Poly(butylene terephthalate) based novel stationary phase (SP), composed of planar aromatic phenyl group together with ester group monomer units, was designed for supercritical fluid chromatography (SFC) use. As expected from its structure, this phase shows planarity recognition of isomeric aromatics and closely similar compounds.
Journal of Chromatography A, 1549 (2018) 85–92 Contents lists available at ScienceDirect Journal of Chromatography A journal homepage: www.elsevier.com/locate/chroma Poly(butylene terephthalate) based novel achiral stationary phase investigated under supercritical fluid chromatography conditions Kanji Nagai, Tohru Shibata ∗ , Satoshi Shinkura, Atsushi Ohnishi DAICEL Corporation, CPI Company, Life Science Development Center, Innovation Park, 1239, Shinzaike, Aboshi-ku, Himeji, Hyogo, 671-1283, Japan a r t i c l e i n f o Article history: Received 26 January 2018 Received in revised form 13 March 2018 Accepted 15 March 2018 Available online 17 March 2018 Keywords: Supercritical fluid chromatography Stationary phase Polymer Ligand Poly(butylene terephthalate), PBT Selector a b s t r a c t Poly(butylene terephthalate) based novel stationary phase (SP), composed of planar aromatic phenyl group together with ester group monomer units, was designed for supercritical fluid chromatography (SFC) use As expected from its structure, this phase shows planarity recognition of isomeric aromatics and closely similar compounds Interestingly, for most analytes, the retention behavior of this SP is significantly distinct from that of the 2-ethylpyridine based SPs which is among the most well-known SFC dedicated phases Although the poly(butylene terephthalate) is coated on silica gel, the performance of the column did not change by using extended range modifiers such as THF, dichloromethane or ethyl acetate and column robustness was confirmed by cycle durability testing © 2018 The Authors Published by Elsevier B.V This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Introduction Supercritical fluid chromatography (SFC) is implemented today as routine technique in many laboratories and arises strong scientific and practical interest [1] SFC uses pressurized carbon dioxide (CO2 ) with miscible polar organic solvents (modifier) as a mobile phase and has become a powerful separation technique complementary to conventional high performance liquid chromatography (HPLC) and gas chromatography (GC) [2–10] In the early developments of the technique, SFC was strongly driven by the enantioseparation field benefitting from the already existing chiral stationary phases (CSPs), particularly at preparative scale in pharmaceutical industry [11–18] Recently, SFC expanded also in the achiral separation field, using achiral phases, but even applying the CSPs as powerful tools in separation of closely related sample impurities or molecules [19,20] The mobile phase in SFC has low viscosity and high diffusivity, which makes it particularly adapted for fast flow analysis Furthermore, SFC is regarded as an environmentally friendly separation technique because it uses nontoxic recycled CO2 and the total amount of organic solvents is smaller than in conventional HPLC This high throughput chromatographic performance, as well as ∗ Corresponding author E-mail address: tr shibata@jp.daicel.com (T Shibata) “green” aspect, make SFC very attractive for numerous applications [21–31] The retention and separation characteristics in SFC mainly depend on a combination between mobile phase and stationary phase (SP) [6,32–34] The chemical diversity of the currently available SPs has been significantly extended, benefiting from the large variety of commercially available HPLC SPs (e.g reverse phase, normal phase, and/or HILIC) that can be also used in SFC mode Besides this trend, some column manufacturers and research groups have originally developed SFC dedicated stationary phases One wellknown SP designed specifically for achiral SFC separation is the 2-ethylpyridine (2-EP) bonded silica phase This 2-EP SP offers good peak shapes, especially for basic compounds, even without any additives [35] Other novel achiral SPs dedicated to SFC have been developed [36–40], however, most of them consisted of a low-molecularweight ligand, coated or covalently attached onto a solid