Shmaryahu Ezrahi, Abraham Aserin, Rivka Efrat, Dima Libster, Eran Tuval, and Nissim. Garti. 2012. “Surfactants in solution - basic concepts.” In Nanotechnol. Solubilization Delivery Foods, Cosmet. Pharm., Pp. 1–30. DEStech Publications, Inc. Abstract
A review on fundamental concepts that are pertinent to understanding surfactants. It also describes self-assembled aggregate structures of surfactants. [on SciFinder(R)]
Dima Libster, Abraham Aserin, and Nissim. Garti. 2012. “Topical delivery of pharmaceuticals using liquid crystalline structures.” In Nanotechnol. Solubilization Delivery Foods, Cosmet. Pharm., edited by I. Amar-Yuli, Pp. 151–186. USA: DEStech Publications, Inc. Abstract
A review. Transdermal delivery has lately emerged as a valuable alternative method to improve bioavailability and increase pharmaceutical efficacy of various drugs. Transdermal administration can potentially minimize side effects as well as first-pass metab. It has been used successfully for hormone replacement therapy, smoking cessation, and pain management. However, there have been challenges in the expanding use of the technol. to numerous types of pharmaceuticals, including extremely hydrophilic or lipophilic drugs, peptides, proteins, and other macromols. In this context, colloidal drug carriers, and in particular lyotropic liq. crystals (LLCs), seem to be promising candidates as the vehicles of unconventional delivery for various drugs. Such vehicles can provide enhanced drug soly., relative protection of the solubilized drugs, and controlled release of drugs, while avoiding substantial side effects. Exhibiting interesting properties for a topical delivery system, LLCs were considered and have been studied as delivery vehicles of pharmaceuticals via the skin and mucosa. This review focuses on lyotropic non-lamellar lyotropic mesophases (hexagonal and cubic) and their nano-dispersions as topical delivery vehicles. Recent advances in transdermal and mucosal drug delivery via LLC carriers are demonstrated and discussed. [on SciFinder(R)]
Liron Bitan-Cherbakovsky, Dima Libster, Abraham Aserin, and Nissim. Garti. 2011. “Complex Dendrimer-Lyotropic Liquid Crystalline Systems: Structural Behavior and Interactions.” Journal of Physical Chemistry B, 115, 42, Pp. 11984–11992. Abstract
The incorporation of dendrimer into three lyotropic liq. cryst. (LLCs) mesophases is demonstrated for the first time. A second generation (G2) of poly(propylene imine) dendrimer (PPI) was solubilized into lamellar, diamond reverse cubic, and reverse hexagonal LLCs composed of glycerol monooleate (GMO), and water (and D-$\alpha$-tocopherol in the HII system). The combination of PPI with LLCs may provide an advantageous drug delivery system. Cross-polarized light microscope, small-angle X-ray scattering (SAXS), and attenuated total reflectance Fourier transform IR (ATR-FTIR) were utilized to study the structural behavior of the mesophases, the localization of PPI within the system, and the interactions between the guest mol. and the system's components. It was revealed that PPI-G2 functioned as a "water pump", competing with the lipid headgroups for water binding. As a result, L$\alpha$→HII and Q224→HII structural shifts were detected (at 10 wt % PPI-G2 content), probably caused by the dehydration of monoolein headgroups and subsequent increase of the lipid's crit. packing parameter (CPP). In the case of HII, as a result of the balance between the dehydration of the monoolein headgroups and the significant presence of PPI within the interfacial region, increasing the quantity of hydrogen bonds, no structural transitions occurred. ATR-FTIR anal. demonstrated a downward shift of the H-O-H (water), as a result of PPI-G2 embedment, suggesting an increase in the mean water-water H-bond angle resulting from binding PPI-G2 to the water network. Addnl., the GMO hydroxyl groups at $\beta$- and $\gamma$-C-OH positions revealed a partial interaction of hydrogen bonds with N-H functional groups of the protonated PPI-G2. Other GMO interfacial functional groups were shown to interact with the PPI-G2, in parallel with the GMO dehydration phenomenon. In the future, these outcomes can be used to design advanced drug delivery systems, allowing administration of dendrimers as a therapeutic agent from LLCs. [on SciFinder(R)]
