutical Secondary Standard, PSS) are used as a standard in an assay, identifications, or purity test. CRS or PSS are often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing [25].
For in-house prepared radiopharmaceuticals the confirmation of the chemical identity and purity of the precursor are the minimum quality control required, in order to qualify the material for subsequent clinical radiolabeling. Additional testing may apply if necessary for the specific process. For example, testing of trace metals content may not be necessary when the material will be subsequently radiolabeled with halogens, but is absolutely critical when the material is intended for labelling with radiometals [26].
To bring a novel radiopharmaceutical into the clinic it is needed that specific quality requirements for the radiopharmaceutical precursor are established, the range of testing would depend on their status and/or intended use. It is worth noting that for Phase I clinical trials full analytical validation is not necessary (only method suitability should be confirmed) [21]. While analytical methods used to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound [27].
There are some specific requirements for the large-sized molecules (e.g. proteins or monoclonal antibodies) as radiopharmaceutical precursors [28]. Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Their biological activities are characterized by a specific binding characteristic to a target ligand (e.g. antigen) and they may be generated by recombinant DNA (rDNA) technology, hybridoma technology, B lymphocyte immortalization or other technologies. Generally, when chemical precursors are manufactured using substances of human or animal origin, the requirements of Ph. Eur. chapter 5.1.7. Viral safety [29] and the general monograph Products with risk of transmitting agents of animal spongiform encephalopathies (1483) [30] apply.
Stability testing is part of the chemical precursor’s characterization. Detailed requirements for carrying out stability studies are included in the ICH guideline Q1A (R2) [31]. The purpose of stability testing is to provide evidence on how the quality of a substance varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period and recommended storage conditions. Stability studies should be carried out on at least three batches and include testing parameters of the chemical precursor that are susceptible to changes during storage and may affect quality, safety and efficacy (e.g. chemical purity and/or assay). The validated analytical methods should be used in these tests. For method validation, it is essential to investigate degradation products and establish degradation pathways under stress conditions (e.g. heat, humidity, light, acid/base hydrolysis and oxidation).
Peptides are an emerging class of compounds that have application in theranostics of several diseases, mainly in cancer [32, 33, 34, 35, 36]. These chemical precursors are positioned between the classic small organic molecules and the high molecular weight biomolecules. The interest of the scientific community for peptide drugs has been continuously growing. Currently, more than 60 peptide-based pharmaceuticals are marketed, over 150 peptides are in active clinical trials and estimated 500 more are in preclinical stages of development [37, 38]. Chemically, peptides have poly-amino acids structure ranging from 3 to 100 amino acids (less than 10 kDa) linked by a peptide (amide, –CONH–) bond, and are lacking a tertiary structure. From the biological point of view, peptides are important regulators of growth and cellular functions in normal tissue and tumors. They can act as cytokines, chemokines, neurotransmitters, hormones and growth factors. Generally, they offer many advantages over other groups for radiopharmaceutical applications. Peptides demonstrate high receptor specificity and selectivity, as well as binding affinity, good tissue penetration and favorable pharmacokinetic profiles. Most of them is characterized by low toxicity and immunogenicity [39, 40]. Their compact size results in rapid targeting and blood clearance. As a consequence low nonspecific uptake in non-targeted tissues and high target-to-background ratios are achieved. Moreover, peptides can be easily chemically synthesized in high purity, modified and stabilized to obtain optimized pharmacokinetic parameters. These all attributes together with ability to attach different chelating agents, prosthetic group and availability of various bioconjugation techniques make peptides an important target platform for theranostic radiopharmaceuticals [41, 42].
Peptide-based radiopharmaceuticals were introduced into the clinic more than three decades ago [43]. Since that time, several theranostic radioligand platforms are used for diagnosis and peptide receptor radionuclide therapy (PRRT) of different cancer types. In this concept, peptide analogs directed against somatostatin receptors (SSTR) play a crucial role [44]. The most prominent example of the theranostic pair of radiolabeled peptides are DOTA-conjugated SSTR agonist DOTA-(D-Phe1, Tyr3, Thr8)-octreotate (DOTA-TATE) labeled with 68Ga and 177Lu (Figure 3). The marketing authorization of NETSPOT® ([68Ga]Ga-DOTATATE) in 2016 and LUTATHERA® ([177Lu]Lu-DOTATATE) in early 2018 [45] encouraged the research in this field to develop improved radiolabeled peptides targeting other receptor/antigen families, exemplified by the prostate specific membrane antigen (PSMA) [46], gastrin-releasing peptide receptor (GRPr) [47] and cholecystokinin-2 receptor (CCK2R) [48, 49]. Some of these peptides are currently under clinical investigation.
