Accepted Manuscript

Title: Applications of liquid–phase microextraction techniques

in natural product analysis: A review

Author: Yunyan Yan Xuan Chen Shuang Hu Xiaohong Bai

PII: S0021-9673(14)01524-6
DOI: http://dx.doi.org/doi:10.1016/j.chroma.2014.09.068
Reference: CHROMA 355857

To appear in: Journal of Chromatography A

Received date: 4-5-2014

Revised date: 24-9-2014
Accepted date: 25-9-2014

Please cite this article as: Y. Yan, X. Chen, S. Hu, X. Bai, Applications of
liquidndashphase microextraction techniques in natural product analysis: A review,
Journal of Chromatography A (2014), http://dx.doi.org/10.1016/j.chroma.2014.09.068

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 1 Applications of liquid–phase microextraction techniques in natural product

2 analysis: A review

3 Yunyan Yan, Xuan Chen, Shuang Hu, Xiaohong Bai*

4 School of Pharmacy, Shanxi Medical University, Taiyuan 030001, PR China

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6 * Corresponding author.

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7 E-mail: bxh246@163.com (X.H. Bai).

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8 Phone: +86-13935105965; Fax: +86-351-4690114.

9 Mailing address: School of Pharmacy, Shanxi Medical University, Taiyuan 030001, PR China.

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10

11 Abstract Over the last years, liquid-phase microextraction (LPME) as a simple, rapid, practical

12
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and effective sample-preparation technique, coupled with various instrumental analytical methods,

13 has been increasingly and widely used to research and determination trace or ultra-micro-levels of
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14 both inorganic and organic analytes from different matrix-complex samples. In this review,

15 different kinds of LPMEs such as single drop liquid-phase microextraction, dispersive

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16 liquid-liquid microextraction, and hollow fibre liquid-phase microextraction are summarized and

17 recent applications of LPMEs in trace compounds in vivo and in vitro from different natural
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18 product matrice analysis such as tea, vegetables, seeds, herbs, and galenical are also discussed.

19 Finally, future developments and applications of LPMEs in complex sample analysis are
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20 prospected.

21
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22 Keywords: Liquid-phase microextraction; Natural product analysis; Herbal medicine; Traditional

23 Chinese medicine; In vivo; In vitro

24

Page 1 of 59
25 Contents

26 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27 2. Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28 2.1. Single drop liquid–phase microextraction . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .

29 2.2. Dispersive liquid–liquid microextraction . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .

30 2.3. Hollow fibre liquid–phase microextraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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31 3. Concluding remarks and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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32 1. Introduction

33 Natural product analysis constitutes one of the most important fields of the science at present.

34 The analysis of organic and inorganic compounds in natural products has gained considerable

35 interest in recent years [1–3]. This interest is particularly focused on herbal medicines (HMs),

36 including herbs, herbal preparations, herbal materials and finished herbal products, which contain

37 active ingredients of natural products, other natural product materials or combinations [4]. HMs,

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38 such as traditional Chinese medicines (TCMs), have performed crucial functions in clinical

39 therapy for numerous diseases and provided valuable and easily obtainable healthcare resource in

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40 many oriental countries for thousands of years [5]. During the last few decades, the use of TCMs

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41 has expanded globally, both as primary health care of the poor in developing countries and as the

42 predominant medical treatment in the national health care system [6]. With the widespread use of

43

44
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traditional medicine, safety and effectivity, as well as quality control of HMs and traditional

preparation procedure, have become important concerns for both health authorities and the public.
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45 However, little is known about the chemical compositions, pharmacokinetics, pharmacodynamics

46 and metabolomics of TCMs to date. In addition, data about identification, efficacy and safety of
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47 TCMs are far from sufficiently meeting the criteria to support their use worldwide. This state is

48 mainly due to the following considerations: (1) TCMs are complex matrix, multi-component

49 integration and collaborative systems; (2) TCMs contain low active ingredient content; and (3)
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50 pretreatment technology or method is not adequate or acceptable for TCMs research and
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51 evaluation.

52 Target compound analysis in complex samples generally includes two steps of sample
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53 pretreatment (extraction, separation, purification and concentration) and target compound

54 determination (identification, qualitative and quantitative analysis). Given the evolution of

55 computer, information, and instrument technologies, analysis methods and technologies have been

56 greatly promoted and developed. However, sample pretreatment technologies or methodology

57 have yet to adapt instrument development and meet target analyte requirements in identification,

58 qualitative and quantitative analysis. Therefore, increased efforts are currently being focused on

59 sample pretreatment improvement. In this sense, current trends are moving towards (1) reducing

60 the number of steps required for the procedure, (2) reducting or totally eliminating solvents

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61 required for extraction, (3) extending the adaptability to field sampling, and (4) automation [7].

