Journal of Chromatography A Volume 1153, Issues 1-2, 15 June 2007, Pages 74-89 Advances in Sample Preparation - Part II doi:10.1016/j.chroma.2007.01.028 | How to Cite or Link Using DOI Copyright © 2007 Elsevier B.V. All rights reserved. Cited By in Scopus (6) Permissions & Reprints Review Recent developments in sample preparation for chromatographic analysis of carbohydrates M.L. Sanza and I. Martínez-Castro a , a, Instituto de Química Orgánica General, Consejo Superior de Investigaciones Científicas (CSIC), C/Juan de la Cierva, 3 E-28006 Madrid, Spain Available online 12 January 2007. Abstract Carbohydrates are a very important group of compounds due to their roles as structural materials, sources of energy, biological functions and environmental analytes; they are characterized by their structural diversity and the high number of isomers they present. While many advances have been made in carbohydrate analysis, the sample preparation remains difficult. This review aims to summarize the most important treatments which have been recently developed to be applied prior to the analysis of carbohydrates by chromatographic techniques. Due to the multiplicity of structures and matrices, many different techniques are required for clean-up, fractionation and derivatization. A number of new techniques which could be potentially adequate for carbohydrate characterization have also been revised. Keywords: Sample treatment; Carbohydrates ; Fractionation; Derivatization; Clean-up; Chromatographic techniques Article Outline 1. Introduction 2. Main processes in carbohydrate sample preparation 2.1. Clean-up 2.1.1. Filtration 2.1.2. Extraction 2.1.2.1. Liquid extraction 2.1.2.2. Solid phase extraction 2.1.2.3. Miscellaneous 2.2. Fractionation 2.2.1. Membrane fractionation 2.2.1.1. Ultrafiltration and nanofiltration 2.2.1.2. Dialysis and microdialysis 2.2.1.3. Liquid membranes 2.2.1.4. Polymeric membrane extraction 2.2.2. Carbon fractionation 2.2.3. Size exclusion chromatography 2.2.4. Field flow fractionation 2.2.5. Ion exchange chromatography 2.2.6. Simulated moving bed chromatography 2.2.7. Microbiological treatments 2.2.8. Supercritical fluid extraction 2.2.9. Pressurized liquid extraction 2.2.10. Molecularly imprinted polymers 2.2.11. Hydrophilic interaction chromatography 2.3. Chemical treatments 2.3.1. Hydrolysis 2.3.2. Derivatization 2.3.2.1. Derivatives for LC and CE 2.3.2.2. Derivatives for GC 2.3.3. Derivatives used for structural analysis 2.3.4. Thermochemolysis 3. Concluding remarks Acknowledgements References 1. Introduction Carbohydrates are probably the most abundant organic molecules on the Earth, since they are present in the cells of all living organisms and are the main constituents of plants and trees, representing the major form of photosynthetically assimilated carbon in the biosphere. They comprise up to 75 wt% of vascular plant tissues as structural polysaccharides [1] and [2] Carbohydrates can be divided into classes of monosaccharides, oligosaccharides and polysaccharides. All of them are polar molecules which encompass a high diversity of molecular size, glycosidic linkage and functionality. They are always constituted by carbon, hydrogen and oxygen but may contain other elements such as nitrogen, sulphur, phosphor, etc. They are characterized by the high number of hydroxyl groups but other functional groups such as carbonyl, carboxyl, amino, ether, etc. could be present. Carbohydrates also occur linked to proteins or lipids which form glycoproteins or glycolipids, respectively. These two classes of substances are especially interesting in the biochemistry field and will not be considered here. In recent times big advances in analytical techniques for carbohydrate determination are taking place: improvements in resolution and sensitivity [3], multiple couplings, oligosaccharide arrays and glyco-chips [4], etc. which make necessary a corresponding advancement in those techniques dealing with sample preparation. Carbohydrates are subjects of chromatographic analysis in different fields: agriculture, food, medicine, organic chemistry, biology, environmental science [2], [5] and [6] and also in historic/archaeological studies, old paintings, etc. [7]. Regarding sample preparation it is necessary to take into account some physical and chemical properties: - Molecular weight, molecular size and shape: their molecular weights range within that of a tetrose (C4H8O3) and those of polysaccharides with several thousands of monosaccharide units which form polymers with straight- or branched-chain. The monosaccharide units are usually in the form of hemiacetal rings. The number and types of isomers they are capable of displaying is higher than that of any other group of compounds. - Solubility in water and polar solvents is a function of molecular weight: they are generally water-soluble and for many polymers complex equilibria can be expected, such as gelification, helix formation, adsorption, etc., but there are a number of insoluble matrices such as cellulose and other polysaccharides. Solubility in alcohols and polar solvents like pyridine, dimethyl sulfoxide and dimethylformamide is restricted to small saccharides. The word “sugars” usually refers to water-soluble carbohydrates. - Although some saccharides are hygroscopic or thermally unstable, they can generally stand at room temperature and are air-stable. - Thermal stability: is very low; carbohydrates easily undergo dehydration and further degradation such as the well-known caramelization reactions. - Very high chemical reactivity: they react with acids, bases, amino groups and many reagents. It is easy to make derivatives or to introduce protecting groups for specific functional groups; but in order to keep the molecules unchanged it is necessary to hold pH near neutrality and to avoid isomerization or decomposition reactions which easily take place in alkaline or acid media. Isomerization of glucose to fructose has been confirmed even during some chromatographic processes under alkaline conditions [8] and [9]. - They do not have properties of fluorescence emission and they only absorb in UV at very short wavelengths. Carbohydrates are becoming increasingly important due to their biological properties such as prebiotic or antiadhesive effects [10] and [11] and the necessity of developing analytical methods which can allow their characterization is growing. Putting aside the biochemical applications, analyses of carbohydrates in most fields have different requirements according to their objectives: it can be convenient to fractionate by molecular weight, or to discriminate between two groups of molecules with different functional groups. This review describes the main classes of processes of sample preparation that can be necessary for chromatographic analysis of carbohydrates in different matrices, based on the classification proposed by Smith [12]: to remove interferents (clean-up), to separate some carbohydrates from other carbohydrates or to increase their concentration (fractionation) and to convert the analyte into a more suitable form for detection or separation (chemical treatments). Most of the techniques here described can be applied to HPLC, GC or CE analysis mainly depending on the characteristics of the sample to be analysed (monosaccharides, oligosaccharides or polysaccharides, simple matrices or complex mixtures, etc.). The literature cited covers the last few years and is intended to be representative of the field rather than comprehensive. 2. Main processes in carbohydrate sample preparation Fig. 1 shows a diagram of the main processes required for carbohydrate analysis. In some foods, beverages or pharmaceutical products, sample preparation for carbohydrate analysis can be limited to a simple dilution and filtration procedure [13] and [14]; however, all the above mentioned steps (clean-up, fractionation, hydrolysis and/or derivatization) may be necessary for complex samples. Full-size image (32K) Fig. 1. Diagram of sample preparation prior to chromatographic analysis of carbohydrates. View Within Article 2.1. Clean-up This procedure is usually carried out to discard insoluble material, lipids and proteins, desalt the sample and remove impurities. These steps are essential for the success of many techniques used for carbohydrate analysis such as gas, liquid chromatography and capillary electrophoresis. Clean-up is also directed towards removing from the sample those substances with chromatographic behaviour similar to that of sugars which may act as potential interferents (carboxylic acids, polyphenols, etc.). Old methods were based on precipitation with ethanol and subsequent filtration or centrifugation of the insoluble material [15]. Currently, some of them continue to rely on standard methods and regulations [16] but modern procedures such as membrane filtration are preferred for more complex mixtures. Clean-up procedures can be grouped into filtration and extraction techniques. 