Structure of DOTA-TATE for labelling with theranostics pair of radionuclides: Gallium-68 (68Ga) and lutetium-177 (177Lu).
Peptides as precursors for radiopharmaceutical preparations, similarly to other chemical precursors, require adequate specification as a part of their quality assurance in order to demonstrate the safety and efficacy of the final radiopharmaceutical preparation. Currently, no individual pharmacopeia monograph of peptide used as radiopharmaceutical precursors is available. Thus, the quality specification should be established according to the general requirements [4, 50]. Herein, we provide an overview of recommended methods and test limits for the characterization of peptides. The set of analytical procedures that need to be considered is presented in Table 1. However, it should be noted that new analytical methods and modifications to existing ones are continuously being developed and should be utilized where appropriate.
The preliminary quality evaluation of peptides is based on the visual inspection of the appearance/color and solubility. This parameter is given only for information, it is not a requirement in a strict sense. If any of the characteristics change during storage, this change should be investigated and appropriate action taken. A typical description of peptide appearance is: white to almost white, freeze-dried powder and solubility is stated in water, ethanol and dilute solutions of acids and alkali [38, 51].
According to the ICH Q6A guideline [25] identification testing should allow to discriminate between compounds of closely related structure which are likely to be present (e.g. peptides with altered sequences or functional groups that may be formed during the synthesis). The identification test should include combination of different procedures (mostly two) and should be specific and unequivocal. Several techniques are currently in use for confirmation of peptide identity: HPLC-UV, nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MS), infrared absorption spectrophotometry (IR), amino acid analysis (AAA) or peptide sequencing [51]. The method of choice is typically HPLC-UV based on retention time by comparison with reference standard, since the separation by RP-HPLC is often utilized and the method is widely available. UV detection of peptides is realized at 210–220 nm and 250–290 nm for aromatic side chains of phenylalanine, tyrosine and tryptophan. Identification solely by a chromatographic retention time is not regarded as specific and should be complemented by spectrometric techniques. The NMR spectroscopy is the method that allows to unequivocally define the structure of a peptide in the terms of amino acid composition, sequence and chirality. Identification by NMR spectrometry is usually limited to peptides comprising up to 15 amino acids and requires complex data interpretation. For this reason NMR technique is primarily replaced by mass spectroscopy (MS). This technique provides highly accurate molecular weight information on intact molecules, which is an advantage of MS for peptide identification. The peptide molecular mass is most commonly determined by using the electrospray ionization method (ESI), which occurs through the addition or removal of protons and appears as singly or doubly charged ions. As alternative for the more sophisticated spectroscopic methods, amino acid analysis (AAA) could be considered. This technique involves the hydrolysis of the peptide (usually in acidic conditions) to its individual amino acid residues, followed by chromatographic separation and detection/quantification. The method also enables the determination of the enantiomeric purity with the use of appropriate reference standards. However, this method may not be applicable to peptides containing unnatural amino acids and/or specific chelators. The NMR and AAA as well as peptide sequencing techniques are generally used for characterization of PSS.
In the two recently published papers the identity of DOTA-TATE has been confirmed using suitable instrumental techniques; Sikora et al. [52] confirmed the identity of DOTA-TATE using three different methods: MS, IR and HPLC. Similarly, in the work by Raheem at al [53] the final product was analyzed using high resolution mass spectrometry for identification and analytical HPLC for purification; it was detected via analytical HPLC at a retention time of 9.52 min and detected by HRMS-ESI (calc m/z for [(DOTA-TATE +2H)/2]+: 718.3028, found: 718.3046 with −0.1144 ppm error).
In our experience ESI-MS in positive ionization mode was used to confirmed whether the masses of ions at m/z 1435.6 ± 1.0 [M + H]+ and 718.3 ± 1.0 [M + 2H]2+correspond to the monoisotopic mass of peptide [M] as presented in Figure 4. DOTA-TATE PSS was used as reference in IR analysis. Also a gradient HPLC-UV (220 nm) served as identity test of DOTA-TATE by comparison with the reference standard (Rt ± 5.0%). The same HPLC method was used for determination of peptide purity and assay. The representative HPLC chromatograms of DOTA-TATE and DOTA-TATE PSS are given in Figure 5.