62 Such enhancement poses a challenging task, especially in the field of natural product analysis, in

63 which the sample is a high complex, multi–component and has low levels of active ingredients

64 systems. Therefore, it is essential to establish a sample pretreatment technology that can retain the

65 effective ingredient at the extreme, as well as to separate and remove ineffective ingredient and

66 impurities. Sample preparation is the basic and crucial step in the success for any analytical

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67 method.

68 Sample preparation is the basic and most crucial step in the success of any analytical method.

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69 A successful sample pretreatment method typically has three major objectives: (1) sample matrix

70

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simplification and/or replacement, (2) analyte enhancement or concentration, and (3) sample

71 clean-up [7]. Over the last years, several new miniaturized solvent-based extraction procedures,

72

73
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which are known as liquid-phase microextraction (LPME) techniques, have been introduced and

applied with success [8–14]. LPME emerged from liquid–liquid extraction, which is probably the

74 most widely used sample extraction and separation procedure despite its clear disadvantages such
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75 as high consumption of time and strong toxicity of solvent, as well as its tedious application [15].

76 LPME normally takes place between several microliters of water-immiscible solvent extraction
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77 phase or acceptor phase (AP) and an aqueous sample phase or donor phase (DP), which contains

78 the target analytes of interest. LPME can be classified into three main categories [7, 16]: single
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79 drop liquid–phase microextraction (SD–LPME) [5, 17, 18], dispersive liquid–liquid

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80 microextraction (DLLME) and hollow fibre liquid–phase microextraction (HF–LPME) [23–26].

81 Figure 1 shows a schematic of several LPME modes. Several variations have also recently been
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82 introduced in each mode, which clearly demonstrate the methodology’s versatility. The LPME

83 technique combines sampling, extraction, separation and concentration in one step, meanwhile a

84 relatively high enrichment factor (EF) of analyte is obtained since its low AP volume (Va) and high

Vd
85 DP volume (Vd) (that is   , phase ratio to be the higher), and the AP is easily introduced into
Va

86 a chromatographic or electrophoretic system.

87 LPME performs a primary function in the extraction of inorganic and organic compounds

88 from water samples, such as inorganic substance (fluorine [27], vanadium [28], arsenic, stibium,

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 89 bismuth, plumbum, stannum and mercury [29], iodate [30], and arsenic (III) and arsenic (V) [31]);

90 as well as organic substance (polycyclic aromatic hydrocarbon (PAH) [32, 33], organochlorine

91 pesticides [34–36], chloroacetanilide herbicide [37], sulphur compounds [38]) and so on. However,

92 the matrix complexity, as well as the varied, low level contents of components in natural samples

93 is a considerable drawback that makes the application in this area difficult. Even so, multiple

94 developments and applications highly focused on the TCMs analysis field have been proposed,

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95 which represent the start of the expansion of LPME in TCMs or complex samples analysis.

96 Therefore, this review will primarily focused on the different applications of LPME techniques,

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97 such as SD–LPME, D–LLME, HF–LPME and so on, coupled with various instrumental analytical

98

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methods, such as high performance liquid chromatography (HPLC), gas chromatography (GC),

99 liquid chromatography/mass spectrometry (LC/MS), ultra-high performance liquid

100

101
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chromatography/mass spectrometry (UHPLC/MS), gas chromatography/mass spectrometry

(GC/MS), capillary electrophoresis (CE), ultraviolet–visible spectrophotometry (UV) and atomic

102 absorption spectrophotometry (AAS), in the field of natural product analyses during the past few
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103 years.

104 The advances of LPME technique, in vivo and in vitro, for the analysis of organic and
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105 inorganic compounds from different natural product types, such as tea, vegetables, seeds, herbs

106 and galenical, which will be summarized and discussed below, clearly demonstrate the potential of
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107 the LPME technique as a powerful sample preparation tool in complex sample analysis. To the
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108 best of our knowledge, the present paper is the first review article dealing with the specific

109 application of LPME techniques in natural product analysis.

