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ARTICLE IN PRESSG ModelHROMA-349343; No. of Pages 12

Journal of Chromatography A, xxx (2008) xxx–xxx

Contents lists available at ScienceDirect

Journal of Chromatography A

journa l homepage: www.e lsev ier .com/ locate /chroma

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ountercurrent chromatography: People and applications

. Berthoda,∗, M.J. Ruiz-Ángelb, S. Carda-Brochc

Laboratoire des Sciences Analytiques, Université de Lyon, CNRS UMR5180, Bat. CPE, 69622 Villeurbanne, FranceDepartament de Química Analítica, Universitat de València c/Dr. Moliner 50, 46100 Burjassot, SpainDepartament de Química Física i Analítica, Universitat Jaume I, Cra. Borriol s/n, 12071 Castelló, Spain

r t i c l e i n f o

rticle history:vailable online xxx

eywords:ountercurrent chromatographyuthors

mpact indexournals

a b s t r a c t

The scientific literature was scanned for the published research articles dealing with countercurrent chro-matography (CCC) over the time period 1980-May 2008. The search returned 1638 articles that wereanalyzed focussing on people and applications. Concerning the people, it was found that the geographicallocation of the CCC authors was relatively well balanced between USA, Asia with mainly China and Japanand Europe. Yoichiro Ito, the inventor of the technique, is by far the most productive author in the fieldwith 331 articles or more than one over five CCC articles published in the time period. Without surprise,English is the dominant language with more than 82% of the articles. A significant 8% amount of CCC

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atural productsnantiomersxtractionurification

articles were published in Chinese in Chinese journals. Chromatography journals are the logical tribunefor half of the published CCC articles. Concerning the applications, the separation and purification of nat-ural compounds is the dominant theme in CCC making the subject of more than one article over two.Starting from the plant extract, CCC in few steps can produce significant amounts of more than 95% purecompounds used for identification and/or property studies. Other applications are found in the pharma-ceutical and chemical field. The separation of enantiomers on the preparative scale is a field of growing

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importance.
© 2008 Elsevier B.V. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. The CCC people . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1. Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Geographical author location . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. Impact index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. The journals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1. Number of articles published . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. Journal impact factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3. Languages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Keywords and applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.1. Keywords . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.2. Natural product isolation and purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5.2.1. Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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Please cite this article in press as: A. Berthod, et al., J. Chromatogr. A (2008

5.2.2. Fractionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.3. Macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.4. Enantioseparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5.5. Other applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +33 472431434; fax: +33 472431078.E-mail address: [email protected] (A. Berthod).

021-9673/$ – see front matter © 2008 Elsevier B.V. All rights reserved.oi:10.1016/j.chroma.2008.10.071

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), doi:10.1016/j.chroma.2008.10.071

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

dx.doi.org/10.1016/j.chroma.2008.10.071

http://www.sciencedirect.com/science/journal/00219673

http://www.elsevier.com/locate/chroma

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ARTICLEHROMA-349343; No. of Pages 12

A. Berthod et al. / J. Chro

. Introduction

Numerous reviews on countercurrent chromatography (CCC)ppeared during its 40 years of existence since its inception byoichiro Ito in the late sixties [1]. Only the most recent onesre given in the reference list [2–8]. It is now well establishedhat CCC is a separation technique that uses a support-free liq-id stationary phase. The separation relies on the partition of aample between two immiscible liquid phases prepared by mix-ng two or more solvents. In this chromatographic method, one ofhe liquid phases is employed as the stationary phase while thether phase is pumped through the column as the mobile phase9,10]. The relative proportion of the solute passing into each ofhe two phases is determined by the respective partition coeffi-ients.

The two main advantages of CCC compared to classical liquidhromatography (LC) are (1) the solute loading capability and (2)he absence of adsorptive matrix. The solutes are introduced in theCC column dissolved in the mobile phase. In the CCC column theyave access to the whole volume of the liquid stationary phase,ot just to the surface of the solid stationary phase like in LC. Col-mn overload is much less of a problem in CCC than it is in LC.omplications coming from the LC silica stationary phase, irre-ersible solute adsorption, contamination, size exclusion, residualilanols, pH limitations do not exist with the CCC liquid stationaryhase.

The main problem in CCC is the retention of the liquid sta-ionary phase when the liquid mobile phase is pushed throught. Centrifugal forces are used in all modern CCC columns [9,10].he hydrodynamic CCC columns use one or several multilayeroils of open tubing mounted in a rotor that will induce a plan-tary rotation mode of the coils. The coil rotates around its axishich simultaneously rotates around the central axis of the hold-

ng rotor. This type of CCC columns is called coil planet centrifuges.he hydrostatic CCC columns retain the liquid stationary phasen channels working with a constant centrifugal field [11]. Hydro-ynamic and hydrostatic columns are equally useful to retain the

iquid stationary phase [12]. The limited efficiency of CCC columnss compensated by their high-resolution power obtained when thetationary phase volume makes a significant portion of the columnolume.

This review was presented as an invited talk in the 5th Inter-ational CCC Symposium held in Rio de Janeiro (Brazil) in July008. Since the audience was well aware of the ability of theechnique, the review will not give any technical details. It willtart by putting the interest on the people working hard toevelop and improve the technique and only next it will clas-ically focus on the most recent applications of CCC in variousreas.