2.1.1. Filtration It is well known that filtration is an important part of sample preparation mainly for HPLC and CE analysis to avoid insoluble material blocking the column. Different types of filters including paper, glass fiber and membrane filters are used [12]. Moreover, other filtration techniques based on the use of membranes such as ultrafiltration (UF), nanofiltration (NF) or reverse osmosis (RO) are commonly utilized to obtain high-purity carbohydrates from complex matrices [17], [18], [19] and [20] which are useful for both biological applications and food analysis. These techniques allow the purification of carbohydrates and the concentration of the analyte over the matrix in order to decrease the detection limit [21] and [22]. A combined membrane processing system with UF and NF membranes was evaluated by Kamada et al. [23] showing a promising effectiveness for purifying and concentrating oligosaccharides from chicory rootstock. Wang et al. [24] studied the use of NF membranes in diafiltration mode to separate inorganic electrolytes (NaCl, KCl, MgCl, Na2SO4 and MgSO4) from carbohydrates. Different models of transport mechanism through NF membranes have also been designed to predict the results of purification of oligosaccharides under different operation conditions [25]. In carbohydrate chemistry the use of these procedures for sample preparation has not only been applied to the purification of samples: these techniques also constitute an important tool for carbohydrate fractionation. Therefore, they will be discussed more extensively in the fractionation section. While several advances have been made in chromatographic techniques in an attempt to decrease the time of analysis and increase the resolution and the sensitivity, sample preparation process is still tedious and frequently lacks automatization. However, some advances have recently been achieved in membrane extraction techniques hyphenated with HPLC, GC and CE [21]. High performance anion exchange chromatography (HPAEC) on-line or off-line coupled with electrospray ionization (ESI) or matrix assisted laser desorption ionization time of flight (MALDI-TOF) appears to be a useful tool for oligosaccharide analysis. However, the high pH of the mobile phase employed in HPAEC (pH ≈ 13) involving the instability of the oligomers for long periods of time (see Section 1) and the presence of large amounts of sodium acetate, make the desalting of the mobile phase necessary for detection by MS. The use of on-line membrane suppressors has been found to be successful for this purpose [26] and [27]; however, in these applications only sodium is removed and the presence of acetic acid can disturb MALDI-TOF analysis. Other assays have been developed using a cation membrane suppressor connected in series to an anion membrane suppressor [28]. This system has showed good results for on-line desalting of HPAEC eluent [28] and [29]. A new method for carbohydrate pre-purification based on the use of a two-dimensional liquid chromatographic system has been suggested by Rogatsky and Stein [30]. This automated system was used to isolate and concentrate carbohydrates present in small amounts from biological matrices prior to LC–ESI–MS–MS analysis. 2.1.2. Extraction As indicated by Smith [12], extraction is the oldest and most basic sample preparation method used to purify the analyte of interest from interfering substances or from a matrix using solvents. Carbohydrates have been extracted using traditional methods such as solid–liquid and liquid– liquid extractions. Enhanced solvent extraction methods like supercritical fluids or accelerated solvent extraction systems are used at present as an interesting alternative for the analysis of pesticides and non-polar substances. Very few of the latter techniques are applied to carbohydrates since they are more orientated towards fractionation; therefore they will be discussed later. Precipitation of undesirable compounds with reagents is another way of extracting carbohydrates from complex matrices. Different reagents such as Carrez are often used to precipitate proteins or lipids prior to carbohydrate analysis [31], whereas precipitation with acetate buffer/acetonitrile or perchloric acid has also been used [32]. To extract extracellular bacterial polysaccharides from culture media containing proteins, trichloroacetic acid (TCA) and enzyme treatments have commonly been employed to precipitate and hydrolyse the proteins, respectively [33]. 2.1.2.1. Liquid extraction Numerous standard sample preparation methods are based on liquid–liquid extraction (LLE) as described in a recent review [21]. However, this technique still has several drawbacks: difficult automatization and large volumes of organic solvent are involved. Extraction of carbohydrates from aqueous media is a difficult task due to their wide structural variety and their low solubility in organic solvents. Xylose and other sugars have been extracted from complex matrices using boronic acid extractants [34], whereas Matsumuto et al. [35] formed ion-pairs with boronate anion and quaternary ammonium cation for carbohydrate extraction. A macrotricyclic cage has been used to extract monosaccharides from water to chloroform [36] and the use of carrier-mediated extraction has been shown to be possible [37]. The same authors [38] have investigated 14 different solvents such as hydrocarbons, aromatics, alcohols and methyl tert-butyl ethers for the selective recovery of neutral sugars (6 monosaccharides and 3 disaccharides) from aqueous media, using primary, secondary and tertiary amines as carriers. The extraction rates varied between 20 and 90%, but several points need to be clarified (for example, the interaction aminecarbonyl which could give rise to Maillard reaction). The effect of hot water on the extraction of carbohydrates from different matrices has been reviewed by King [39] utilizing several examples from the literature. On the other hand, alcohols have been used for the extraction of total soluble carbohydrates from complex matrices. Different alcohols (methanol, ethanol, isopropanol) at different concentrations (10–80%) allow the extraction of complex mixtures of carbohydrates to be obtained for subsequent analysis as has been shown by several authors [40], [41], [42], [43] and [44]. 2.1.2.2. Solid phase extraction Solid phase extraction (SPE) has commonly been used to purify samples prior to their analysis [45], [46] and [47]. In SPE, samples are percolated through a solid sorbent, previously conditioned, which is placed in a cartridge or column. The analytes of interest are retained by the sorbent and further eluted in a small volume of an appropriate solvent [48]. Solid sorbents and solvents should be chosen according to the analyte. This technique is easily automated, and is flexible and environmentally friendly. Moreover, SPE also allows the hyphenation with chromatographic techniques such as HPAEC-PAD (pulsed amperometric detection) [49] which simplify sample analysis. The advantages and disadvantages of this technique have been summarized [50], whereas new stationary phases, strategies and on-line systems have been reviewed by Gilar et al. [51]. SPE seems to be the most popular alternative to removing interferences with the same chemical behaviour as carbohydrates [52]. The main characteristics of this technique as applied to carbohydrate analysis have been reviewed by Herbreteau [32]. Carbohydrates are commonly eluted with water, diluted sulphuric acid or water modified with organic solvents, depending on the sorbent. SPE C18 cartridges are commonly employed to purify carbohydrates prior to their analysis [32], [53], [54], [55] and [56] but other sorbents such as styrene-divinylbenzene [52] aminopropyl silica [57], and ion-exchange phases