ESI-MS spectrum for DOTA-TATE.
HPLC-UV (220 nm) chromatograms of (I) DOTA-TATE Rt = 19.831 min and (II) DOTA-TATE PSS Rt = 19,936 min. HPLC method: Luna C18(2) column; Mobile phase - A: water with 0.1% TFA, B: Acetonitrile with 0.1% TFA; gradient profile – From 0 to 25 min: 0–50% B; flow - 0.8 mL/min, oven temperature - 30°C.
Peptides are usually chemically synthesized using solid-phase peptide synthesis (SPPS) [54]. In this multi-stage process, amino acids are linked to each other during individual coupling steps, thus constructing the desired peptide sequence. This occurs when the carboxylic end of the sequence is covalently attached to a solid support matrix. The complexity of the peptide production process results in a greater diversity of potential impurities. Heterogenicity of the impurity profile is observed even among peptides manufactured by the same synthetic route. The impurities can originate from raw materials, the manufacturing process, degradation or may be formed during storage. Although protecting groups, scavengers or activated functional groups are used to prevent undesired side-chain reactions the peptide manufacturing process leads to formation of closely related impurities. The most common impurities are products of racemization, deamidation, amino acid deletion or insertion, acetylation, oxidation, β-elimination, cyclization, reduction and incomplete deprotection [51]. The presence of related peptide impurities is typically determined using gradient reversed-phase HPLC method with UV detection, because of its selectivity, high sensitivity, low limit of detection, quantification and robustness. The developed HPLC method should allow sufficient separation of potential impurities from manufacturing process as well as degradation products. The acceptance criteria for related substances according to the Ph. Eur. General Monograph 2902 [4] are presented in Table 2.
Parameters | Typical methods | Typical acceptance criteria |
---|---|---|
Characters | ||
- Appearance/color | Visual inspection | White or almost white powder |
- Solubility | Visual inspection | Solubility in water, ethanol and dilute acid or alkali |
Identification | ||
- Active moiety | RP-HPLC-UV | Retention time versus reference |
MS or | Mass spectrum versus reference | |
NMR | NMR spectrum versus reference | |
IR | IR spectrum versus reference | |
AAA (GC) | AA: theoretical content ±20% | |
Purity tests | ||
- Related substances | HPLC-UV | Individual, unidentified: < 2.0% Total: ≤ 3.0% |
- Residual solvents | (Headspace) GC | Acetonitrile: ≤ 0.5% |
- Residual metals | AAS/ICP-AES/ICP-MS | Pt, Pd, Ir, Rh, Ru, Os, Mo, Ni, Cr, V, Pb, Hg, Cd, Tl: ≤ 0.01% |
- Residual reagents | HPLC-UV/IC/GC | Trifluoracetic acid: ≤ 1.0%* |
Counter-ion content | HPLC-UV/IC/GC | Acetic acid: target ±5% Trifluoracetic acid: target ±5% |
Water content | Karl-Fisher | ≤ 10.0% |
Assay (net peptide content) | RP-HPLC-UV or CHN | ≥ 75.0% |
Bioburden | TAMC plate count | ≤ 103 CFU/g for bulk ≤ 102 CFU per container |
TYMC plate count | ≤ 102 CFU/g for bulk ≤ 101 CFU per container | |
Bacterial endotoxins | Gel-clot | ≤ 100 IU/g for bulk ≤ 10 IU per container |
Summary of the recommended quality parameters for peptides used as radiopharmaceutical precursors.
The residual TFA content is determined when AcOH or HCl are used as counter-ions.
Reporting threshold | 0.2 per cent |
Identification threshold | 2.0 per cent |
Total unspecified impurities | Maximum 3.0 per cent |
Acceptance criteria for related substances [4].
Specific thresholds should be applied for impurities known to be unusually potent or to produce toxic or unacceptable pharmacological effects.