. Protocol

It was deliberately chosen to work on a selection of arti-les that was obtained through the SciFinder® database of themerican Chemical Society (Medline and CAS database). The

wo search words “countercurrent” and “chromatography” werenput as research topic with the filtering set on publication year980–2008 and document types being exclusively selected as jour-al and/or review articles, any language, any institution and alluthors. Books, book chapters, patents, industrial and/or techni-

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al reports were intentionally left out. This search was done onay 22, 2008, and returned 1764 articles. The “remove dupli-

ate” button was used to size the number down to 1638 differentrticles that were saved in a file and are the basis of thistudy.

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PRESSr. A xxx (2008) xxx–xxx

. The CCC people

.1. Authors

The 1638 articles were authored by 2381 scientists, professorsr research directors, investigators, research associates, techniciansnd/or students. The full list of the authors’ names was extractednd statistically analyzed. Since many authors wrote more than onerticle, it turned out that the names of the 2381 scientists appeared790 times in the database. It makes an average 3.5 authors per CCCrticle. It means that not many CCC articles were written by a singleorker only.

Table 1 lists the names of the CCC scientists having their namen more than 22 articles. It is not a surprise to find Yoichiro ItoBethesda, NIH, USA), the founder of CCC, being by far the mostroductive CCC authors with 331 articles on this time period. Theecond most productive CCC author, Peter Winterhalter (Techni-al University of Braunschweig, Germany), published 83 articles orbout four times less than Yoichiro Ito did. Several of the listed mostroductive authors find themselves associated with another listedsenior or principal) author. This is to say that most of the pub-ished CCC works of this particular author have the senior authorame as the co-author. This is indicated in Table 1 by an asso-iated name in parentheses after the author name. For example,ost of the 26 CCC articles published by Kenishi Harada haveisao Oka (both Aichi Public Health, Nagoya, Japan) as a co-author

Table 1).Table 1 also shows that 1578 authors, or 66.3% of the full name

ist, published a single article in the CCC field. Since the database has638 articles, it means that most of them (96.3%) have an authorhat never published again in the field. 646 authors (27.1%) pub-ished between two and five CCC articles and 135 authors (only.7%) are associated with more than five CCC articles and less than2.

.2. Geographical author location

The geographical location of the 20 most productive CCC authorsf Table 1 can be detailed as follows: three authors from the USuthored the largest number or 378 articles; Asia is the secondroducer of CCC articles with nine authors authoring a total of 334rticles. Six authors are from Europe and authored 271 articles;ext two Russian authors are found with 52 articles that could welle claimed by both Europe and Asia. More information about lan-uage and main author geographical distribution will be given inhe journal section.

.3. Impact index

In the proposal and investigator evaluation process, national ornternational funding organizations are more and more concernedot only by the number of articles published by the principal inves-igator, but also by the value, the interest and significance of theserticles. This is quantified by ranking the journals using an impactactor. The journal impact factor is evaluated by counting the totalumber of cites made in the last full year for the considered journalnd dividing this number by the total number of articles publishedy the journal during that year [13]. The impact factor of journalshanges every year. The 2007 impact factor of Journal of Chromatog-aphy A is 3.64, that of Journal of Chromatography B is only 2.94

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13]. On a similar way, SciFinder® allows knowing how many timesgiven article was cited by other articles. Table 1 lists under the

cited by” heading the cumulative number of citations received byll published CCC articles of a given author. The author impact indexust be corrected from the self-citation number. A self-citation is


ARTICLE IN PRESSG ModelCHROMA-349343; No. of Pages 12

A. Berthod et al. / J. Chromatogr. A xxx (2008) xxx–xxx 3

Table 1Most prolific CCC authors (1980-May 2008) and statistical analysis of their scientific impact.

Author Articles Cited by Self-citations Auto-cite percentage Impact index

Ito Yoichiro 331 945 168 17.8 2.35Winterhalter Peter 83 567 70 12.3 5.99Zhang Tian You 74 375 30 8.0 4.66Berthod Alain 52 186 38 20.4 2.85Sutherland Ian Alexander 48 97 36 37.1 1.27Du Qizhen 44 168 26 15.5 3.23Shibusawa Yoichi 43 111 25 22.5 2.00Oka Hisao 42 184 16 8.7 4.00Hostettmann Kurt 35 220 10 4.5 6.00Shinomiya Kazufusa 33 116 21 18.1 2.88Foucault Alain 30 175 13 7.4 5.40Maryutina Tatiana 29 76 19 25.0 1.97Harada Kenichi (Oka) 26 122 9 7.4 4.35Kabasawa Yozo (Shinomiya) 25 62 13 21.0 1.96Ma Ying (Ito) 25 135 8 5.9 5.08Yang Fuquan (Ito) 24 269 36 13.4 9.71Cao Xueli 23 116 3 2.6 4.91Marston Andrew (Hostettmann) 23 173 10 5.8 7.09Spivakov Boris (Maryutina) 23 73 20 27.4 2.30Conway Walter 22 82 4 4.9 3.55Authors of 16–21 articles 16–21 19 authorsAuthors of 11–15 articles 11–15 30 authorsAuthors of 6–10 articles 6–10 86 authorsAuthors of three to five articles 3–5 298 authorsAuthors of two articles 2 348 authorsAuthors of a single article 1 1578 authors