Idit Amar-Yuli, Jozef Adamcik, Shoshana Blau, Abraham Aserin, Nissim Garti, and Raffaele. Mezzenga. 2011. “Controlled embedment and release of DNA from lipidic reverse columnar hexagonal mesophases.” Soft Matter, 7, 18, Pp. 8162–8168. Abstract
DNA-lipid interactions have important implications for biol. functions, gene therapy and biotechnol. In the present work, the authors exploit hydrogen bonding and ionic interactions between lipids and DNA to control the entrapment, the binding and the release properties of DNA confined within the water channels of reverse hexagonal columnar phases. Two lipid formulations were considered, consisting of glycerol monooleate/tricaprylin and glycerol monooleate/oleyl amine/tricaprylin, yielding the nonionic and cationic-based systems, resp. In the presence of water, or water-DNA dil. solns., both formulations led to the formation of reverse hexagonal columnar mesophases. To study the confinement of DNA in the reverse hexagonal mesophases, and to understand its interactions with the nonionic and cationic lipid formulations, the authors relied on small-angle x-ray scattering (SAXS) and attenuated total reflectance-Fourier transform IR (ATR-FTIR) spectroscopy. The release of the DNA from these hosting systems in excess water was monitored by UV spectrophotometry and single mol. at. force microscopy (AFM). In the case of the nonionic columnar system, DNA confined within the water cylinders, was stabilized by hydrogen bonding with the lipid polar heads, as revealed by the dehydration of the glycerol monooleate polar headgroups and a decrease in the water channel diam. The diffusion of DNA out of the mesophase water channels was found to occur in 3 steps correlated with the different contour lengths of the DNA fragments generated enzymically from the same pristine DNA macromol. In contrast, the presence of a low dose of cationic surfactants in the formulation enabled strong electrostatic interactions with the DNA mols., swelling the water cylinders and entirely suppressing the release of DNA. These results show that lipidic mesophases constitute an appealing, fully biocompatible carrier, allowing a fine control on the encapsulation and delivery of DNA in excess water environment. [on SciFinder(R)]
Natali Amar-Zrihen, Abraham Aserin, and Nissim. Garti. 2011. “Food volatile compounds facilitating HII mesophase formation: Solubilization and stability.” Journal of Agricultural and Food Chemistry, 59, 10, Pp. 5554–5564. Abstract
Four lipophilic food volatile mols. of different chem. characteristics, phenylacetaldehyde, 2,6-dimethyl-5-heptenal, linalool, and trans-4-decenal, were solubilized into binary mixts. of monoolein/water, facilitating the formation of reverse hexagonal (HII) mesophases at room temp. without the need of solvents or triglycerides. Some of the flavor compds. are important building blocks of the hexagonal mesostructure, preventing phase transition with aging. The solubilization loads were relatively high: 12.6, 10.0, 12.6, and 10.0 wt% for phenylacetaldehyde, 2,6-dimethyl-5-heptenal, linalool, and trans-4-decenal, resp. Phenylacetaldehyde formed mixts. of lamellar and cubic phases. Linalool, 2,6-dimethyl-5-heptenal, and trans-4-decenal induced structural shift from lamellar directly to HII mesophase, remaining stable at room temp. Lattice parameters were found to increase with water content and to decrease with temp. and/or food volatile content. trans-4-decenal produces more stable HII mesophase compared to linalool-loaded mesophase. At 40-60 °C, depending on the chem. structure and on the solubilization location of the food volatile compds., the HII mesophase transforms to isotropic micellar phase, facilitating the release of the food volatile compds. Mol. interactions suggest the existence of two consecutive stages in the solubilization process. [on SciFinder(R)]
Nissim. Garti. 2011. “In honor of Prof. Kyitaka Sato on his retirement.” Current Opinion in Colloid & Interface Science, 16, 5, Pp. 357–358.