are also used. Kitahara and Copeland [58] compared the interaction between starch molecules and C8 and C18 cartridges. Differences of adsorption were based on the hydrophobic character of starch. These authors demonstrated that glucose and maltose were not adsorbed on either sorbent. Maltoheptaose was not retained in C8, however, (1–4)-α-glucans were completely adsorbed on C18. In addition, fractionation of these glucans based on their degree of polymerization (DP) could be carried out by this technique. Schiller et al. [59] used three-step SPE to separate carbohydrates from a plant dry extract: firstly, a hydrophobic polystyrene/divinylbenzene copolymer cartridge was used followed by anion- and cation-exchange cartridges. Cartridges based on hydrophilic interaction chromatography (HILIC) have been used for desalting of glycans using a micro-scale SPE device packed with an HILIC sorbent; the glycans were eluted using 25–50 μl of solvent and analyzed directly without derivatization using MALDI-MS [60]. Graphitized cartridges have also been used for removing impurities such as salts, detergents, proteins, peptidic material, etc. [61] and [62] from glycans for their subsequent analysis and permit the separation of groups of oligosaccharides [63]. Nakano et al. [62] compared the use of three SPE cartridges (cation-exchange, C18 and graphitized carbon) for removing peptides and glycopeptides from glycans prior to their analysis. Authors found that N-glycans were not efficiently separated from interferences using C18 and cation exchange cartridges. However, graphitized carbon cartridges were successfully used for this purpose. Removal of detergents and possible hydrophobic contaminants from small quantities of oligosaccharides has been carried out by Huang et al. [64] on a small-batch addition of a hydrophobic resin directly into the sample. 2.1.2.3. Miscellaneous Solid phase microextraction (SPME) is based on the use of a fibre coated with a liquid (polymer), a solid (sorbent), or a combination of both. The analytes are absorbed in the case of liquid coatings or adsorbed in the case of solid coatings and further analysed by direct introduction into the gas chromatograph. Recently, a new technique based on SPME with helical-solid-sorbent has been developed [65] and applied to the analysis of carbohydrates [66]. Per-O-methylated mono- and disaccharides were extracted using a helical support coated with polydimethylsiloxane (PDMS). The helical solid sorbent reduces the extraction time and improves the GC resolution. Ultrasonic waves are also used for faster extraction of substances adsorbed onto solid materials. This method has been used for the analysis of soluble carbohydrates from particulate organic matter from the sea [67] and polysaccharides in marine sediments [68]. A microwave oven and a steam treatment reactor have been used to extract hemicellulosic oligomers from spruce wood [69]. The oligomers obtained in the heat-treated liquid fraction were also separated by gel filtration [70]. 2.2. Fractionation Most sugars are isomers which only differ in the configuration of hydroxylic groups and molecular weight distribution. The characterization of these carbohydrates is not an easy task and sometimes requires the use of different techniques for their previous fractionation to simplify the sample before subsequent analysis. These techniques should provide the enrichment of the samples without losses of the analytes; otherwise, the use of an internal standard becomes necessary. 2.2.1. Membrane fractionation Different membrane techniques have been used for sample preparation in analytical chemistry [71]. In this section, we are going to remark on the recent applications of the main techniques to carbohydrate fractionation based on the use of different technologies (ultrafiltration, nanofiltration, dialysis, membrane-assisted solvent extraction) or different materials that membranes are made of (supported liquid membranes, polymeric membranes). 2.2.1.1. Ultrafiltration and nanofiltration Microfiltration (MF) and ultrafiltration (UF) processes have widely been used to purify, concentrate and fractionate carbohydrates in biotechnology and the fermentation industry [72], [73] and [74]. However, although acceptable results have been obtained in the separation of oligosaccharides from polysaccharides, the separation of low molecular weight carbohydrates can become a difficult task with these techniques. Swennen et al. [75] suggested the use of UF membranes with different molecular mass cut-off to fractionate arabinoxylooligosaccharides in their different degrees of polymerization (DP) and substitution (DS) whereas Confer and Logan [76] used UF membranes to monitor the molecular weight distribution of polysaccharides in solution during degradation. Nanofiltration (NF) can be a useful tool for the fractionation of carbohydrate mixtures. The separation properties of nanofiltration membranes were evaluated in 1997 by Urano et al. [77] for model oligosaccharide fractions and applied to the purification of oligosaccharides obtained from the artichoke. Aydogan et al. [78] stated that the NF separation of carbohydrates with differing molecular sizes in several glucosyl units was not viable due to its poor selectivity. Nishizawa et al. [79] studied the use of a membrane reactor system with a NF membrane to separate glucose from a mixture of fructooligosaccharides (FOS), whereas Lopez Leiva and Guzman [80] used cross-flow nanofiltration with a polyethylensulphone membrane for the fractionation of lactose hydrolysates. More recently, Goulas et al. [81] evaluated the pressure, feed concentration and filtration temperature effects of cross-flow nanofiltration working in full recycled mode to fractionate oligosaccharide mixtures (model systems for mono-, di- and trisaccharides). Further studies of these authors [82] demonstrated the efficiency of NF membranes (cellulose acetate) in diafiltration mode to separate monosaccharides from di- and trisaccharides with minor losses of these carbohydrates. UF membrane gave rise to a similar separation of these carbohydrates but with higher losses of di- and oligosaccharides (UF membrane pores are typically much larger than those of NF membranes). Nanofiltration processes have been also used by other authors to obtain oligosaccharide fractions free from monosaccharides using different kinds of membranes such as thin film composite membranes [83], [84] and [85], cellulose acetate membranes [83], tubular ceramic membranes [86] and [87], etc. Yuan et al. [88] also stated the energy-saving advantages of nanofiltration as compared to other conventional methods for oligosaccharide purification. 2.2.1.2. Dialysis and microdialysis Although the main applications of dialysis and microdialysis relative to carbohydrates have been focused on their purification and concentration [89], [90] and [91], these techniques have also been used to fractionate these compounds. Nilsson et al. [92] used microdialysis to elucidate the molecular structures of starch, previously hydrolysed using different enzymes (β-amylase, pullulanase and isoamylase). Simultaneous sampling fractionation and clean-up was achieved with this technique which was used on-line with HPAEC-PAD. One of the most useful applications of dialysis is the separation of carbohydrates of high molecular weight, such as oligosaccharides and polysaccharides, from those of lower molecular weight [43], [93] and [94]. 2.2.1.3. Liquid membranes Liquid membranes of the “water–oil–water” type consist of an organic phase placed between two aqueous phases [95]. The best liquid membrane configuration for industrial applications is the supported liquid membranes (SLM). The use of these membranes for analytical chemistry was first described by Audunsson [96]. The membrane is constituted by an organic solvent, which is held by capillary forces in the pores of hydrophobic porous membranes [67]. SLM has been used for the selective transport of some alditols (erythritol, threitol, ribitol and xylitol) [97], as well as sugars and deoxy-sugars [95], [98] and [99]. The separation of sugars through SLM is based on the use of specific carriers that form complexes with the isomeric carbohydrates. Boronic acid derivatives [100] and [101] and neutral lipophilic macrocycles designed on different sugar receptors [95], [99], [102] and [103] have been used as carriers for sugar transport. Plasticized liquid membranes have also been proposed to separate fructose from glucose to provide sufficient concentration of fructose for the formation of high fructose syrup [104]. Moreover, these membranes have been used to separate sucrose, glucose and fructose from crude sources such as molasses, sugar cane juice and beet sugar juice. The proposed industrial applications could easily be adapted to analytical conditions. 