T ore than 90% of the articles published by the cited author. The auto-cite percentage is ther pact index is the ratio of the number of citations, excluding the auto-citations, over then

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he names in parentheses correspond to an author associated as the co-author in matio of the number of self-citations over the total number of citations. The author imumber of published articles.

reference made by an author to another of his (her) own work.he author impact index is the total number of citations receivedinus the citations made by the author himself and divided by the

umber of published CCC articles.It is interesting to note that Yang Fuquan (Bethesda, NIH, USA)

as the highest impact index, 9.71, of the CCC authors of theatabase analyzed. It means that the 24 articles published by Yangere cited on an average basis almost 10 times. This author alwaysublishes with Yoichiro Ito, so it is possible that the senior authorttracted citations. If the impact index of Yoichiro himself is consid-red, it is only 2.35. This is due to the very large number of articleshat he published. Most CCC authors cite at least one Ito’s articlesroducing the large number of citations received (Table 1). How-ver, on an average basis, each article signed by Yoichiro is citedbout two times only.

It is important to use these data to point out clearly that theitation impact index is certainly not an exact scale measuring theuality of a scientist. The database used in this work is based on980–2008 articles. Yoichiro Ito’s first article funding the CCC tech-ique was published in 1966 and is not part of the database [14].his article was cited 35 times. Two articles in Science with Bowmans co-author firmly established the CCC technique and appearedn 1970 [1,15]. They are not part of the database when they arewo of the most cited CCC articles so far with 45 and 25 citations1,15]. Clearly, if these only three articles of Yoichiro Ito were part ofhe database, his citation number would pass 1000 and his impactndex would jump at more than 3.0.

Fig. 1 shows the author impact index plotted versus the ten-ency of the author to cite his own work. A clear trend is observed:he higher the self-citation and the lower the impact index. The

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igh impact indexes of Marston (7.09), Hostettmann (6.0) (bothniversity of Lausanne and now Geneva, Switzerland) or Winter-alter (5.99) are associated with a low number of self-citationsTable 1). The similarities between the statistical results obtainedith Marston and Hostettmann are due to a strong correlation

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ig. 1. Author impact index plotted versus the self-citation percentage (see Table 1).

etween these two authors. The 23 Marston’s corresponding arti-les are, for more than 90%, also Hostettmann’s articles. This showsnother possible weakness of the impact index method.

. The journals

The database returned that the 1638 articles were publishedorldwide in 338 different journals. It apparently makes an average

f five CCC articles published by each journal. This is absolutely nothe case since a majority of journals (200 or 59%) just published

), doi:10.1016/j.chroma.2008.10.071

single CCC article over the 28-year time period. This means thatew journals published the majority of the CCC articles. Consideringhe wide variety of the journal’s subjects, it also means that CCC isn analytical and/or preparative technique that can help to solve aimilarly wide range of problems.



4 A. Berthod et al. / J. Chromatogr. A xxx (2008) xxx–xxx

Table 2Journals publishing articles in the CCC field.

Journal full name ISSN Impact factor of 2007 Articles published

Journal of Liquid Chromatography & Related Technologies 1082-6076 0.98 325Journal of Chromatography A 0021-9673 3.64 277Journal of Chromatography (a) (a) 100Journal of Agricultural and Food Chemistry 0021-8561 2.53 41Analytical Chemistry 0003-2700 5.29 31Chromatographic Science Series – – 31ACS Symposium Series – – 29Journal of Chromatography B: Biomedical Applications 1570-0232 2.94 23Phytochemical Analysis 0958-0344 1.52 20Journal of Separation Science 1615-9306 2.63 19Chemical Engineering Science 0009-2509 1.78 17Chromatographia 0009-5893 1.15 17Journal of Natural Products 0163-3864 2.56 17Planta Medica 0032–0943 1.85 16Chemical Analysis (New York, NY, United States) – – 14Fenxi Huaxue – – 14Journal of Antibiotics 0021-8820 1.30 14Phytochemistry 0031-9422 2.32 14Sepu – – 14Analusis (b) (b) 12Bunseki Kagaku 0525-1931 0.30 12Journal of Analytical Chemistry Translation of Zhurnal Analiticheskoi Khimii 1061-9348 0.60 11AIChE Journal 0001-1541 1.61 10

Natural Product Research (Letters) 1476-6419 0.68 104 journals published 9 CCC articles 362 journals published 8 CCC articles 163 journals published 7 CCC articles 211 journal published 6 CCC articles 67 journals published 5 CCC articles 357 journals published 4 CCC articles 2822 journals published 3 CCC articles 6666 journals published 2 CCC articles 132200 journals published a single CCC article 200

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tjspeaking country. On the other hand, 125 articles (7.6%) were pub-lished in Chinese exclusively in Chinese journals. Fig. 2 shows therepartition of the languages used in the CCC articles. In the major-ity of the articles published, as shown in Table 1, the authors usedEnglish. Except for Chinese, language and geographical locations of

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38 different journals published 1638 CCC articles on the 1980-May 2008 time perhromatography disappeared in 1995 to split in JCA and JCB. (b) Analusis disappear

.1. Number of articles published

Table 2 lists the journal names that published more than 10 CCCrticles along with their ISSN number and 2007 impact factor. It waslready known that the Journal of Liquid Chromatography & Relatedechnologies was a tribune for the CCC scientists [16]. 325 articlesould be found in this journal on the 28-year time period of thetudy. It is a significant average of 12 CCC articles published eachear by this journal. It could be considered that Journal of Chro-atography is actually the favourite support for CCC publications.

n 1995, this journal split in Part A for the fundamental aspects of thehromatographic technique and Part B for biological and biomed-cal applications. Cumulating the three numbers listed in Table 2or the three aspects of this journal, a total of exactly 400 articlesre obtained. These two journals specialized in chromatographyotalled 725 articles or 44.3% of all CCC articles published over thetudied 28-year time period.