The presence of inorganic impurity should also be considered, in particular when radiolabeling of the peptide with radiometals is concerned. According to the Ph. Eur. general monograph (2902), the metal residues in peptides should be determined if the manufacturing process is known or suspected to lead to its presence, e.g. due to the use of specific metal catalyst (e.g. Pd) or metal containing reagents. The content for each of the following metals: Pt, Pd, Ir, Rh, Ru, Os, Mo, Ni, Cr, V, Pb, Hg, Cd, Tl in the peptide precursors are limited to 0.01%. The metal impurities are typically examined using atomic absorption spectrometry (AAS), inductively coupled plasma with atomic emission spectrometry detection (ICP-AES) or mass spectrometry detection (ICP-MS) techniques. Determination of residual metals in peptides can be crucial for precursors intended for radiometal labeling [55]. It has been proven that the presence of certain metals can significantly affect the labeling efficiency through competitive chelation.
In addition to related substances the residual solvents are required to be examined as impurities in peptide precursors. Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the manufacturing process. The solvents are not completely removed by practical manufacturing techniques (e.g. lyophilization process). General guidelines established by the ICH divide solvents into three classes [56]. The Class 1 solvents should not be used in the final step of the manufacturing process of chemical precursors, because of toxicity and environmental impact. The use of the Class 2 solvents should be limited due to potential toxicity and Class 3 solvents are regarded as posing a lower risk to human health. Based on the permitted daily exposure (PDE), Class 2 and 3 solvents are limited to 0.5%. Residual solvents are typically determined using chromatographic techniques such as gas chromatography (GC) coupled with static headspace sampling. Many solvents are usually used in the peptides synthetic process. However, as the advantage of the SPPS and lyophilization process, the most frequently detected solvent is only acetonitrile (Class 2 solvent), used as the component of the mobile phase in the final purification process by preparative HPLC.
Synthetic peptides usually contain counter-ions on protonated amino functional groups (N-terminus, Arg, His, Lys, etc.). The presence of counter-ions such as acetate, chloride or trifluoroacetate results from the peptide post synthetic cleavage and/or purification process. Depending on the peptide sequence they reduce the net peptide content by 5 to 25%, but are not considered as impurity. Radiopharmaceutical preparations for diagnostic or therapeutic purposes are based on the net peptide content and thus the amount of residual counter-ions needs to be assessed. To determine counter-ion amounts different method are being used such as: GC, HPLC-UV or ion chromatography (IC). Trifluoroacetic acid (TFA) determined by IC at the level of ca. 20% in DOTA-TATE [52], corresponded to three TFA molecules associated to single peptide molecule. TFA is commonly used as a chemical reagent to remove residual protecting groups during purification of peptides and also as a mobile-phase modifier in a reversed-phase chromatography. Therefore, when the counter-ion finally is AcOH or HCl, determination of the TFA residual content is mandatory.
In order demonstrate a lot-to-lot consistency the test for water content (residual moisture remaining from the lyophilization process) should be also performed. This parameter may affect the stability of the peptide. For residual water Karl-Fischer titration method as well as GC method with thermal conductivity detector (TCD) [57] are commonly used and water content is limited to max. 10%.
Generally, assay is defined as a net peptide content. The lyophilized peptide contains also water, counter ions and residual solvents. The net peptide content is referred to percentage of peptide material in the lyophilized peptide. According to ICH guideline Q6A, a specific stability-indicating procedure should be included in the specifications to determine the content of the drug substance. There are two main approaches to determine net peptide content. The first method is a relative assay against a well-defined chemical reference substance, performed using comparative chromatographic procedures. Usually the same RP-HPLC method is used for both assay, identification and related substances. The second approach is an absolute assays involving a functional group (e.g. AAA or titration methods) or a nitrogen content analysis. The nitrogen content is determined from the results of elemental analysis CHN. The calculation of the net peptide content is based on the relation between determined %N to the theoretical content in the peptide structure. For example, this method was used to DOTA-TATE assay determination. Peptide content calculated from elemental analysis was ca. 78.0%, which was in agreement with the generally accepted limit ≥75% [52].
The presence of microorganisms may affect the stability of drug substances due to their propensity to degrade/metabolize peptides. Microbiological examinations involve the bioburden control (Ph. Eur 2.6.12) and content of bacterial endotoxins (Ph Eur. 2.6.14). The microbial enumeration tests for total aerobic microbial counts (TAMC) and total yeast and mold counts (TYMC) must adhere to the acceptance criteria of 103 CFU/g and 102 CFU/g for bulk material and 102 CFU/g and 101 CFU per container for chemical precursors packed in single and multi-dose containers, respectively. Bacterial endotoxin can be determined by the gel-clot or photometric methods (turbidimetric and chromogenic techniques) and acceptance criteria are limited to a maximum 100 IU/g for bulk material or maximum 10 IU per container for chemical precursors packed in single-dose and multidose containers.