Dima Libster, Abraham Aserin, and Nissim. Garti. 2011. “Interactions of biomacromolecules with reverse hexagonal liquid crystals: Drug delivery and crystallization applications.” Journal of Colloid and Interface Science, 356, 2, Pp. 375–386. Abstract
A review. Recently, self-assembled lyotropic liq. crystals (LLCs) of lipids and water have attracted the attention of both scientific and applied research communities, due to their remarkable structural complexity and practical potential in diverse applications. The phase behavior of mixts. of glycerol monooleate (monoolein, GMO) was particularly well studied due to the potential utilization of these systems in drug delivery systems, food products, and encapsulation and crystn. of proteins. Among the studied lyotropic mesophases, reverse hexagonal LLC (HII) of monoolein/water were not widely subjected to practical applications since these were stable only at elevated temps. Lately, we obtained stable HII mesophases at room temp. by incorporating triacylglycerol (TAG) mols. into the GMO/water mixts. and explored the phys. properties of these structures. The present feature article summarizes recent systematic efforts in our lab. to utilize the HII mesophases for solubilization, and potential release and crystn. of biomacromols. Such a concept was demonstrated in the case of two therapeutic peptides-cyclosporin A (CSA) and desmopressin, as well as RALA peptide, which is a model skin penetration enhancer, and eventually a larger macromol.-lysozyme (LSZ). In the course of the study we tried to elucidate relationships between the different levels of organization of LLCs (from the microstructural level, through mesoscale, to macroscopic level) and find feasible correlations between them. Since the structural properties of the mesophase systems are a key factor in drug release applications, we investigated the effects of these guest mols. on their conformations and the way these mols. partition within the domains of the mesophases. The examd. HII mesophases exhibited great potential as transdermal delivery vehicles for bioactive peptides, enabling tuning the release properties according to their chem. compn. and phys. properties. Furthermore, we showed a promising opportunity for crystn. of CSA and LSZ in single crystal form as model biomacromols. for crystallog. structure detn. The main outcomes of our research demonstrated that control of the phys. properties of hexagonal LLC on different length scales is key for rational design of these systems as delivery vehicles and crystn. medium for biomacromols. [on SciFinder(R)]
Janna Gurfinkel, Abraham Aserin, and Nissim Garti. 2011. “Interactions of surfactants in nonionic/anionic reverse hexagonal mesophases and solubilization of alpha-chymotrypsinogen A.” COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS, 392, 1, Pp. 322–328. Abstract
In an attempt to form H-II mesophases at room temperature we prepared lyotropic liquid crystals with two surfactants of the same lipophilic tails (glycerol monooleate, GMO, and oleyl lactate, OL) but differing in the size and charge of the headgroups. Increasing OL concentration significantly affected the hydration of the headgroups and subsequently the lipids packing. At low OL content the cubic mesophase was formed, while at higher OL contents the formation of hexagonal mesophase was favored. It was assumed that OL competed on the water binding, tuning the headgroups' curvature and the packing parameter inducing the formation of reverse hexagonal mesophase. It was detected that cubic mesophase transformed upon heating to hexagonal structures. The hexagonal mesophases, which were formed both immediately after preparation and after aging, remained stable at elevated temperatures. alpha-Chymotrypsinogen was solubilized into the obtained LLCs at relatively high concentration (up to 1 wt%). The lattice parameter of the host LLCs exhibited a decrease as a function of the protein content. This process was assigned to partial dehydration of the GMO polar moieties in favor to CTA hydration. Generally speaking, the present study indicated that adding anionic to nonionic lipid is highly beneficial to gain additional compositional and structural characteristics of LLCs. (C) 2011 Elsevier B.V. All rights reserved.