2.2.1.4. Polymeric membrane extraction This technique uses a polymeric membrane, usually a silicone rubber membrane, which is more stable than SLM and with a considerably higher lifetime; however, there are less possibilities for chemical tuning of the separation process [71]. The transport of small saccharides through plasticized polymeric membranes has been investigated by Riggs and Smith [105]. These authors discovered that plasticized cellulose triacetate membranes containing large amounts of trioctylmethylammonium chloride were stable and selectively permeable to neutral mono- and disaccharides. They also studied the saccharide diffusion in relation to the size of the saccharide, the carrier cation and carrier anion [105] and [106]. 2.2.2. Carbon fractionation Column chromatography with activated charcoal and Celite™ has been widely used to fractionate carbohydrates since 1950 when it was first proposed by Whistle and Durso [107]. The use of different ethanol concentrations allows the selective extraction of the carbohydrates previously adsorbed onto the charcoal column, depending on their degree of polymerization. Considering AOAC method [108], selective extraction of monosaccharides can be achieved using 1% (v/v) ethanol in water, disaccharides with 5% (v/v) ethanol and oligosaccharides with 50% (v/v) ethanol. Baker et al. [109] demonstrated that the use of borate ions in alkali environments in the eluent accelerated the elution of certain carbohydrates from charcoal– celite columns and also that, chromate, molibdate and tungstate ions reacted with polyalcohols and caused changes in their separation. Different authors have used this technique to remove monosaccharides from samples constituted by complex mixtures of carbohydrates such as honey [110], [111], [112], [113] and [114]. The presence of structurally similar carbohydrates, the existence of large amounts of monosaccharides and the low contents of oligosaccharides in honey make it difficult to obtain oligosaccharide patterns by chromatographic techniques. Therefore, separation of the most abundant monosaccharides (glucose and fructose) previous to oligosaccharide analysis must be carried out. In a recent study, Morales et al. [115] have substituted the use of activated charcoal columns for an agitation and filtration process of charcoal in ethanol solutions to analyse honey oligosaccharides removing mono and disaccharides. Fig. 2 shows the chromatographic profiles obtained by HPAEC-PAD of a mixture of maltodextrins (A) and the fraction of mono and disaccharides collected after charcoal treatment (B). Only small amounts of trisaccharides were observed in this fraction. Using this method the fractionation of carbohydrates was similar to that achieved with the celite:charcoal column, however, it was simpler and less time-consuming. Full-size image (9K) Fig. 2. HPAEC-PAD chromatographic profiles of a mixture of maltodextrins (a) and the fraction of mono- and disaccharides collected after treatment with activated charcoal and 10% ethanol (b). G1–G7: maltodextrins from DP1 to DP7. View Within Article The combination of activated charcoal:celite columns with other techniques of fractionation constitutes a useful tool to isolate oligosaccharides, permitting their subsequent characterization. In this sense, Wei et al. [116] developed a method for the fractionation of oligosaccharides from honeydew. They used charcoal columns eluted with isopropyl alcohol followed by a fractionation on Bio-gel P2. Other authors [117] have used charcoal:celite columns, preparative liquid chromatography and gel permeation chromatography for the isolation of oligosaccharides from a commercial beet medium invert syrup. Montane et al. [118] have optimized the purification of xylooligosaccharides by activated charcoal adsorption from lignin compounds which were more retained than the oligosaccharides onto the activated charcoal. Similar to the use of graphitized carbon columns for HPLC analysis of oligosaccharides [119], [120], [121] and [122], graphitized carbon cartridges are becoming increasingly popular due to the unique selectivity, high preparative capacity and chemical inertness of the carbon. Moreover, graphitized cartridges have been used to separate monosaccharides from the higher molecular weight carbohydrates of honey [123]. Elution of oligosaccharides was carried out using water containing an organic modifier (alcohol, acetonitrile or trifluoroacetic acid) at different temperatures. 2.2.3. Size exclusion chromatography Size exclusion chromatography (SEC) is one of the most useful tools currently employed for the fractionation of carbohydrates (oligo- and polysaccharides). In SEC, carbohydrates are separated according to their molecular size, this separation also depending on the ratio of their molecular dimensions to the average diameter of the pores of the stationary phase. A considerable number of applications of this technique have been used in the separation of carbohydrates for analytical purposes in the last few years [29], [70], [124], [125], [126], [127], [128], [129] and [130]. Some authors have used SEC columns connected in series to fractionate oligosaccharides from different molecular weights such as Lundqvist et al. [131] for galactoglucomannans extracted from Picea abies and Sun et al. [132] for xylo-oligosaccharides. The advances in SEC of cellulose and related polysaccharides have been recently reviewed by Eremeeva [133]. The application of SEC to cellulose and other polysaccharides is not straightforward due to their crystalline structure which does not allow solvents to penetrate easily into the cellulose fibres and to break the intramolecular hydrogen bonds. Riccardi et al. [134] have compared three methods (ethanol precipitation, dialysis and SEC on a desalting gel) to separate simple carbohydrates from an exopolysaccharide, obtaining the best results with SEC. Finke et al. [135] investigated the productivity (grams of carbohydrate separated per hour) and resolution of the preparative continuous annular SEC. This system consists of two concentric cylinders forming an annulus into which the stationary phase is packed [136]. Finke et al. [135] compared the annular SEC with the fixed bed conventional gel chromatography. The productivity of annular chromatography was 25-fold higher than that of the conventional method. SEC has also been established as a form of high performance liquid chromatography and several advances, mainly in stationary phases and detection systems, have been developed. Improvements and drawbacks of SEC have been summarised [137] and [138]. 2.2.4. Field flow fractionation Field flow fractionation (FFF) was first described by Giddings [139] and is based on the separation of compounds in an open unpacked channel. The sample (in a small volume) is injected at the inlet end of the channel and pushed through it by a longitudinal laminar transport mobile phase flow. At the same time a perpendicular field is applied, driving the compounds to one of the walls. The separation is a balance of the mass transport caused by the field and the oppositely acting Brownian motion [140]. This method shares some similarities with SEC, electophoresis and ultrafiltration. FFF applications to carbohydrates are based on the fractionation of polysaccharides (dextran, pullulan, starch, cellulose derivatives, heteroglycans), which cannot be fractionated by other techniques such as SEC [140] and [141]. 