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110

111 2. Applications

112 2.1 Single drop liquid-phase microextraction

113 One of the modes of the LPME that was first reported by Liu et al. [39] is termed SD-LPME,

114 in which the extraction medium is in the form of a single drop (Fig. 1A and 1B). The technique is

115 based on the distribution of analytes between a microdrop of extraction solvent (usually few

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116 microliters) at the tip of a microsyringe needle and an aqueous sample phase containing the

117 analytes. After extraction, the microdrop is retracted back into the microsyringe and injected into a

118 chromatographic or electrophoretic system for further analysis. Jeannot and Cantwell [40, 41], as

119 well as Lee’s group [11], performed the technique in combination with chromatographic analysis

120 based on a previous work of Dasgupta’s group [39, 42], in which a single drop was used as the

121 analyte collector. SD-LPME can be classified into two-phase [40, 11, 43] and three-phase mode [7,

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122 44]. In the two-phase mode, such as direct immersion SD-LPME (DI-SD-LPME) (Fig. 1A) and

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123 continuous flow SD-LPME (CF-SD-LPME), analytes are extracted from the sample solution (DP)

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124 into the organic solvent (AP) as a microdrop suspended from a microsyringe needle. Considering

125 that suspended particles or impurities in sample solution may disturb the microdrop or even make

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126 that drop highly unstable and easily fall off, the two-phase mode is more suitable for simple matrix

127 sample. In the three-phase mode, such as headspace SD-LPME (HS-SD-LPME) [45] (Fig. 1B)

128
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and drop-to-drop SD-LPME (DD-SD-LPME) [46], analytes are firstly extracted from the DP into

129 the organic solvent or the headspace, and then back-extracted into the single drop aqueous AP.
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130 Compared with the two-phase mode, the three-phase mode is more suitable for the analysis of

131 volatile components in complex samples. In the process, the microdrop remains relatively stable
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132 and nearly not influenced by the stirring, impurities or sample matrix interference.

133 To reduce evaporation risk during the extraction period and obtain the desired results, several
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134 important factors of extraction solvent, such as relatively high boiling point or relatively low

135 vapour pressure, density, high viscosity, suitable chromatographic behaviour and high extraction
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136 efficiency (EE) or EF for the target analytes, must be considered [47]. Based on these factors, the

137 most common extraction solvents used are toluene [48], hexane, octane [49], dodecane [50] and
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138 xylene [5, 45]. Except that, certain ionic liquids (ILs) [51], such as 1-butyl-3-methylimidazollium

139 hexafluorophosphate ([BMIM][PF6]) [14], 1-hexyl-3-methylimidazolium hexafluorophosphate

140 ([HMIM][PF6]) [36] and 1-octyl-3-methylimidazolium hexafluorophosphate ([OMIM][PF6]) [52],

141 can also provide satisfactory results with better reproducibility [53] This performance is due to the

142 ionic liquids’ high viscosity and surface tension, which helps to form a stable drop of a

143 considerably larger volume [54] to prolong the extraction time [55–57]. In addition,

144 β-cyclodextrine [58], surfactants [59] and supramolecular solvents [60] as extractants were also

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145 proposed in the field of SD-LPME. However, in actual work, the extraction solvent should be

146 selected according to particular samples and target analytes. For example, in the case of

147 DI-SD-LPME mode, if the extraction solvent with a significantly different density from the

148 analysed sample is selected, the extraction drop will most probably be broken away from the

149 needle tip. In certain cases, high boiling point is not such significant factor for the extraction

150 solvent. On the contrary, low boiling point could be advantageous because of the possible

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151 coelution of this solvent and the target analytes in the sample.

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152 In addition, the most effective syringe for SD-LPME is a standard GC microsyringe (e.g.,

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153 skew needle). The drop must cling to the tip without wicking up the exterior of the syringe needle,

154 which requires the maximum needle tip surface area. The standard Hamilton #2 curved bevel

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155 syringe tip provides the greatest surface area, and approximately 90% to 95% of the drop can be

156 withdrawn into the syringe after extraction [54]. The mass transfer of analytes in sample phase is

157
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the rate-determining step in this extraction, so a relatively high stirring speed, high extraction

158 temperature and long extraction time can increase and improve the EF or EE of target analyte.
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159 However, the drop volume varies during the extraction process, particularly under extreme

160 extraction conditions (high stirring speed, high temperature and long extraction time), which could
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161 affect drop stability [5] and analytical precision [61]. This problem can be avoided or overcome

162 when an appropriate, quantitative internal standard is introduced into the drop during extraction
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163 [18, 39, 62].