support (e.g silica gel) In contrast, only few polymeric type phases have been described so far for applications in the achiral SFC separation field Such polymeric phases are expected to interact through multiple concerted mechanisms with the analytes [40] Another view point is what kind of major interaction should be embedded in a SP While SPs with a variety of interaction types are needed of course, what are those relatively unmet? The design of new phases may have to start by defining which are the interaction types needed and combined to make an efficient SP, but also which interaction mechanisms are relatively unmet in the already https://doi.org/10.1016/j.chroma.2018.03.032 0021-9673/© 2018 The Authors Published by Elsevier B.V This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) 86 K Nagai et al / J Chromatogr A 1549 (2018) 85–92 Fig Structure of poly(butylene terephthalate) or PBT-based selector of the column DCpak PBT existing SPs In this light, the systematic analysis of interactions in a variety of commercially available SPs under SFC conditions, as investigated by West et al., would represent a very suggestive information [41–43] According to their diagrams, hydrogen-bonding and van der Waals interactions are more densely covered by already existing phases, whereas dipolar and aromatic () interactions are less represented [43] Based on the above consideration, when looking for innovative phases, we focused on a polymer with a dipolar group with/without an aromatic group in or close to its main chain Among many polymers evaluated, poly(butylene terephthalate), well known as PBT, was chosen as a novel selector considering its molecular recognition ability and peak efficiency [44] Its insolubility in most solvents and remarkable chemical stability were also positive merits supporting the selector choice for column commercial launch (Fig 1) In the present study, some features and applications of this SP under SFC conditions are described pressure regulator (ABPR), unless otherwise noted Lab Solutions software (V 5.89) was used for system control and data acquisition Total flow rate was fixed at 3.0 mL/min, column temperature was set at 40 ◦ C, and the automated backpressure regulator (ABPR) was set to 15.0 MPa, unless otherwise noted Other conditions, such as modifier, sample concentration, injection volume, and detection wavelength are described in the figures The Thar SFC instrument supplied by Waters Corporation was used for Section 3.3 dealing with the orthogonal selectivity of the two columns and Section 3.4 dealing with the modifier effect 2.3 Data analysis Relative retention factor (k) was calculated with the equation below k = (V/V ) − 1, (1) where V is the elution volume of an analyte and V0 is the column void volume V0 was estimated by injecting 1,3,5-tritert-butylbenzene as a non-retained marker conducted as an independent analysis of each sample injection 2.4 Dipole moment calculations Dipole moment calculations were conducted using semiempirical molecular orbital method with PM6 implemented in SCIGESS software (version 2.3, Fujitsu Ltd., Tokyo, Japan) [45] Experimental Results and discussion 2.1 Chemicals 3.1 Planarity recognition The modifier used in this study was Japanese Industrial Standard special grade methanol (MeOH) obtained from Nacalai Tesque Inc (Kyoto, Japan) Carbon dioxide of industrial grade (over 99.5%) was purchased from Tatsumi Industry Co., Ltd (Hyogo, Japan) o-Terphenyl, m-terphenyl, p-terphenyl, 3,4-dihydrocoumarin, coumarin, 6-methylcoumarin, 7-methylcoumarin, dimethyl phthalate, dimethyl isophthalate, dimethyl terephthalate, triphenylene, cis-stilbene, trans-stilbene, 2-methylbenzophenone, 3-methylbenzophenone, 4-methylbenzophenone, 2hydroxyflavanone, -hydroxyflavanone, -hydroxyflavanone, phenanthrene, and pyrene were purtheobromine, chased from Tokyo Chemical Industry Co (Tokyo, Japan) 1,3,5-Tri-tert-butylbenzene, 2-acetylanthracene, 9acetylanthracene, 2-acetylphenanthrene, 3-acetylphenanthrene, 9-acetylphenanthrene, and paraxanthine were purchased from Sigma-Aldrich Corporation (St Louis, MO, USA) Naphthacene was purchased from Nacalai Tesque Inc 2-Propanol (IPA), chrysene, estrone, estradiol, estriol, caffeine, theophylline, tetrahydrofuran (THF), dichloromethane, and ethyl acetate were