2.2.5. Ion exchange chromatography Ion exchange chromatography (IEC) has been widely used by the sugar industry to fractionate mono- and oligosaccharides. Sugars, as weak electrolytes, show little interaction with anion exchange resins in an aqueous medium. These interactions are increased with the formation of sugar complexes with borates and the mechanism of separation is mainly ion exchange [32]. For cation exchange resins the retention mechanism involves a mixture of different effects: ligand exchange, exclusion mechanism, complex formation, ion–dipole interactions and hydrogen bonds [32]. Vente et al. [142] have recently studied the influence of Ca2+, Na+ and K+ as cation exchange resins to separate monosaccharides and oligosaccharides. K+ loaded resin had a stronger adsorption of sugars than the Na+ loaded resin. The retention was also related with the number of equatorial-axial oriented sugar OH groups for complexation with the cation. K+ was more suitable to separate glucose from oligosaccharides whereas Ca2+ was the best choice to separate fructose from oligosaccharides. Stefansson and Westerlund [143] have revised the ability of sugars to complex with metal cations in chromatographic systems formed by ion-exchange resins. They pointed out the selectivity of ligand-exchange chromatography at alkaline pHs, where strong complexation between carbohydrates and suitable metal ions take place. The strength depends on the ionic size of the cation and on the shape and flexibility of the complexing molecule [144]. Excellent separations have been obtained with lanthanide cations [145]. Mechanisms and conditions to improve selectivity have been extensively studied [146] and [147]. Anion- or cation-exchange resins have been commonly used, alone or in combination with SEC, to fractionate oligosaccharides such as human milk oligosaccharides [148], cationised starch [149], etc. Paull and Nesterenko [150] have summarised the most significant recent advances made in stationary phases for ion exchange chromatography in complex matrices. 2.2.6. Simulated moving bed chromatography Simulated moving bed (SMB) chromatography was invented in the 1960s and it has been used in the sugar industry for many years for large scale separations (palatinose–trehalulose fractionations) [151]. This technique is based on the adsorption of the samples in columns connected in series. The adsorbents are usually a combination of size-exclusion and ion exchange gels, although other stationary phases can be used. The system is divided into four zones with at least one column each, connected by valves which can be individually opened and closed. A recycling pump inside the system delivers the mobile phase through the columns (flows out of zone 4 and is recycled to zone 1). The feed and the fresh eluent are constantly introduced into the unit at two different injection points, whereas the extract stream enriched with the more retained components and the raffinate stream enriched with the less retained components leave the unit by the two withdrawal points. The flow of adsorbent is simulated by shifting the injection and collection positions one column forward in the direction of the liquid flow at a constant time interval [151], [152] and [153]. Sugar separation is usually designed by computer simulation by selecting different parameters such as column phases and dimensions, total column number, eluent, switch time interval, etc. [151]. This technique has been applied to the separation of binary mixtures of carbohydrates such as glucose–fructose [154] and more recently to the separation of lactose from complex mixtures of human milk oligosaccharides [153] using different stationary phases. 2.2.7. Microbiological treatments The use of yeast to remove certain carbohydrates can also be considered as a fractionation technique. Baumgartner et al. [155] used dried yeast (Saccharomyces bayanus) to remove carbohydrates from carob powder for the purpose of analyzing cyclitols. After yeast treatment, the remaining carbohydrates were removed by anion-exchange chromatography. More recently, Saccharomyces cerevisiae has been used to selectively remove mono and disaccharides [156]. S. cerevisiae showed a high specificity for the removal of some mono- and disaccharides such as glucose, fructose, mannose, galactose and α-linked disaccharides. However, rhamnose, sorbose, β-linked disaccharides and oligosaccharides with four or more monosaccharide units were not removed. This technique has also been used to remove monosaccharides from honey samples [85] and it is currently applied to the analysis of minor compounds in honey in our laboratory. Immobilized cells of the bacterium Z. mobilis have been used [157] to remove glucose, fructose and sucrose present in food grade oligosaccharide mixtures. These carbohydrates were removed within 12 h without any pH control or nutrient addition. 2.2.8. Supercritical fluid extraction Supercritical fluid extraction (SFE) is based on the utilization of a fluid in supercritical conditions. A pure supercritical fluid (SCF) is a gas or liquid at a temperature and pressure above the critical point. Its properties are intermediate between those of a liquid and those of a gas and its solubility behaviour is similar to that of a liquid while penetration into a solid matrix is facilitated by the high diffusivity. As a consequence, the extraction becomes faster than for conventional liquid extraction; also the extraction conditions can be easily controlled. This technology is suitable for extraction and purification of a variety of compounds, especially those with lipophile properties, such as lipids, pesticides and essential oils. As carbohydrates are very polar compounds, SFE has been used to extract less polar compounds from sugar matrices. Solubility of carbohydrates in supercritical carbon dioxide is low [158] but it shows a remarkable increase when alcohols are added as polar co-solvents [159]. It is possible to separate glucose and fructose using supercritical carbon dioxide and ethanol, starting with aqueous solutions of the two sugars [160]. In spite of these findings, very few attempts to use SFE for fractionation of carbohydrates have been made. The viability of selective fractionation of mixtures of lactose–lactulose and galactose–tagatose using supercritical CO2 with a co-solvent based on ethanol:water and isopropanol:water, respectively, has been recently evaluated [161] and [162]. 2.2.9. Pressurized liquid extraction Pressurized liquid extraction (PLE) is a recently introduced technique which allows the isolation of different compounds in a short time using small volumes of solvent. Accelerated solvent extraction (ASE) is the registered name of the commercial equipment. It works with high pressure and controlled temperature and can replace the classical liquid–solid extractions (Soxhlet, sonication, etc.). It allows the use of solvents in subcritical conditions and it has been largely applied to non-polar analytes but very scarcely used for very polar compounds. Nevertheless, solubilities of low-molecular weight sugars in different alcohols may be modulated in order to allow the fractionation of mixtures using these techniques. Subcritical water extraction (SWE) has been scarcely applied to the fractionation of carbohydrates, since the overheated water may act as an effective acid–base catalyst [163] promoting sugar degradation and formation of HMF and other by-products. In spite of the decrease in recovery, some separations have been assayed: sugars from hemicellulose hydrolyzates [164] and even subcritical fluid chromatography of monosaccharides and polyols [165]. ASE has been assayed for polysaccharides from several species of Linghzi (Chinese mushrooms) [166]. It was performed with an ASE 200™ from Dionex, using water at 120 °C and 1500 psi for 5 min of extraction (two cycles). The total amount of extracted carbohydrates was found to be higher than that obtained when using sonication. Some attempts have been done in our laboratory to fractionate disaccharide mixtures with ASE 300™ [167] using different alcohol concentrations and also to obtain oligosaccharide fractions from honey (unpublished results). Although results are very promising, further work is being done in order to optimize PLE-based procedures. 