164 A detailed description of these SD-LPME modes, as well as their theoretical aspects, can be
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165 found in specific review articles [5, 17, 18，56, 63-65] and monographs [7, 44]. In short,
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166 SD-LPME has become one of the most popular sample preparation techniques because of its (1)

167 simplicity and speed, (2) low cost and low environmental pollution, (3) wide range of solvent

168 types being selected and used, (4) applicability to different complex matrices, (5) extraction and

169 separation of both organic and inorganic compounds, and (6) compatibility with chromatographic

170 or electrophoretic injection systems.

171 Despite SD-LPME attracting considerable attention in recent years for the extraction of both

172 organic and inorganic species. This approach is best suited for the separation and enrichment of

173 non-polar or moderately polar analytes from relatively clean matrix environmental samples (e.g.,

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174 tap water or ground water) [66–69]. In contrast, natural product sample (particularly TCM) and

175 biological sample applications have received limited attention, which is probably due to the

176 complex and dirty nature of the sample matrixes.

177 The first application of DI-SD-LPME for natural product analysis was reported in 2004 by

178 Paramita Das et al. [70], who employed DI-SD-LPME combined with GC/MS for the

179 determination of free iodide in aubergine, lotus seeds, lotus stem and potato samples. In the work,

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180 with N,N-dimethylaniline as an iodine derivatization reagent at pH 6.4, a straightforward

181 conversion of iodide into 4-iodo-N,N-dimethylaniline, which was rapid and unaffected by the

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182 presence of many ionic substances, occurred. When 4-iodo-N,N-dimethylaniline was formed,

183

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DI-SD-LPME was employed to extract the 4-iodo-derivative, and then GC/MS was used for

184 determination of iodide content. 4-Iodo-N,N-dimethylaniline was a good candidate for extraction

185

186
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by DI-SD-LPME, followed by sensitive determination by GC/MS. Dried vegetables were

wet-combusted with peroxydisulphate to liberate covalently bound iodine as iodate, which was

187 reduced before derivatization. A rectilinear calibration graph was obtained between 0.1 µg L−1 to
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188 10 mg L−1 for iodide using the DI-SD-LPME method. The correlation coefficient and the limit of

189 detection (LOD) for iodide were 0.9998 and 10 ng L−1, respectively. The article points out that,
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190 compared with solid phase microextraction (SPME), DI-SD-LPME appeared to be a more efficient

191 technique in terms of better LOD and precision. Moreover, the technique is simple to perform,
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192 naturally free from memory effects and cost-effective. To date, DI-SD-LPME has also been
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193 successfully applied to analyse the active alkaloids ingredients of China in human urine [71] and

194 adenine in green tea sample [72].

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195 HS-SDME is more often applied to analytes with relatively high vapor pressure. The first

196 application of HS-SDME for natural product analysis was reported in 2005 by Deng et al [73]. In

197 the work, 27 compounds of the essential oil (for example camphor, borneol, borneol acetate and so

198 on) in the TCM, Fructus amomi, were extracted using pressurized hot water extraction, followed

199 by extraction and concentration with HS-LPME and detection by GC/MS. The concrete steps

200 involved the following: (1) withdraw 1.0 µL of cyclohexane (containing 20 µg L−1 menthol,

201 internal standard) into the microsyringe, (2) insert the microsyringe needle into headspace vial and

202 keep the needle suspended over aqueous extract, and (3) withdraw 5.0 µL of gaseous sample at 1.0

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203 µL s−1, then depress the plunger back the original mark immediately and hold for 5.0 s. The same

204 process was repeated for 20 times. Finally, the microsyringe needle was removed from the

205 headspace vial and injected into GC/MS for analysis. The HS-LPME parameters (extraction

206 solvent, plunger withdrawal rate, dwelling time and extraction cycle) with respect to the EE were

207 optimized and investigated, and method repeatability was studied. Twenty-seven compounds in

208 the essential oil were identified, and only three active compounds camphor, borneol and borneol

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209 acetate in the F. amomi sample were quantitatively analyzed by internal standard method. The

210 proposed method required simple sample preparation and small sample mass, and provided good

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211 repeatability and short analysis time.