purchased from Wako Pure Chemical Industries (Osaka, Japan) n-Hexane (nHex) was purchased from Kanto Chemical Co (Tokyo, Japan) Based on its structural features, the new PBT selector composed of non-polar aromatic phenyl group together with ester group units was expected to interact with aromatic compounds In order to confirm this point, terphenyl isomers (1–3) are investigated, which are regarded as molecular planarity indicators in HPLC [46,47] and SFC [48] Compound deviates from planarity due to the strong steric repulsion of two phenyl rings located in ortho-position, and this steric hindrance diminishes for and (in this sequential order) Fig shows the SFC chromatograms of 1–3 by using the PBT-based column (Fig 2A), compared to the 2-EP SP (Fig 2B) under isocratic conditions The stronger the planarity character of the analyte, the longer retention was observed on the new column In contrast, no resolution between and was achieved on the 2-EP column (Fig 2B) This planarity recognition may be attributed to planar and rigid PBT backbone 2.2 Instrumentation and chromatographic conditions DCpak PBT column (initially launched as DCpak SFC-A), sized 150 mm × 4.6 mm (i.d.), was supplied from DAICEL Corporation (Tokyo, Japan), which is composed of PBT-coated m silica particle A 2-ethylpyridine (2-EP) column of m particle, sized 150 mm × 4.6 mm (i.d.), was purchased from Waters Corporation (Milford, MA, USA) The SFC instrument used in this study is NexeraUC supplied by Shimadzu Corporation (Kyoto, Japan) equipped with a CO2 pump, a modifier pump, a vacuum degasser, a column oven, a multiple wavelength UV detector, and automated back 3.2 Molecular shape recognition Fig shows the chromatograms of coumarin (5), its dihydro form (4), and methyl substituted form (6 and 7) Compound eluted faster than 5, probably because dihydro has less -electrons than 5, resulting in a weaker interaction between analyte and SP The PBT-derived selector can recognize the minor difference of methyl group position (6 and 7), whereas on the 2-EP column, coumarin and its methyl substituted ones eluted almost at the same time Fig 4A and B shows the SFC chromatograms of three plasticizers, dimethyl phthalate (8), dimethyl isophthalate (9), and dimethyl terephthalate (10) on both columns By using the DCpak column, eluted first, followed by and 10 (Fig 4A) Dipole moment of 8, 9, and 10 is 2.98, 1.60, and 0.01, respectively, which is calculated by using SCIGESS software Thus, the smaller polarization of the sample, the longer the retention time tends to be On the 2EP column, the elution order is totally inverse (i.e 10 eluted first, K Nagai et al / J Chromatogr A 1549 (2018) 85–92 87 Fig SFC chromatograms of terphenyl isomers on (A) DCpak PBT and (B) 2-EP SPs Modifier, MeOH (isocratic conditions, 3%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 3.0 mL/min; UV detection, 254 nm followed by and 8, see Fig 4B) The relationship between dipole moments and retention factors by using two columns are displayed in Supplemental Material (Table S1) Estron (11), estradiol (12), and estriol (13) are natural estrogenic hormones, which have almost same skeleton with different number of hydroxyl groups Compound 11 has one hydroxyl group, 12 has two, and 13 has three Interacting with the PBT selector, polar 13 eluted first, followed by 12 and 11 (Fig 4C) In contrast, by using 2-EP, less-polar 11 eluted first, then followed by 12 and 13 (Fig 4D) This result indicates that DCpak PBT can strongly retain less polar samples, whereas it will show less retention for more polar samples (opposite to the 2-EP observations) The results displayed in this section suggests the high orthogonality of the PBT and the 2-EP derived SPs In order to discuss the characteristic molecular shape recognition behavior of the new column, we then analyzed naphthacene (14), chrysene (15), and triphenylene (16) under isocratic conditions These C2 or C3 symmetric polycyclic aromatic hydrocarbons (PAHs) have the same number of aromatic rings and -electrons but different molecular shape, which are often used as molecular shape recognition indicators (Fig 5) Wise et al proposed lengthto-breadth (L/B) ratio for describing two dimensional aspect ratio of such PAHs [49] The smaller L/B ratio indicates the disk-like molecule