.2. Journal impact factors

The journals listed in Table 2 have very different impact fac-ors. Analytical Chemistry is the leading journal in the field withn impact factor of 5.29. 31 CCC articles were published in thisrestigious journal over the 28-year time period. It is only about

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single article per year. Most journals are in the field of chro-atography and separation science. However, journals specialized

n fields such as natural products, plants and phytochemistry, phar-aceutical compounds and techniques, and/or food industry areell represented.

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SN is the International Serial Standard Number. 2007 impact factors. (a) Journal of1998 to become part of Analytical Bioanalytical Chemistry.

.3. Languages

English is the international language of science. 1351 articles ofhe 1638 database or 82.4% were written in English, even though theournal in which they were found was not published in an English

er

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ig. 2. Languages used for the 1980–2008 CCC articles. “Other languages” includepanish, Italian, Polish, Russian and Brazilian (Portuguese).



A. Berthod et al. / J. Chromatogr. A xxx (2008) xxx–xxx 5

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ig. 3. The geographical distribution of CCC authors is relatively well balanced betwhe CCC articles showing that the main authors of more than 85% of the 1980–2008

he authors are not necessarily related. Fig. 3 shows that eight coun-ries, namely China, USA, Japan, Germany, France, UK, Switzerlandnd Russia, were the homeland of the authors of more than 85% ofhe 1980–2008 CCC articles. The main authors of the less than 15%emaining CCC articles were the citizen of 33 countries all aroundhe world (Fig. 3).

. Keywords and applications

t


.1. Keywords

Keywords are attached to articles. These keywords give an ideaf the subjects treated in the article. An average value of three

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able 3ost used keywords in the 1980–2008 CCC articles.

pplications Number of articles

atural products 209lant 93lavonoids 90lkaloids 76lycosides 68roteins 68ood 55eptides 49mino acids 45are earth metals 43olyoxyalkylenes 40atty acids and fat 37henols 36harmaceutical compounds 34nthocyanins 31ea products 29eaf 24aponins 24ntibiotics 23yoglobins 23ine 23

ntioxidants 21

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hree continents. The smallest pie shows the actual countries of the main author ofrticles are actually the citizens of only eight different countries.

eywords was found attached to each CCC article. An automatic sta-istical study of the keywords was used to analyze the selected 1638rticles. It returned 1505 keywords ranging from “Absolute config-ration” to “Zwitterions”. For each keyword, the study returns theumber of articles using this keyword. 964 keywords or 64% of thehole set were found in a single article. 229 keywords (15.2%) were

ound in two articles. 193 (12.8%) keywords were found in three tove articles. The 119 remaining keywords (7.9%) were found in six

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rticles or more. Table 3 lists the keywords being used by more than0 articles.

The keywords listed in Table 3 were divided in two classes: appli-ations and technical themes. Natural products are the subject of09 CCC application articles. The 209 figures grossly underestimate

Technical themes Number of articles

Partition coefficients 104Solvent effects 78Extraction 73Purification 57Simulation and modelling 55Resolution 50Flow 30Nomenclature 25Preparative separations 23Thin-layer chromatography 20


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xxx–xxxTable 4Isolation, purification and sample preparation of natural products by CCC.

Sample (compounds) Scalea (purification) or CCC techniqueused (sample preparation)

Solvent system (v/v) Run time (min) or techniquefor fraction control

Reference

Isolation and/or purification of natural extractsErythromycins and

DidemninsAnalytical Hexane/ethyl acetate/methanol/water

(4:7:4:3)60 [17]

Quercitrin (flavonoids) Preparative: 585 mg (88.6% purity) methylethylketone/water (1:1) 180 [18]

Aconitum sinomontanum (alkaloids)Preparative: 9.0 g (99% purity) Methyl tertbutyl

ether/tetrahydrofuran/water (2:2:3)660 [19]

Preparative: (>98% purity) Chloroform/methanol/HCl (4:1.5:2) 720 [20]

Camelia sinensis (catechins)Analytical Hexane–ethyl acetate/water (10:1:12) 150 [21]Analytical tert-Butyl methyl

ether/acetonitrile/0.1% TFA (2:2:3)60–80 [22]

Rheum officinale, Polygonumcuspidatum(hydroxyanthraquinones)

Preparative: 50 g (>98% purity) pH-modulated MTBE-aqueous basicsystem

720 [23]

Tomato paste (lycopene) Preparative: 8.6 mg (>98.5% purity) n-Hexane/dichloromethane/acetonitrile(10:3.5:6.5)

300 [24]