2.2.10. Molecularly imprinted polymers Molecular imprinting is a well-developed tool in analytical chemistry which can be used as a very efficient fractionating method. Molecularly imprinted polymers (MIPs) are systems capable of recognizing specific molecules with a sorption capacity dependent on the properties and template concentration of the surrounding medium. Different molecularly imprinted polymers have been developed for carbohydrate recognition with two main objectives: a number of works are directed towards obtaining specific traps for glucose which do not bind fructose for biomedical purposes [168] while others are searching for new separation systems for HPLC (and hence a high specificity is necessary). The use of MIPs for racemic resolution of free sugars has been known for many years [169] and [170]. However, recently, several works have been devoted to the development of specific MIPs for glucose, focusing especially on determining their binding capacities with respect to fructose. Poly(allylamine hydrochloride) was non-covalent imprinted with glucose phosphate monosodium salt which produced MIP hydrogels capable of binding glucose in quantitative and isomerically specific ways [171]. Isomeric specificity in hydrogels imprinted for glucose was demonstrated by higher binding capacities of glucose than those of fructose in the same polymers. A novel, solution-to-surface imprinting method based on the different higher-order conformations adopted by boronic-acid-appended poly(l-lysine), in the presence of sugars was developed by Friggeri et al. [172]. The application of a d-glucose-imprinted polymer interface for the selective detection of d-glucose over d-fructose was demonstrated successfully. New networks based on star polymers were designed to be responsive and recognitive. Oral and Peppas [173] obtained over 300% more uptake for d-glucose compared to d-fructose using molecular imprinting with d-glucose and cross-linking with poly(ethylene glycol) dimethacrylate. Polymers based on polyacrylates with improved ability to bind saccharides have been recently designed [174]. Polymer selectivity for discrimination of α- and β-glycosidic bonds as well as the effect of the number of glucose rings was assayed [175]. Porphyrin-based polymers have been prepared for carbohydrate recognition, and assayed with several n-octyl-d-glucopyranosides [176]. Each porphyrin-based polymer demonstrates high affinity and differential selectivity for carbohydrates similar in structure. In spite of the high selectivity achieved with several systems, MIPs are mainly prepared for chromatographic analysis and they have been very scarcely used for sample preparation. Perhaps less selective (and less expensive) polymers could be designed in order to make easier the fractionation of saccharide groups in different samples (food, cosmetics, environment, …). 2.2.11. Hydrophilic interaction chromatography HILIC has been applied to carbohydrate analysis for more than 30 years although not under this name [177]. Retention is caused by partitioning of the carbohydrate between a waterenriched layer of stagnant eluent on a hydrophilic stationary phase and a relative hydrophobic bulk eluent. As previously mentioned HILIC SPE has been used as a sample preparation technique, not only for clean-up, but also for carbohydrate fractionation. An interesting and very long fractionation was carried out to isolate (S)-malic acid-1-O-d-glucopyranoside from the morel mushroom (Morchella deliciosa) through multistep ultrafiltration on 10 and 0.5 kDa, GPC on Shephadex G-15, and semipreparative HILIC on TSK-GelAmide-80. The glycoside was identified by ESI and NMR and showed to be responsible for the umami taste of the morel extract [178]. 2.3. Chemical treatments 2.3.1. Hydrolysis Hydrolysis is a necessary step before chromatographic analysis of different high molecular weight polysaccharides. Acid hydrolysis has been used for many years for this purpose using mainly trifluoroacetic acid (TFA) or HCl at different concentrations and thermal conditions [179] and [180]. Polysaccharides can be also subjected to methanolysis with hydrochloric acid in methanol for hydrolysis [22]. Enzymatic depolymerization of big molecules using different enzymes is also very extended and has been summarized in several reviews [181], [182] and [183]. The determination of the main neutral sugars in pectin [184] has been carried out using a new method which involves a mild chemical attack (0.2 M TFA at 80 °C) followed by an enzymatic hydrolysis. Among recent advances of hydrolysis it is necessary to remark on the application of microwave irradiation. Microwaves are gaining popularity for different heating treatments including methanolysis and hydrolysis of saccharides [185]. An analytical procedure for the characterisation of polysaccharides and identification of plant gums in very old polychrome paintings was based on hydrolysis with 2 M TFA assisted by microwaves, clean-up of the hydrolysate by ion-exchange resin, and analysis by high-performance anion-exchange chromatography with pulsed amperometric detection [7]. Hydrolysis time was reduced to 20 min. A new procedure based on microwave irradiation with a catalytic amount of potassium persulfate promoted the total hydrolysis on alumina support of eight different seed gums [186]. Different hydrolysis protocols used by marine biogeochemists to extract sugars from various marine matrices including sinking particulate organic matter (POM), dissolved organic matter (DOM), ultrafiltrated dissolved organic matter (UDOM), and sediments have been revised [5]. It was demonstrated that mild and strong hydrolysis gives comparable results for open ocean samples. It was also verified that most of the published sugar data obtained by chromatographic techniques are related to suspended or sinking POM and sediments, and that there is a need for data on sugar composition in DOM and UDOM, which involves further analytical difficulties for chromatographic analysis. 2.3.2. Derivatization Derivatives of carbohydrates are prepared for two different purposes: to increase volatility (for GC) and to enhance sensitivity (for LC and CE); the type and requirements of both are different and will be treated separately. Besides the general conditions for analytical derivatization (reactions have to be fast and complete, giving stable derivatives without by-products) [187], some additional requirements arise when working with carbohydrates. It is necessary to take into account that the only functional group common to all saccharides is the hydroxyl. Some useful derivatization reactions are amenable to aldoses and not to ketoses; some very common sugars have no reducing group (sucrose, trehaloses, raffinose, etc.) which makes a difference when the carbonyl group has to react; sugar acids can exist as open forms or lactones (which will give different derivatives) depending on the pH; and so on. The state-of-the-art in derivatives preparation has been included in some reviews dedicated to chromatographic analysis of sugars [188] and [189], therefore, in this section we only resume the more recent publications on this subject. 2.3.2.1. Derivatives for LC and CE Carbohydrates can be analyzed in liquid phase without derivatization, using UV detectors at low wavelengths, refractive index or light scattering detectors; IEC is very often connected to amperometric detectors which detect free sugars. Nevertheless, in the search for enhancing sensitivity and selectivity, different methods to introduce chromogenic and fluorogenic groups in the saccharide molecules have been proposed. Derivatives can be prepared before the analysis (precolumn derivatives) or by making a chemical reaction after separation but before detection. The last type of derivatives will not be considered as “sample preparation” and will be not be discussed here. Precolumn derivatives are applicable to both HPLC and CE. This subject was revised in 1996 [190], 1998 [191] and 1999 [192] and more recently in 2003 [189]. Most methods are based on the condensation of a carbonyl group in carbohydrates with primary amines to give a Schiff base which is then reduced to a N-substituted glycosil amine. The primary amine has to posses the desired chromophore or fluorophore substituent, usually an aromatic ring. Reductive amination has been carried out with 2-aminopyridine (2-AP), different trisulphonates, esters of p-amino benzoic acid, 2-aminoacridone, etc. Carbohydrates possessing a free amino group can react with O-phtalaldehyde (OPA) to be transformed into OPA derivatives or with phenyl isothiocyanate. p-Nitrobenzoates have been used to substitute all the hydroxyl groups in mono-, di-, and trisaccharides [193] and perbenzoylation has been used for the sensitive detection of monosaccharides [189]. Besides the derivatives cited in the above mentioned reviews, new reactions have been assayed. 