Indeed, L/B ratio of 14, 15, and 16 is 1.89, 1.72, and 1.12, respectively On DCpak PBT, disk-like 16 eluted first, followed by 15, and 14 with a large aspect ratio eluted lastly (Fig 5A) Contrary to this, by using 2-EP, 14 with a large aspect ratio eluted first, followed by 15, and 16 eluted lastly (Fig 5B) The retention factor (k) of these PAHs on the two columns is summarized in Table S2 in Supplemental Material Their selectivity trends are orthogonal again It is clearly seen that the PBT selector tends to retain the linear PAH Fig SFC chromatograms of coumarin derivatives on (A) DCpak PBT and (B) 2-EP SPs Modifier, MeOH (isocratic conditions, 2%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 3.0 mL/min; UV detection, 220 nm with large aspect ratio, and 2-EP tends to retain disk-like PAH with small aspect ratio 3.3 Orthogonality investigations As described in previous sections, the separation behavior of two investigated columns was significantly distinct Therefore, they were expected to display complementary selectivity, i.e orthogonal selectivity To obtain a deep insight into orthogonality aspects, we then compared their retention factors measured under isocratic conditions by using commercially available neutral and slightly basic 23 samples These test compounds are classed into seven different isomeric or closely similar sample families Fig shows the double logarithmic plots of k obtained by two columns The detail of samples and retention factors are summarized in Table S3 in Supplemental Material As expected, the plots were well dispersed Indeed, their Pearson’s correlation coefficient (R2 ) was 0.62, indicating there is not strong correlation between them 3.4 Modifier effect Considering that the PBT selector was coated on silica gel, one may fear “column damage” of selector by using extended solvent choices, such as THF, dichloromethane (CH2 Cl2 ), or ethyl acetate (EtOAc) We then examined the stability of retention by using regioselective acetylated anthracene (17, 18) and phenanthrene (19–21) as analytes 88 K Nagai et al / J Chromatogr A 1549 (2018) 85–92 Fig (A, B) SFC chromatograms of plasticizers (phthalates) and (C, D) estrogenic hormones on (A, C) DCpak PBT and (B, D) 2-EP SPs (A, B) Modifier, MeOH (isocratic conditions, 1%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 3.0 mL/min; UV detection, 230 nm (C, D) Modifier, MeOH (isocratic conditions, 30%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 3.0 mL/min; UV detection, 210 nm Fig SFC Chromatograms of C2 or C3 symmetric polycyclic aromatic hydrocarbons (PAHs) on (A) DCpak PBT and (B) 2-EP SPs Modifier, MeOH (isocratic conditions, 25%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 3.0 mL/min; UV detection, 254 nm Fig 7A shows the SFC chromatogram of five analytes mixture with 10% of MeOH Although some peaks were overlapped, these peaks eluted without heavy peak tailing After analysis, the mod- ifier was gradually changed by gradient program The program started after hold with 5% of MeOH, linear gradient ramped up to 30% of MeOH over 20 min, followed by 39 hold at 30% K Nagai et al / J Chromatogr A 1549 (2018) 85–92 Fig Double logarithmic plots of retention factor (k) obtained with DCpak PBT and 2-EP SPs Filled circles (᭹), 2-methylbenzophenone, 3-methylbenzophenone, and 4-methylbenzophenone; open circles ( ), cis-stilbene and trans-stilbene; filled squares (), o-terphenyl, m-terphenyl, p-terphenyl, and triphenylene; filled triangles ( ), 2-acetylanthracene, 9-acetylanthracene, 2-acetylphenanthrene, 3acetylphenanthrene, and 9-acetylphenanthrene; open diamonds (♦), caffeine, theophylline, theobromine, and paraxanthine; filled diamonds ( ), -hydroxyflavanone, -hydroxyflavanone, and -hydroxyflavanone; open triangles ( ), hydrocortisone and prednisolone Modifier, MeOH (isocratic conditions, 5%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, 4.0 mL/min 89 of MeOH After the gradient rinsing program was finished, the same acetylated PAH mixture was injected under isocratic condition (CO2 /MeOH = 90/10) Fig 7B shows its SFC chromatogram with 10% of MeOH, and retention time and peak symmetry were essentially unchanged Then, the rinsing modifier was changed to THF/MeOH = 5/1, the same gradient cycle was repeated, and the same acetylated PAH mixture was evaluated