Radionuclide precursors are offered as solutions for radiolabeling with MA, they are also locally produced for the in-house preparation of radiopharmaceuticals. There is an ongoing debate whether radionuclide precursors always have to be considered as medicinal product, or also can be provided as a starting material [58]. Unlike for chemical precursors for radiopharmaceutical preparation, up to date there is no monograph in the Ph. Eur. that sets out general requirements for radionuclide precursors. This is due to the fact that the quality requirements for radionuclides used to obtain diagnostic and therapeutic preparations are highly varying and depend on the irradiation route and chemical processing involved, which mainly affect the parameters of radionuclide purity or specific activity.
However, there are several individual Ph. Eur. monographs for radionuclide precursors. Two of these concern radionuclide precursors used to prepare radiopharmaceuticals for therapeutic use. These are: Lutetium (177Lu) solution for radiolabelling (mon. 2798) [59] and Yttrium (90Y) chloride solution for radiolabelling (mon. 2803) [60]. There are also six monographs published for radionuclide precursors for preparation of diagnostic radiopharmaceuticals: Fluoride (18F) solution for radiolabelling (mon. 2390) [61], Sodium iodide (123I) solution for radiolabelling (mon. 2314) [62], Sodium iodide (131I) solution for radiolabelling (mon. 2121) [63], Indium (111In) chloride solution (mon. 1227) [64] and Gallium (68Ga) chloride solution for radiolabelling (mon. 2464) [65] and a newly published monograph for Gallium (68Ga) chloride (accelerator-produced) solution for radiolabelling (mon. 3109) [66].
Focusing attention on theranostic radiopharmaceuticals, herein the quality requirements only for metallic radionuclide precursors used in diagnostics and therapy are compared. Table 3 shows the exemplary quality requirements for radionuclide precursor for therapeutic use (177Lu) and a matching radionuclide precursor for diagnostic use (68Ga).
Lutetium (177Lu) solution for radiolabelling (Ph. Eur. 2798 [59]) | Gallium (68Ga) chloride solution for radiolabelling (Ph. Eur. 2464 [60]) |
---|---|
pH: 1.0 to 2.0, using a pH indicator strip R. | pH: maximum 2, using a pH indicator strip R. |
Lutetium: Inductively coupled plasma-atomic emission spectrometry (2.2.57), for determination of specific radioactivity. Copper: maximum 1.0 μg/GBq Iron: maximum 0.5 μg/GBq Lead: maximum 0.5 μg/GBq Zinc: maximum 1.0 μg/GBq | Iron: maximum 10 μg/GBq Zinc: maximum 10 μg/GBq |
RADIONUCLIDIC PURITY Lutetium-177: minimum 99.9 per cent of the total radioactivity. Gamma-ray spectrometry. Results: - the total radioactivity due to ytterbium-175 (impurity B) is not more than 0.1 per cent; – the total radioactivity due to lutetium-177 m (impurity A) is not more than 0.07 per cent; – the total radioactivity due to radionuclidic impurities other than A and B is not more than 0.01 per cent. | RADIONUCLIDIC PURITY Gallium-68: minimum 99.9 per cent of the total radioactivity. A. Gamma-ray spectrometry. Limit: peaks in the gamma-ray spectrum corresponding to photons with an energy different from 0.511 MeV, 1.077 MeV, 1.022 MeV and 1.883 MeV represent not more than 0.1 per cent of the total radioactivity. B. Germanium-68 and gamma-ray-emitting impurities. Gamma-ray spectrometry. Result: the total radioactivity due to germanium-68 and gamma-ray-emitting impurities is not more than 0.001 per cent. |
RADIOCHEMICAL PURITY [177Lu]lutetium(III) ion: minimum 99 per cent of the total radioactivity due to lutetium-177. | RADIOCHEMICAL PURITY [68Ga]gallium(III) ion: minimum 95 per cent of the total radioactivity due to gallium-68. |
Bacterial endotoxins (2.6.14): less than 175 IU/V, V being the maximum volume to be used for the preparation of a single patient dose, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins. | Bacterial endotoxins (2.6.14): less than 175 IU/V, V being the maximum volume to be used for the preparation of a single patient dose, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins. |
Sterility: If intended for use in the manufacture of parenteral preparations without a further appropriate sterilization procedure, it complies with the test for sterility prescribed in the mon. 0125. The preparation may be released for use before completion of the test. |
Comparison of Ph. Eur. requirements for selected radionuclide precursors.