Roy Hoffman, Nissim Garti, Abraham Aserin, and Chava. Pemberton. 2011. “Liquid compositions and uses thereof for generating diffusion ordered nmr spectra of mixtures.”. Abstract
Provided are homogeneous liq. systems substantially 1H-NMR inactive and/or devoid of protons and are capable of enhancing the diffusion sepn. of a mixt., the system is substantially devoid of at least one NMR active nucleus present in the mixt. Further provided are methods of using the homogeneous liq. systems for enhancing the diffusion sepn. of a mixt. and/or generating a diffusion ordered spectrum of a mixt. and/or minimizing the peak width in a liq. state diffusion ordered spectrum of a mixt. [on SciFinder(R)]
Chava Pemberton, Roy Hoffman, Abraham Aserin, and Nissim. Garti. 2011. “New insights into silica-based NMR "chromatography."” Journal of Magnetic Resonance, 208, 2, Pp. 262–269. Abstract
Silica is used as an important component for NMR "chromatog.". In this study the effect of the binding strength to silica of a variety of compds. on their diffusion rate is measured for the first time. Over two orders of magnitude of diffusion difference enhancement was obtained in the presence of silica for some compds. An explanation of the enhancement is given that also allows one to predict the "chromatog." behavior of new compds. or mixts. The binding strength is divided into categories of weakly bound, singly bound and multiply bound. Carboxylates, sulfonates, and diols are found to be particularly strongly bound and to diffuse up to 21/2 orders of magnitude more slowly in the presence of silica. [on SciFinder(R)]
Chava Pemberton, Roy E Hoffman, Abraham Aserin, and Nissim. Garti. 2011. “NMR Chromatography Using Microemulsion Systems.” Langmuir, 27, 8, Pp. 4497–4504. Abstract
NMR spectroscopy is an excellent tool for structural anal. of pure compds. However, for mixts., it performs poorly because of overlapping signals. Diffusion ordered NMR spectroscopy (DOSY) can be used to sep. the spectra of compds. with widely differing mol. wts., but the sepn. is usually insufficient. NMR chromatog. methods were developed to increase the diffusion sepn. but these usually introduced solids into the NMR sample that reduce resoln. Using nanostructured dispersed media, such as microemulsions, eliminates the need for suspensions of solids and brings NMR chromatog. into the mainstream of NMR anal. techniques. DOSY was used in this study to resolve spectra of mixts. with no increase in line-width as compared to regular solns. Components of a mixt. are differentially dissolved into the sep. phases of the microemulsions. Several examples of previously reported microemulsions and those specifically developed for this purpose were used here. These include a fully dilutable microemulsion, a fluorinated microemulsion, and a fully deuterated microemulsion. Log(diffusion) difference enhancements of up to 1.7 orders of magnitude were obsd. for compds. that have similar diffusion rates in conventional solvents. Examples of com. pharmaceutical drugs were also analyzed via this new technique, and the spectra of up to six components were resolved from one sample. [on SciFinder(R)]
Idit Amar-Yuli, Doron Azulay, Tehila Mishraki, Abraham Aserin, and Nissim. Garti. 2011. “The role of glycerol and phosphatidylcholine in solubilizing and enhancing insulin stability in reverse hexagonal mesophases.” Journal of Colloid and Interface Science, 364, 2, Pp. 379–387. Abstract
The potential of reverse hexagonal mesophases based on monoolein (GMO) and glycerol (as cosolvent) to facilitate the solubilization of proteins, such as insulin was explored. HII mesophases composed of GMO/decane/water were compared to GMO/decane/glycerol/water and GMO/phosphatidylcholine (PC)/decane/glycerol/water systems. The stability of insulin was tested, applying external phys. modifications such as low pH and heat treatment (up to 70°), in which insulin is known to form ordered amyloid-like aggregates (that are assocd. with several neurodegenerative diseases) with a characteristic cross $\beta$-pleated sheet structure. The impact of insulin confinement within these carriers on its stability, unfolding, and aggregation pathways was studied by combining SAXS, FTIR, and AFM techniques. These techniques provided a better insight into the mol. level of the component interplay in solubilizing and stabilizing insulin and its conformational modifications that dictate its final aggregate morphol. PC enlarged the water channels while glycerol shrank them, yet both facilitated insulin solubilization within the channels. The presence of glycerol within the mesophase water channels gave stronger hydrogen bonds with the hosting medium that enhanced the thermal stability of the protein and remarkably affected the unfolding process even after heat treatment (at 70° for 60 min). [on SciFinder(R)]