It should be mentioned that no unidentified peak was observed during this rinsing process Fig 7C shows the SFC chromatogram of the same mixture under 10% of MeOH Again, unidentified peaks did not appear during the gradient program, and the chromatogram was almost same as original one This gradient rinsing program was repeated by using CH2 Cl2 /MeOH = 5/1 as modifier, and the same sample mixture was analyzed, whose chromatogram was almost same (Fig 7D) Finally, this procedure was run over by EtOAc/EtOH = 5/1, and the same sample mixture was analyzed with no change in the resulting chromatogram (Fig 7E) According to these experiments, no sign of degradation was observed during the gradient process or the chromatographic testing, which suggest that no column damage was observed by passing through the extended range modifier sequence The PBT selector does not dissolve in many organic solvents, which enabled us to use almost all organic solvents though it was coated on silica gel Fig SFC chromatograms of acetylated anthracene (17, 18) and phenanthrene (19–21) on DCpak PBT SP by passing through various modifiers Chromatographic conditions of the tests: Modifier, MeOH (isocratic conditions, 10%); temperature, 40 ◦ C; ABPR, 15 MPa; flow rate, mL/min; UV detection, 254 nm 90 K Nagai et al / J Chromatogr A 1549 (2018) 85–92 Fig (A) Cycle dependent SFC chromatograms and (B) cycle versus retention factors of PAHs on DCpak PBT column Modifier; MeOH (isocratic conditions, 25%); temperature, 40 ◦ C; ABPR, 15 MPa; total flow rate, mL/min; UV detection, 230 nm; sample concentration, 0.2 mg/mL in nHex/THF = 9/1; injection volume,1 L 3.5 Cycle durability test To confirm the cycle durability, three PAHs, phenanthrene (22), pyrene (23), and triphenylene (16) were used as analytes, under isocratic conditions The same experiment was run over 80 cycles This test was not performed with the aim of covering method validation parameters, but to confirm the lack of solubility of the coated selector Any selector loss under operating conditions would lead to changes with the applied protocol Fig 8A shows the SFC chromatogram of the first injection of three PAHs on the column, where the three peaks were well separated The chromatograms after 20, 40, 60, and 80 cycles are also shown in Fig 8A, and the retention time of these samples never changed until the 80 cycles Fig 8B shows cycle versus their retention factors (k) and confirms the column stability in cycle durability test attributed by the macromolecular ligand Conclusions A novel PBT based stationary phase was designed and confirmed as versatile tool for SFC use This SP shows characteristic planarity recognition of isomeric PAHs and structurally related analytes such as coumarin derivatives, phthalate plasticizers, and estrogenic hor- mones For most compounds, the retention behavior of this SP was found to be significantly distinct from that of the 2-EP based SP, which indicate the orthogonal retention relationship between them Its stability of the PBT selector towards an extended solvent range and the cycle durability of the column in the operating conditions were also confirmed These results demonstrated that synthetic polymers might be promising candidates as selectors for achiral separations in SFC mode Indeed, this column was used as SFC column screening for method development in the pharmaceutical industry (see Fig 10.8 in Ref [1]) Further investigations dealing with applications of this new SP in different chromatographic modes are currently in progress The design and screening of other synthetic polymer based ligands are also in the scope of our research team Acknowledgments The authors wish to thank Dr Pilar Franco and Tong Zhang in Chiral Technologies Europe S.A.S for valuable discussions The authors also appreciate Dr Masashi Iwayama in DAICEL Corporation for dipole moment calculations This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors K Nagai et al / J Chromatogr A 1549 (2018) 85–92 Appendix A Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.chroma.2018.03 032 References [1] C.F Poole (Ed.), Supercritical Fluid Chromatography (Handbooks in Separation Science), Elsevier, 2017 [2] T.A Berger, Separation of polar solutes by packed column 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