Phospholipids and glycolipids

Analytical A: Chloroform/methanol/water (5:4:3) – [25]B: Hexane/ethyl acetate/ethanol/0.1%aqueous ammonia (5:5:5:4)C: Hexane/ethanol/water (10:15:4) or(5:4:3)

Analytical Hexane/ethyl acetate/ethanol/0.1% TFA(5:5:5:4) or (3:5:3:4)

– [26]

Salvia miltiorrhiza(tanshinones)

Analytical and preparative: 7–16 mg(>95% purity)

Light petroleum/ethylacetate/methanol/water (2:3:2.5:1.7)

240–600 [27]

Panax notoginseng (saponins) AnalyticalA:Chloroform/methanol/2-butanol/water(5:6:1:4)

300 [28]

B: Ethyl acetate/1-butanol/water(1:1:2)

Oroxylium indicum (flavonoids)

Preparative: 3.2–6.8 mg (>95% purity) Hexane/ethyl acetate/methanol/water(1:1.2:1:1) and (1:1.2:3:1)

120 [29]

Analytical Hexane/ethyl acetate/methanol/water(1:1.2:1:1)

40 [30]

Preparative: 25–100 mg (>95% purity) Hexane/ethyl acetate/methanol/water(1:1.2:1:1) and (1:1.2:3:1)

10–60 [31]

Analytical Hexane/ethyl acetate/methanol/water(1:1.2:1:1)

– [32]

Marigold flower petal (lutein) Preparative: 15.3 mg (98.5% purity) n-Heptane/chloroform–acetonitrile(10:3:7)

120 [33]

Rheum officinale (rhein) Analytical and preparative: 6.7 mg(>97% purity)

Hexane/ethyl acetate/methanol/water(3:7:5:5)

360 [34]

Natural coloring agents(Kaoliang and Lac colors)

Analytical and preparative: 6–790 mg (>96%purity)

A: Diethyl ether/acetonitrile/water(4:2:5)

240 [35]

B: MTBE/n-butanol/acetonitrile/water(2:2:1:5)

Crude extracts of plantmaterials: spinach and sweetcorn (carotenids)

Analytical Hexane/ethanol/water (6:5:1.3) 340–480 [36]

Gardenia jasminoides(geniposide)

Preparative: 389 mg (>98% purity) Ethyl acetate/n-butanol/water (2:1.5:3) 350 [37]www.Counte

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Patrinia villosa (flavonoids) Preparative: 38.2 mg (99.2% purity) n-Hexane/ethylacetate/methanol/water (5:6:6:6)

400 [38]

Angel-icadahurica(fura-nocoumarins)

Preparative: 8.6–19.9 mg (>98% purity) n-Hexane/ethylacetate/methanol/water (1:1:1:1)

240 [39]

Preparative: 16.4–35.6 mg (>98%purity)

n-Hexane/ethylacetate/methanol/water (5:5:4:6)

780 [40]

Coenzyme Q10 Preparative: 130 mg (97.8% purity) Heptane/acetonitrile/dichloromethane(12:7:3.5)

150 [41]

Anemarrhena asphodeloides(neomangiferin andmangiferin)

Preparative: 165.6 and 292.8 mg (>98%purity)

n-Butanol/water (1:1) 420 [42]

Artocaptus altilis (flavonoids) Preparative: 9–78 mg (>97% purity) n-Hexane/ethylacetate/methanol/water (5:5:7:3) and(5:5:6.5:3.5)

500 [43]

Agrimonia Pilosa (hyperosideand lutein-glucoside)

Preparative: 7.3 and 10.4 mg (>97%purity)

Ethyl acetate/methanol/water (5:1:5) 540 [44]

Arctium lappa, Magnolia officinalis(honokiol, magnolol), Psoralea corylitolia(psoralen, isopsoralen)

AnalyticalA: Ethylacetate/n-butanol/ethanol/water(5:0.5:1:5)

<60 [45]

B: n-Hexane/ethylacetate/methanol/water (1:0.4:1:0.4)C: n-Hexane/ethylacetate/methanol/water (1:0.7:1:0.8)

Clematis mandshurica(saponins)

Preparative: (>97% purity) Ethylacetate/n-butanol/ethanol/0.05%TFA(5:10:2:20)

400 [46]

Punica granatum (gallic acid) Preparative: 15 mg (96% purity) Ethyl acetate/methanol/water(50:1:50)

100 [47]

Laggera ptedoronta(antivirals)


Ethyl acetate/n-butanol/water (3:2:5) 350 [48]

Magnolia officinalis(anti-tumor derivatives ofhonokiol)

Preparative: 21.2–121.6 mg (>98.6%purity)

Hexane/ethyl acetate/methanol/water(1:0.4:1:0.4)

150 [49]

Punica granatum(punicalagin)

Preparative: 105 mg (>92% purity) Butyl alcohol/TFA/water (100:1:100) 360 [50]

Tripterygium (alkaloids) Preparative: 90–220 mg (>90% purity) Petroleum ether/ethylacetate/ethanol/water (6:4:5:8)

300 [51]

Huperzia serrata (alkaloids) Analytical n-Heptane/ethylacetate/n-propanol/water(10:30:15:45), triethylamine (8 mM)and methane sulfonic acid (6 mM)

150 [52]

Aconitum coreanum(alkaloids)