Marganit Cohen-Avrahami, Dima Libster, Abraham Aserin, and Nissim. Garti. 2011. “Sodium Diclofenac and Cell-Penetrating Peptides Embedded in HII Mesophases: Physical Characterization and Delivery.” Journal of Physical Chemistry B, 115, 34, Pp. 10189–10197. Abstract
Glycerol monooleate (GMO)-based mesophases offer extensive prospects for incorporation of various bioactive mols. This work deals with the solubilization of selected cell-penetrating peptides (CPPs) together with sodium diclofenac (Na-DFC) within the HII mesophase for transdermal applications. The effect of CPPs such as RALA (an amphipathic CPP), penetratin (PEN), and oligoarginine (NONA) on Na-DFC skin permeation kinetics to provide controlled release and tune the drug transdermal diffusion was studied. The location of the drug and the CPPs within the mesophase was probed by DSC and FTIR. Na-DFC was found to be located at the interfacial region between the surfactant chains, leading to denser HII mesophase. The hydrophilic NONA was intercalated into the aq. cylinders and caused their swelling. It induced a significant decrease in the hydrogen binding between the GMO carbonyls and their surrounding. The amphiphilic PEN was entrapped within two different regions, depending on its concn. PEN and NONA improved Na-DFC permeation by 100%, whereas RALA enhanced permeation by 50%. When estg. Na-DFC migration rate out of the mesophase toward surrounding aq. media, it appeared to be slower with the CPPs. The peptides were not involved at this diffusion-controlled step. It seems that their effect on skin permeation is based on their specific interaction with the skin. [on SciFinder(R)]
Ben Achrai, Dima Libster, Abraham Aserin, and Nissim. Garti. 2011. “Solubilization of Gabapentin into HII Mesophases.” Journal of Physical Chemistry B, 115, 5, Pp. 825–835. Abstract
In the present work, we report on the solubilization of gabapentin (GBP) into lyotropic hexagonal mesophases composed of monoolein, tricaprylin, and water. It was demonstrated that the hexagonal structure remained intact up to 2 wt. % gabapentin, whereas the lamellar phase coexisted with the hexagonal one in the concn. range of 3-4 wt. % of the drug. At gabapentin content of 5-6 wt. %, only lamellar phases contg. defects such as dislocations and multilamellar vesicles were detected. Incorporation of GBP decreased the lattice parameter of the HII mesophase from 56.6 to 50.6 \AA, while the structural dimensions of the lamellar phase were not affected. ATR-FTIR anal. suggested enhanced hydrogen bonding between the protonated amine of GBP and the O-H groups of the GMO and the water surrounding in the inner hydrophilic interface region. This led to intercalation of the drug into the water-lipid interface. At higher GBP loads of 4-6 wt. %, thermal anal. revealed disordering within the lipid packing, apparently induced by the spatially altered interface area. Rheol. measurements correlated the macroscopic features of the systems with alterations on the mol. level and allowed distinguishing between closely related mesophases due to their different rheol. characteristics. In vitro transdermal delivery studies showed that the examd. mesophases enabled a sustained release of GBP compared to its aq. soln. Sustained release was more pronounced in the case of the hexagonal mesophase, compared to the lamellar one. [on SciFinder(R)]
Idit Amar-Yuli, Abraham Aserin, and Nissim. Garti. 2011. “Some characteristics of lyotropic liquid-crystalline mesophases.” In Self-Surfactant Struct., Pp. 89–120. Wiley-VCH Verlag GmbH & Co. KGaA. Abstract
This review is dedicated to the memory of Professor Kunieda Hironobu and his Fundamental scientific contribution in the study of lyotropic liq. crystals. It displays an assortment of studies from his research group describing unique liq.-cryst. systems and novel phases.which represent their contribution to this topic. Finally, modern studies focusing on the formation of novel and modified structures on the basis of nonionic surfactant, monoolein, are discussed. [on SciFinder(R)]