Comparing the requirements of these two monographs there are apparently large differences in numerical values seen, especially for metal ion content and radiochemical purity. However, when the radioactivity of these radionuclides (different for therapeutic or diagnostic use) is considered, there are basically no differences in quality requirements for both radionuclides. This can be demonstrated on the example of the DOTA-TATE preparations with 177Lu and 68Ga. For therapy 7.4 GBq of [177Lu]Lu-DOTA-TATE is used and this preparation contains ca. 0.2 mg of DOTA-TATE. Typical dose of [68Ga]Ga-DOTA-TATE is 200 MBq and the ligand content in the preparation should not exceed 0.05 mg. Therefore, when analyzing the limit of metallic impurities, e.g. Zn in the radionuclide precursor, similar values are obtained in both cases, i.e. maximum 37 ng and 40 ng per microgram of DOTA-TATE for lutetium-177 and gallium-68, respectively.
When the radiochemical purity is compared, the higher limit of permissible other forms of diagnostic radionuclide ([68Ga]gallium(III) ion: minimum 95%) than for the therapeutic radionuclide ([177Lu]Lutetium(III) ion: minimum 99%) does not result in a higher risk to the patient. Thus, 5% of other forms of a trivalent gallium-68 ion may result in the deposit of 10 MBq of this radionuclide in undesirable chemical form in non-target organs, while for 1% lutetium-177 it is as much as 74 MBq of uncontrolled chemical form. However, it must be noted that a stricter limit for the latter radionuclide is difficult to achieve due to the limitations of the analytical methods, which are characterized by an approximate 1% uncertainty of determination.
Bearing in mind that the differences in the profile of radionuclide contamination depend on the radionuclide production process [67], it is unlikely that uniform quality requirements for radionuclide precursors will be set in numerical terms. Each radionuclide precursor should be evaluated on a case-by-case basis, taking into account the physical characteristics of the radionuclide, its mode of irradiation and chemical processing as well as the envisaged clinical use and the dose planned for administration to the patient. This is clearly reflected in monographs referred in this Chapter. The monograph for 177Lu [59] applies to both the direct and indirect production routes of 177Lu in nuclear reactors and covers all quality aspects regardless the different specific radioactivity and impurity profiles. The decision is left to the producer of the final radiopharmaceutical preparation to use the appropriate solution for radiolabeling. However, the relevant information needs to be stated on the label. This is different in case of 68Ga, there are two different monographs specifying its quality requirements depending whether it’s generator [65] or accelerator produced [66]. One can expect that a similar individual approach applies to the future monographs for new theranostic radionuclides, for example 47Sc, which can be either accelerator or reactor produced [68].
Are the requirements for radiopharmaceutical precursors overregulated? With the development of new theranostic procedures involving radiopharmaceuticals, there is a need for proper qualitative evaluation of the final radiopharmaceutical preparation and both of the radiopharmaceutical precursors to ensure efficacy and safety of the treatment. An excellent example of the long pathway of a radiopharmaceutical, 111In-CP04, a peptide targeting the cholecystokinin-2 receptor, from the preclinical development over establishing the required pharmaceutical documentation to designing and submitting a clinical trial in patients with Medullary Thyroid Carcinoma, was recently presented [16]. All the quality aspects of CP04 as chemical precursor have been addressed in the IMPD in view of the quality and suitability of the radiolabeled preparation, 111In-CP04, in order to bring it to the clinic.
In this Chapter, the quality requirements applicable to radiopharmaceutical precursors in the context of their regulatory status in Europe were reviewed. EMA and Ph. Eur. provide public standards for manufacture and quality control of these precursors by establishing specifications and acceptance criteria. While in the case of radiopharmaceuticals with MA and CT regulations quite strictly define the quality and documentation requirements, such standards for in-house produced radiopharmaceuticals are still awaited.
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