Preparative: 9.2–25.7 mg (>95.5%purity)

n-Hexane/ethylacetate/methanol/0.2 M HCl(1:3.5:2:4.5)

250 [53]

Rabdosia rubescens (oridoninand ponicidin)

Preparative: 60 and 10 mg (>95%purity)

n-Hexane/ethylacetate/methanol/water (1:5:1:5 and3:5:3:5)

500 [54]

Secondary metabolites fromcommercial tea products

Analytical n-Hexane/methylacetate/acetonitrile/water (4:4:3:4)

70 [55]

Spinach (carotenoids) Preparative: 15 mg (94% purity) Hexane/ethanol/water (5:5:4.5) 240 [56]

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Table 4 (Continued)

Sample (compounds) Scalea (purification) or CCC techniqueused (sample preparation)

Solvent system (v/v) Run time (min) or techniquefor fraction control

Reference

Pseudostellaria heterophylla(peptides)

Preparative: mg levels (>96% purity) n-Butanol/ethyl acetate/water(0.6:4.4:5)

300 [57]

Taraxacum mongolicum(flavonoids)


n-Hexane/n-butanol/water (1:1:2) 300 [58]

Millettia pachycarpa(flavonoids)

Preparative: 14.6–160.2 mg (93–95%purity)

n-Hexane/ethylacetate/methanol/water (1:0.8:1:0.6)

400 [59]

Prefractionation steps of natural extractsTabernaemontana pandacaqui

(linoleic acid)Hydrostatic CPC Heptane/ethyl acetate/methanol/water

(6:1:6:1)TLC [61]

Anethum graveolens (polarconstituents)

Multilayer coil CCC Chloroform/methanol/water (7:13:8) TLC [62]

Enoxaparin sodium(heparins)

Hydrostatic CPC Methyl isobutyl ketone/water (4.5:5) HPSEC and H NMR [63]

Polyketide antibiotics HSCCC Hexane–ethyl acetate/methanol/water(1.2:2:2:1)

HPLC [64]

Traditional ChineseMedicines (TCMs)(anthraquinone)

HSCCC Chloroform/methanol/water (7:13:8) TLC [65]

TCM (flavonoids) HSCCC Chloroform/methanol/water(4:2.5–4.5:2)

TLC [66]

Tieghemella heckelii(saponins)

HSCCC Methyl t-butyl ether/1-butanol–acetonitrile/trifluoroaceticacid (1:3:3:5)

TLC [67]

Grape skins (anthocyanins) Multilayer coil CCC Methyl t-butyl ether/n-butanol–acetonitrile/trifluoroaceticacid (2:2:0.1–5:5)

HPLC [68]

Erythroxylum (alkaloids) pH zone refining HSCCC Methyl t-butyl ether/water (1:1) HPLC–MS [69]Seabuckthorn juice

concentrate (polyphenols)HSCCC n-Hexane–n-butanol–water (1:1:2) Direct coupling with

ESI-MS–MS[70]

Plants (ethyl acetate extracts) Multi-channel CCC Hexane/ethanol/water (6:5:1) HPLC [71]

a Scale refers to the amount of product isolated—analytical: amount <2 mg; preparative: amount >2 mg up to grams.

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he real number of CCC articles dealing with natural products. Theeywords “plant” (93 articles), flavonoids (90 articles), alkaloids,lycosides, phenols, anthocyanins, tea product, leaf and saponinsre all related to natural products. Adding up the articles for theseeywords would make a more realistic number of 711 articleselated to natural products. The other application keywords showood applications including fat, wine and tea, inorganic chemistryith rare earth metals, pharmaceutical and chemical compounds.

The solute partition coefficient is responsible for the elutionolume of the compounds. Not surprisingly, “partition coefficient”s the most used technical theme keyword with 104 articles. It iseminded that this term is not recommended by IUPAC; “distribu-ion ratio” should be preferred. The next major subject is “Solventffects”. The solvent system is the core of the CCC process. Selectinghe solvent system corresponds to the column and mobile phaseelection in classical LC. The difference is that both mobile andtationary phases cannot be selected independently. They are inquilibrium. Any change made in one phase affects the other. Thismportant role of the liquid system composition explains the signif-cant number of articles dealing with “Simulation and modelling”Table 3).

Keywords lead to applications. The keywords listed in Table 3 areood representative of the CCC applications found in the selectedrticles.

.2. Natural product isolation and purification

To complete this review article, the focus is made on particularrticles detailing their content and roughly following the Table 3eyword list.

.2.1. IsolationThe main topic of CCC articles is natural products. Many bioac-

ive compounds extracted from medicinal plants officially listedn the Traditional Chinese Medicine (TCM) or Japanese Pharma-opoeia have been separated using the large loading ability of CCC.his permits to carry out proper quality control that improves theuality of the existing products. The absence of a solid supportvoids problems of irreversible adsorption of injected crude sam-les. Table 4 summarizes some examples where different naturalroducts have been isolated or purified either with analytical orith preparative purposes [17–59]. As it can be seen, alkaloids andavonoids are the natural products most often purified. The phar-acological effects of alkaloids and the antioxidant properties of

avonoids make their production for further studies interesting.ther bioactive compounds, such as carotenoids or saponins, haveeen successfully purified by CCC [36,46,56]. Many applications arearried out in a gram preparative scale (Table 4). The amount ofsolated purified material varies depending on the sample but thechieved purities are often above 95%. Studies on natural productsnvolve complex samples containing compounds in a wide rangef polarities, which require a thorough selection of the biphasicolvent system. Table 4 also shows the two-phase liquid systemsnd the proportions tested in a wide variety of reported applica-ions. The alkane/ethyl acetate/methanol/water and the Arizonaompositions of this system are the most often used and the mostppropriate systems for natural product purification [60].