2011. Edible oleogels : structure and health implications. Champaign: American Oil Chemist Society Press.
2011. “Edible Oleogels: Structure and Heath Implications.” In , 111th ed. USA: AOCS Press. Abstract
Chapters 1 and 11
Tehila Mishraki, Maria Francesca Ottaviani, Alexander I Shames, Abraham Aserin, and Nissim. Garti. 2011. “Structural Effects of Insulin-Loading into HII Mesophases Monitored by Electron Paramagnetic Resonance (EPR), Small Angle X-ray Spectroscopy (SAXS), and Attenuated Total Reflection Fourier Transform Spectroscopy (ATR-FTIR).” Journal of Physical Chemistry B, 115, 25, Pp. 8054–8062. Abstract
Insulin entrapment within a monoolein-based reverse hexagonal (HII) mesophase was investigated under temp.-dependent conditions at acidic (pH 3) and basic (pH 8) conditions. Studying the structure of the host HII system and the interactions of insulin under temp.-dependent conditions has great impact on the enhancement of its thermal stabilization and controlled release for the purposes of transdermal delivery. Small angle X-ray spectroscopy (SAXS) measurements show that pH variation and/or insulin entrapment preserve the hexagonal structure and do not influence the lattice parameter. Attenuated total reflection Fourier transform spectroscopy (ATR-FTIR) spectra indicate that, although insulin interacts with hydroxyl groups of GMO in the interface region, it is not affected by pH variations. Hence different microenvironments within the HII mesophase were monitored by a computer-aided ESR anal. using 5-doxylstearic acid (5-DSA) as a pH-dependent probe. The microviscosity, micropolarity, order of systems, and distribution of the probes in different microenvironments were influenced by three factors: temp., pH, and insulin solubilization. When the temp. is increased, microviscosity and order parameters decreased at both pH 3 and 8, presenting different decrease trends. It was found that, at pH 3, the protein perturbs the lipid structure while "pushing aside" the un-ionized 5-DSA probe to fit into the narrow water cylinders. At the interface region (pH 8), the probe was distributed in two differently structured environments that significantly modifies by increasing temp. Insulin loading within the HII mesophase decreased the order and microviscosity of both the microenvironments and increased their micropolarity. Finally, the EPR anal. also provides information about the unfolding/denaturation of insulin within the channel at high temps. [on SciFinder(R)]
Rivka Deutch-Kolevzon, Abraham Aserin, and Nissim. Garti. 2011. “Synergistic cosolubilization of omega-3 fatty acid esters and CoQ10 in dilutable microemulsions.” Chemistry and Physics of Lipids, 164, 7, Pp. 654–663. Abstract
Water-dilutable microemulsions were prepd. and loaded with two types of omega-3 fatty acid esters (omega-3 Et esters, OEE; and omega-3 triacylglycerides, OTG), each sep. and together with ubiquinone (CoQ10). The microemulsions showed high and synergistic loading capabilities. The linear fatty acid ester (OEE) solubilization capacity was greater than that of the bulky and robust OTG. The location of the guest mols. within the microemulsions at any diln. point were detd. by elec. cond., viscosity, DSC, SAXS, cryo-TEM, SD-NMR, and DLS. We found that OEE mols. pack well within the surfactant tails to form reverse micelles that gradually, upon water diln., invert into bicontinuous phase and finally into O/W droplets. The CoQ10 increases the stabilization and solubilization of the omega-3 fatty acid esters because it functions as a kosmotropic agent in the micellar system. The hydrophobic and bulky OTG mol. strongly interferes with the tail packing and spaces them significantly - mainly in the low and medium range water dilns. When added to the micellar system, CoQ10 forms some reverse hexagonal mesophases. The inversion into direct micelles is more difficult in comparison to the OEE system and requires addnl. water diln. The OTG with or without CoQ10 destabilizes the structures and decreases the solubilization capacity since it acts as a chaotropic agent to the micellar system and as a kosmotropic agent to hexagonal packing. These results explain the differences in the behavior of these mols. with vehicles that solubilize them in aq. phases. Temp. disorders the bicontinuous structures and reduces the supersatn. of the system contg. OEE with CoQ10; as a result CoQ10 crystn. is retarded. [on SciFinder(R)]
Elena A Mourelatou, Dima Libster, Ido Nir, Sophia Hatziantoniou, Abraham Aserin, Nissim Garti, and Costas. Demetzos. 2011. “Type and Location of Interaction between Hyperbranched Polymers and Liposomes. Relevance to Design of a Potentially Advanced Drug Delivery Nanosystem (aDDnS).” Journal of Physical Chemistry B, 115, 13, Pp. 3400–3408. Abstract
Advanced drug delivery nanosystems (aDDnSs) combining liposomal and dendritic materials have only recently appeared in the research field of drug delivery. The nature and localization of the interactions between the components of such systems are not yet fully described. In this study, liposomes are combined with hyperbranched polyesters for the development of new aDDnSs. The polymer-lipid interactions along with their dependence on the polyesters pseudogeneration no. and the liposomal lipid compn. have been examd. The results indicate that the interaction between the materials takes place in the headgroup region, where H-bonds between the polymers terminal hydroxyls and the phospholipids phosphate moiety are formed. Due to the polymers' compact imperfect structure, which varies with pseudogeneration no., no linear trends are obsd. with increasing pseudogeneration no. Moreover, it is shown that high percentages of cholesterol in the lipid bilayer affect the penetration of the polymers in the headgroup region. [on SciFinder(R)]