2-Methyl-3-oxo-4-phenyl-2,3-dihydrofuran-2-yl acetate was developed for the analysis of primary amines and aminated carbohydrates by means of HPLC, CE and MALDI/MS [194]. The obtained derivatives could be successfully analyzed by these techniques. Oligosaccharides were derivatizated with various aminobenzoic esters (methyl, ethyl and butyl) and aminobenzonitrile [195] for micelar electrokinetic chromatography (MEKC) with sodium dodecyl sulphate (SDS). Butyl aminobenzoate derivatives gave the longest retention times and the best resolution of the sugars, whereas derivatives of aminobenzonitrile gave the worst separation which was attributed to their high polarity. The method was optimized and applied to maltooligosaccharides and to human milk oligosaccharides. p-Aminobenzoic acid (p-AMBA) was used for derivatization of neutral sugars, amino sugars and uronic acids, enabling fluorescence or photometric detection [196]. p-AMBA and other reagents, i.e., p-AMBA propyl ester, 1-aminopyrene, 2-(2-aminophenyl)indole, and 4-aminoazobenzene, were compared to derivatize neutral sugars, amine sugars and uronic acids for RP-HPLC analysis [197]. Separation was complete and detection limits suitable; p-AMBA allowed the determination of target compounds in landfill leachates and lysimeter percolates. A novel reagent, 4-(3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid (PMPA) was assayed [198] in order to improve methods based on 1-phenyl-3-methyl-5-pyrazolone (PMP) developed by Honda et al. [199]. PMPA derivatives from 17 neutral sugars, 2 aminosugars, 3 N-acetylaminosugars and 2 uronic acids were chromatographed. Eight of them were selected for validation: linearity was good and detection limits ca. 10 pmol. The PMP method was simplified by Zhang et al. [200] and applied to determination of monosaccharides and oligosaccharides in Aloe powder and food by MEKC and HPLC (Fig. 3). Full-size image (9K) Fig. 3. Separation of PMP-labeled carbohydrates in Aloe powder by (a) MEKC and (b) HPLC. 1: Analysis of aloe powder and 2: analysis of the hydrolysate of aloe powder. (Reprinted from [200], with the permission from Elsevier © 2002). View Within Article A method of ultramicroanalysis for mono- and disaccharides using CE with laser-induced fluorescence (LIF) detection was based on conversion to 7-nitro-2,1,3-benzoxadiazole (NBD) Nmethyl glycosylamines [201]. The reaction consisted of two steps (reductive N-methylamination followed by condensation with NBD). Conditions were mild and did not cause desialylation. Attomols could be detected (amount injected). Sialic acids require mild procedures which have been revised [202]. Carbohydrates in milk powder were derivatized with p-nitroaniline by irradiation with microwaves prior to HPLC analysis with UV detection. Reaction was complete in 5 min and the sensitivity was high (detection limits within 3.3 and 5.1 μg/mL, 10 and 15 nmol) [203]. In spite of the wide possibilities available to choose derivatives for LC or CE, new procedures continue to appear either to improve those already existing or to develop new applications. Derivatives obtained through reductive amination are commonly used, since there are many possibilities to select an amino compound with the required properties; but the analysis of nonreducing sugars and/or polyalcohols requires derivatization of hydroxyl groups. Maximum sensitivity has been reached with LIF (laser-induced fluorescence) but many procedures may be carried out with less sensitive procedures. 2.3.2.2. Derivatives for GC Carbohydrates always need to be converted into volatile compounds before GC analysis. The classical methods consist of replacing all the active-hydrogen atoms by non-polar substituents. Methyl, trifluoroacetyl, trimethylsilyl and tert-butyldimethylsilyl ethers have been the most popular derivatives, allowing GC analysis of saccharides with up to four to five monosaccharide units, as well as sugar alcohols, aminosugars and acids. These reactions give a different compound for every anomeric form of the sugar (up to six), which can be easily separated in capillary columns [187]; this fact can be considered as an advantage for equilibrium studies of single carbohydrates, but an inconvenience when a complex mixture has to be separated. In recent times, some well established derivatization methods have been improved. A classical method for GC analysis of carbohydrates in fruit products was modified introducing a preequilibration time of the sample in dry pyridine at 50 °C for 20 min before the addition of the trimethylsilylimidazole (TMSI) [204]. This method was shown to give significantly lower variation coefficients for sugars in apple juice concentrates, pure and adulterated with syrup, when compared to the original capillary GC method. Several attempts have been made to reduce the number of chromatographic peaks of each derivatized carbohydrate. Very stable alditol acetates may be obtained by reduction and acetylation, but their volatility is low and these derivatives are only adequate for monosaccharides. An automated derivatization instrument has been developed for preparation of alditol acetates for GC–MS profiling of bacterial carbohydrates [205] which was also applied for the determination of muramic acid in organic dust [206]. Another commonly used approach is to convert the free carbonyl groups into oximes or N-alkyl oximes before silylation, which affords only two peaks for each reducing sugar (corresponding to E and Z isomers of the oxime). These compounds are also quite stable and hence have become very popular. The oximation–silylation method has been modified and optimized [207]: aniline was found to be the best reaction medium for oxime formation with hydroxylamine hydrochloride, and N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) was the most efficient of the assayed silylation reagents. Short analysis time was achieved with few by-products. The method was evaluated for arabinose, xylose, fructose, glucose, sucrose and salicin (internal standard) and found to be suitable for processed food analysis. Aldononitrile acetates are derivatives from aldoses which give a unique peak for every sugar; but they are not reliable for ketoses [187]. Methods for quantitative analysis of di-O-isopropylidene acetate (IPAc) derivatives of hexoses or pentafluorobenzoyl (PFBz) esters have been reported [208] in order to study multiple isotopomers by chemical ionization GC–MS. The PFBz derivative was about 100-fold more sensitive than that of acetate: the useful range for isotopic tracer studies was 25–2500 pmol for electron impact (EI) analysis of the acetate derivative and 0.1–55 pmol for nitrogen chemical ionization (NCI) analysis of PFBz derivative (sample amount injected). EI–GC/MS analysis of the IPAc derivative was preferred for most studies where sample size was not limited. A type of carbohydrate derivative that retains the charge on the anomeric carbon of the original monosaccharide (dialkyl-dithioacetal acetates) was optimized for the quantitative evaluation of 13 C distribution into isotopomers of 13C-labeled aldoses and ketoses [209]; these derivatives were well suited for measuring isotopic enrichment into the characteristic anomeric carbon of aldose sugars and could probably facilitate the global analysis of metabolic flux in carbohydrate pathways. Microwave-assisted preparation of sugars and organic acids for simultaneous determination in citric fruits by GC was accomplished [210] using a domestic microwave oven. Sugars were converted to trimethylsilylated oximes in 5 min, avoiding filtration and centrifugation. Recoveries were within 95–100% of the assayed sugars. TMS oximes were prepared in the presence of the fruit matrix for quantitation of sugar alcohols, mono-, di- and trisaccharides in sour cherries; the GC–MS procedure was very reproducible, RSD% averaging 2.3 for components present in concentrations ≥1% and 3.6 for those present in concentrations <1% [211]. The procedure was further successfully extended to other fruits [212]. Also Brazilian propolis was directly derivatized [213]. Although some of the existing procedures for preparing GC derivatives are quite satisfactory, and some of them have even been improved [207] and [211], one of the goals of these methods – to achieve only one chromatographic peak for each individual sugar – seem to need further work. 2.3.3. Derivatives used for