.2.2. FractionationIn the field of drug discovery it is interesting to carry out a

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creening of natural products because of the availability of high-hroughput screening methods using receptor binding assays ornzyme assays. However, the presence of other bioactive com-ounds may cause non-specific inhibition in the assay and hampershis screening step. Therefore, a prefractionation prior to screening

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PRESSr. A xxx (2008) xxx–xxx 9

ight be required. Proper fractionation of crude extracts followedy the subsequent analysis of the collected fractions facilitates iso-ation and structure elucidation of novel bioactive compounds.

The application of a CCC method for this purpose has beenery useful to develop fast and simple selection methods as aeneral prefractionation step able to separate a broad range ofompounds. Recently, new apparatus have been developed to per-orm multi-channel fractionations that meet the requirements ofhe high-throughput fractionation of natural products. A summaryf the reported procedures dealing with fractionation of differentamples is shown in Table 4 [61–71].

.3. Macromolecules

Aqueous two-phase systems (ATPSs) form when two polymersith flexible chains or a polymer and a high concentration salt areixed with water. Polyethyleneglycol (PEG) and potassium phos-

hate are efficient and often used as ATPS. The aqueous upper layerontains most of the PEG and the lower aqueous layer containsost of the inorganic salt. ATPSs are used in CCC for an efficient

solation and purification of macromolecules and proteins. The pro-edure involves the partition of the biological material between thewo aqueous phases of the selected ATPS [72]. ATPSs were foundxtremely successful to purify biological material and especiallyare proteins [4]. They were earlier used in CCC for this purpose [73]nd their CCC use today has not decayed [74–80]. The high viscositynd low interfacial tension of aqueous polymer two-phase systemsend to cause emulsification of the two phases, which results iness efficient retention of stationary phase in the hydrodynamic CCColumns. Hydrostatic CCC columns seem to be superior in handlingTPSs for protein separation [81].

Recently, it was found that a fully water-soluble ionic liquid, 1-utyl-3-methyl imidazolium chloride (BMIM Cl), was able to formwo aqueous phases when dibasic potassium phosphate was addedo its solution [82]. This particular ATPS was also tested in CCC withgroup of polar proteins and compared with the results given byTPSs formed by PEG 1000 and 10,000 [83]. The ATPS containinghe ionic liquid BMIM Cl showed properties different from those ofPEG-based ATPS. At similar compositions, the density of the upper

onic liquid phase was significantly lower than the upper PEG richiquid phase producing a larger phase density difference for theonic liquid ATPS, which made the ionic-liquid-based ATPS easiero retain in a hydrodynamic CCC column than the PEG-based ATPS.he other major difference between the two ATPSs was polarity.he ionic liquid rich upper phase had a polarity significantly lowerhan the corresponding PEG rich upper phase [83].

.4. Enantioseparations

The keyword “enantioseparations” is not listed in Table 3ecause it is used by only nine articles of the 1683 article database.he focus on this subject was selected because it is one of the mostotent applications of CCC on the preparative scale. The separationf enantiomers is achieved by adding a suitable chiral selector (CS)o the appropriate biphasic liquid system. An exhaustive reviewn the enantiomeric separations in CCC was published by Foucaultith much more than nine examples of CCC chiral applications [84].nalytical enantiomer separations are most often performed byither HPLC or capillary electrophoresis, but CCC could offer thedvantage of the easy scaling-up to preparative scale.

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A successful chiral separation requires the availability of auitable CS. In CCC, the CS is added to one of the phases of theiphasic system provided that it is soluble enough in the selectedolvent mixture to allow elution and separation of the target ana-ytes. The CS is preferentially added to the more lipophilic phase


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xxx–xxxTable 5Chiral separations by CCC.

Compounds Chiral selector Solvent system (v/v) Analysis time (min) Reference

Dinitrobenzoyl amino acids N-dodecanoyl-l-proline-3,5-dimethylanilide

Hexane/ethylacetate/methanol/10 mM HCl(8:2:5:5)

– [74]

7-Des-methyl-ormeloxifene

Sulfated �-cyclodextrin Ethylacetate/methanol/triethylammoniumacetate buffer (10:1:9)/2%sulphated �-cyclodextrin

80 [75]

dl-Dansyl-aminoacids Vancomycin Different solvent mixtures – [76]

Enantiomers of N-derivatized amino acidsand 2-aryloxypropionic acids

Cinchona alkaloid derivatives (a) Ammonium acetatebuffer/tert-amylalcohol/methanol/heptane

(a) 50–145 [77]

(b) Ammonium acetatebuffer/methyl isobutyl ketone(MIBK) or diisopropyl ether

(b) 116–282

(c) Ammonium acetatebuffer/2-PrOH/diisopropylether

(c) 115–235

(d) Ammonium acetatebuffer/diisopropyl ether

(d) 71–92

Gemifloxacin enantiomers (+)-(18-Crown-6)-tetracarboxylic acid(18C6H4)

1-Butanol/ethyl acetate/20 mMbis–tris acetate buffer (6:5:10)

300 [78]

Dichlorprop(2-(2,4-dichlorphenoxy)propionic acid)

Chiral additive derivedfrombis-1,4-(dihydroquinidinyl)phthalazine

pH zone refining: 10 mM CSPAin methyl tert-butyl ether and100 mM sodium phosphatebuffer (pH 8.0)

160 [79]

N-((3,5-dinitrobenzoyl)-(±)-leucine and(±)-ketoprofen)

l-Proline and (4R)-hydroxy-l-prolinederivatives

(a) MIBK/0.2 M sodiumphosphate buffer solution (pH8.0)

(a) 23–61 [80]

(b) MTBE/buffer solution (b) 45–269

Chlorpheniramine Carboxymethly-�-cyclodextrin

Ethyl acetate:methanol:water(10:1:9) with 20 mmol/L ofcarboxymethly-�-cyclodextrin

120 [81]

Enantiomers of warfarin,oxazepam, trans-stilbeneoxide, pindolol,naproxen, DNB-Leu,2,2,2-trifluoro-1-(9-anthryl) ethanol,propranolol

Cellulose and amylasearylcarbamates

pH zone refining:MIBK/aqueous solution (HCl5 mM) Methyl tert-butylether/aqueous solution(NH4OH 2.5 mM)

50–143 [82]

Pindolol and warfarinenantiomers

Modified cellulose MIBK, t-butyl methyl ether orethyl acetate/aqueousammonium acetate or sodiumphosphate buffer

47–58 [83]

Diastereoisomeric cis-trans dicarboxylic acids.(a) 1-methyl- and1,3-dimethyl-1,3-cyclohexane dicarboxylicacids; (b) maleic and furmaric acids; (c)1,4-cyclohexane dicarboxylic acids; (d)phthalic, isophthalic and terephthalic acids

Diastereoisoisomers do not need chiralselector to be separated

pH zone refining: (a), (b) and (c): methylt-butyl ether–acetonitrile–water(4:1:5) + trifluoroacetic acid (d):n-hexane/ethylacetate/methanol/water(5:1:5) + ammonium hydroxide

(a) 240 [84](b) 180(c) 180(d) 270

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hat is usually employed as the stationary phase while the moreydrophilic, often an aqueous solution, acts as the mobile phase.hen involving chiral separations, the pH zone refining elutionode is usually selected to carry out the separations of ionisable

nantiomers [84]. As for the CSs employed, these are not differentrom those directly used in HPLC and capillary electrophoresis.mong them, a variety of polysaccharide derivatives, bovineerum albumin, vancomycin, cellulose and amylase-type, l-prolineerivatives, carboxymethyl �-cyclodextrins and cinchona alkaloiderivatives have been successfully applied to the CCC separation ofnantiomers [84]. Table 5 shows some recent examples involvinghe use of CSs in CCC [85–95].

.5. Other applications

As shown in Table 3, CCC has been studied and used mainly forhe isolation and purification of bioorganic substances extractedrom crude plants. However, it has also been applied for the prepa-ation of synthetic pharmaceuticals [96,97], herbicides [98,99],esticides [100] and inorganic compounds [101,102].

It is often not required to fully purify an active principle. Rawaterial, extracts, powders and other preparations are often used.rapid quality control of the preparation is crucial to assure the

eliability of the final commercialized product. Thin-layer chro-atography (TLC), HPLC and gas chromatography (GC) are the most

ommonly used techniques for such a control [103]. Some recenteports by Gu et al. have shown that CCC can be applied to developngerprint for TCMs [104–108]. The CCC procedure uses a stepwiselution with two solvents (0.1% aqueous trifluoroacetic acid and.1% aqueous trifluoroacetic acid–acetonitrile) in sequence. Withegard to HPLC, CCC offers advances in terms of scales of crudeamples and non-common peak area. In contrast, HPLC was foundaster and more accurate.

. Conclusions

Since its inception three decades ago, CCC has grown up to aature preparative technique. A literature study of 1638 articles

ublished on the 1980-May 2008 time period returned that 2381uthors used the technique worldwide. The geographical distri-ution of the authors is relatively well balanced between Northmerica (mainly USA), Asia (China and Japan) and Europe. English

s the dominant language for these articles. Concerning the CCCpplications, it is established that CCC is a powerful technique forhe isolation and purification of natural products, by far its mainpplication. Different elution modes have been developed along theears, which have permitted the establishment of routine methodsnd the enhancement of the separation efficiency. The techniqueas proved to be useful for the prefractionation of complex crudeatural product extracts or fingerprint. Other approaches such ashe separation of macromolecules and chiral compounds representhe growing fields of study in CCC.

cknowledgments

A.B. thanks the Centre National de la Recherche ScientifiqueCNRS UMR5180 P. Lanteri) and Université de Lyon (Villeurbanne,rance) for continuous support. M.J.R.A. thanks the support fromhe Ministerio de Educación y Ciencia from Spain for a Ramón yajal contract and Project CTQ2007-61828/BQU.

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eferences

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PRESSr. A xxx (2008) xxx–xxx 11

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