structural analysis The so-called methylation analysis is an analytical method largely used for structural studies of polysaccharides. It involves methylation of the free hydroxyls in the intact polysaccharide, cleavage of the glycosidic links and acetylation of the new formed hydroxyls. Several similar methods have been developed, based on achieving monosaccharides with two different types of substituents, one of them marking the position of the glycosidic linkage in the original polysaccharide, and the other helping to make the molecule volatile. All these methods allow the monosaccharide components and positions of the glycosydic linkages to be studied in the original polysaccharide [214]. Classical techniques have been revised and compared [215] in order to obtain a rapid method for simultaneous identification of furanosides and pyranosides in heteropolysaccharides. A novel method for the methylation of polysaccharides using microwave (MW) irradiation has been described [216]. Seed gum from Cyamopsis tetragonolobus (Guar) was fully methylated with dimethyl sulphate and sodium hydroxide using 100% microwave power for 4 min in 68% yield. The completely methylated seed gum thus obtained was hydrolyzed by 70% formic acid followed by 0.5N H2SO4 under full microwave power for 1.16 and 1.66 min, respectively. The partially methylated monosaccharides were separated and identified. Glycerol was used to improve solubilization of high molecular weight polysaccharides prior to methylation for linkage analysis [217]. Four model polysaccharides: neutral, acidic (both within 1000–2000 kDa), dextran 40 kDa and 2000 kDa showed significant increases in derivatization yield as measured by recovery of partially methylated alditol acetates. More work should be conducted on this subject in order to continue to improve the above mentioned results. 2.3.4. Thermochemolysis Thermochemolysis of carbohydrates was described by Fabbri and Helleur in 1999 [218] as an interesting characterization method of insoluble polysaccharides. Permethylated deoxy aldonic acids were identified as key products allowing identification of the original molecules. Challinor reviewed in 2001 [219] the developments of the thermally assisted hydrolysis and methylation (THM) techniques in analytical pyrolysis. THM is applied in pyrolysis coupled to GC and GC– MS to polysaccharides in environmental, food and agricultural studies. Thermally assisted hydrolysis and alkylation were applied to aerosol samples [6]. Levoglucosan, and other compounds of polysaccharide origin were identified as their methyl ester and ether derivatives among the products of thermally assisted methylation. The mechanisms involved in these reactions have been discussed by Schwarzinger [220] and [221]. This a very specific field where further developments in instrumentation are the key to advancement. 3. Concluding remarks Sample preparation methods for chromatographic analysis are in continuous progress; nevertheless, evolution seems to be faster in certain fields such as volatiles or pesticides, whereas others like carbohydrates need special attention. The dissimilarity in saccharide properties and structures could be partly responsible for this. New techniques involving vapour-phase transference or low polarity media are clearly unsuitable for carbohydrates; but a considerable number of new techniques could be potentially adequate for carbohydrate characterization to which more research should be dedicated to reach this objective. Although alternative techniques such as helical-solid-sorbent extraction or the use of ultrasonic waves have been used for carbohydrate clean-up, the traditional filtration and extraction procedures are still the most widely used techniques. Treatments with alcohols and the use of solid phase extraction are especially convenient for carbohydrate purification. Nevertheless, the trend of clean-up processes is orientated towards greater automatization, the on-line systems being a promising way of carbohydrate purification. Before discussing the utility of the fractionation techniques, it is necessary to distinguish between the separation of carbohydrates depending on their molecular weight and the separation of isomers. Most of the previously mentioned techniques can be successfully used for the first aim; however, the fractionation of carbohydrates with the same molecular weight which only differs in their monosaccharide composition or glycosidic linkages becomes a difficult task. It is well known that the most common technique used for DP fractionation is SEC followed by IEC. Activated charcoal columns have also been widely used; nevertheless the selectivity of this technique towards the different structures of the carbohydrate limits its application. Moreover, the use of charcoal columns can be tedious, although in recent times graphitized cartridges are gaining popularity. The membrane techniques can also be a good alternative to these methodologies, although selection of membrane should be carefully considered depending on the carbohydrate. Moreover, membrane techniques offer good possibilities for automation. Ricciardi et al. [134] have compared three methodologies (ethanol precipitation, dialysis and SEC) to separate simple carbohydrates from an exopolysaccharide (EPS). Ethanol precipitation was faster and less expensive, however losses of EPS could be observed. Dialysis and SEC recovered 100% of the EPS, however, SEC was a simpler and less expensive technique. We have recently compared three fractionation techniques (nanofiltration, activated charcoal and yeast treatments) to separate monosaccharides from oligosaccharides in honey [85]. Gas chromatographic profiles of untreated honey and the samples obtained by the three methods are shown in Fig. 4. The nanofiltration process did not show the complete removal of monosaccharides, although a great diminution of these sugars was observed. On the contrary, almost 100% of monosaccharides were removed using activated charcoal and yeast treatments. However, some di- and trisaccharide concentrations decreased due to the selectivity of the fractionation, while nanofiltration preserved the original profile. Full-size image (47K) Fig. 4. GC profile of TMS-oximes of carbohydrates in honeydew honey (a) untreated, (b) after nanofiltration process, (c) after fermentation with yeast, (d) after activated charcoal treatment. 1: Monosaccharide, 2: disaccharides and 3: trisaccharides; i.s.: internal standard. (Redrawn from [85], with the permission from ACS © 2005). View Within Article The separation of isomers is not a straightforward procedure. Traditional techniques such as IEC or activated charcoal are not orientated towards this purpose. Therefore, other techniques such as MIPs, PLE, SFE or SLM have been developed. Nevertheless, all these techniques have been assayed with simple mixtures and their applications are scarce. Some assays comparing SFE and PLE [166] and [167] are being carried out in our laboratory with simple disaccharide mixtures. Both techniques are showing promising results in the separation of carbohydrates whereas PLE seems to present higher recovery than SFE. More experiments should be done to compare: effectiveness, recovery and feasibility of all the above mentioned techniques which could encourage their applicability. According to the derivatization methodologies, in spite of the number of proposed reactions, an optimal derivative does not exist. The desired sensitivity, the nature of the analytes, and the instrument to be employed in every specific problem determine the type of derivative to be chosen. From the very extensive literature which has been examined, it can be deduced that during recent years the advances in some aspects of carbohydrate pre-treatments have been scarce; some promising techniques which have been successfully used in other fields have hardly been applied to saccharides. It is worth noting that some attempts are being made in order to extend the application area of several techniques. Some fractionation methods used at present in the sugar industry could be easily devised at analytical scale level (as happened with SFE). A special case is that of derivatization, which seems to progress faster in HPLC/CE area than in GC, where the existing derivatives are still not totally satisfactory. 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