212

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Since then, HS-SDME has also been reported for the analysis of the essential oil in

213 Zanthoxylum bungeanum Maxim [74], dried S. aromaticum (L.) Merr. et Perry, Cuminum

214

215
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cyminum L [75] and C. cyminum L [76]. The technique was also used to analyse the volatile

components in Artemisia capillaris Thunb [45], Myrtus communis L [77], Foeniculum vulgare

216 Mill [78] and Curcuma wenyujin Y. H. Chen et C. Ling [79], thymoland carvacrol from Thymus
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217 transcaspicus [80]. This last case, which corresponding to the HS-SDME work of Yang [81], in

218 which hydrodistillation coupled with HS-SDME with IL as the extraction solvent, followed by GC
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219 analysis technique, was successfully developed to determine the volatile and semi-volatile

220 compounds in the seeds of C. cyminum L. Table 1 summarizes these applications of SD-LPME in
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221 natural product analysis, including sample, target analyte, optimum extraction condition, EFs,
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222 detection methods and quantitative analysis parameters. Among these applications, given the

223 possibility of in situ complexation or derivatisation, less sample pollution and strong purification
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224 ability, HS-SDME was the technique that has been most used in this sense.

225 2.2. Dispersive liquid-liquid microextraction

226 Dispersive liquid–liquid microextraction [82-86] (DLLME, Fig. 1C) as a novel sample

227 preparation method was first introduced by Assadi and co-workers in 2006 [87]. Conventional

228 DLLME is based on a ternary component solvent system, including disperser solvent, extraction

229 solvent (AP) and aqueous phase sample (DP) containing the analyte of interest. When an

230 appropriate mixture of the extraction solvent and dispersive solvent is injected into an aqueous

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231 phase sample, a cloudy solution is formed. The hydrophobic target analytes are enriched in the AP,

232 which is dispersed into the bulk aqueous solution. After extraction, the AP gathers and precipitates

233 at the bottom of DP or floats on its surface, the analytes enhanced in the AP are analysed by

234 conventional techniques.

235 In traditional D-LPME, extraction solvent, dispersing solvent and assistant-dispersive

236 measure are the major effect factors. In generally, the extraction solvent typically uses microliter

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237 volumes of solvent including low-density [88-90] or high-density [28, 90-104] solvents more than

238 water. Common high-density extraction solvents include chlorobenzene, dichloromethane, carbon

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239 tetrachloride, tetrachloroethylene, ILs and so on. Several low-density extraction solvents, for

240

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instance, long-chain alcohols like 1-undecanol, 1-dodecanol, 1-octanol, n-hexanol, etc., are used.

241 Common disperser solvents are both water dissolved and extraction solvent dissolved, small

242

243
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molecule organic solvent, such as acetone, methanol, acetonitrile, ethanol, tetrahydrofuran, etc. In

addition, the researcher [105, 106], used magnetic nanoparticles (MNPs) as the disperser in the

244 DLLME process and developed new DLLME technology-based MNPs. These shaking- [55, 107,
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245 108], stirring-, temperature- [109-111], vortex- [112-114] and ultrasound-assisted [115-117] steps

246 are used as assisting measure for hastening AP dispersion in the DP and enlarging the contact
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247 between the AP and DP to rapidly attain extraction equilibrium.

248 Surfactant solutions [118-120] and ILs, which are also regarded as environmentally-friendly
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249 solvents that are easily commercially available, have been proposed as alternatives to organic
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250 solvents because of their low vapour pressure, high viscosity, good thermal stability, miscibility

251 with water or organic solvent and greater use of larger, reproducible extracting volume [64]. These
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252 solutions are easily synthesised or commercially available. Tian et al. [55] developed and

253 introduced organic solvent DLLME (OS-DLLME) and ionic liquid DLLME (IL-DLLME)

254 coupled with HPLC for analysing an active ingredient, emodin, and its metabolites (aloe-emodin,

255 anthraquinone-2-carboxylic acid, rhein, danthron, chrysophanol and physcion) in urine samples.

256 Under optimal conditions, the EFs for emodin and its metabolites by OS-DLLME and IL-DLLME

257 were within the range of 90 to 295 and 63 to 192 respectively. The relative standard deviations

258 (RSDs, n = 3) for intra-day and inter-day precisions were lower than 7.2% and 8.7% by

259 OS-DLLME and lower than 5.7% and 6.4% by IL-DLLME. Finally, recoveries ranged from

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260 87.1% to 108% for OS-DLLME and from 87.5% to 106% for IL-DLLME. The group verified that

261 no significant deviations existed between the two methods for the determination of emodin and its

262 metabolites. From the results of HPLC/UV of the urine sample after DLLME, the metabolites of

263 aloe-emodin, rhein, chrysophanol and physcion were identified by comparing the retention times

264 with the standards. From the results of HPLC/MS of urine sample after D-LPME,

265 anthraquinone-2-carboxylic acid and danthron as unreported metabolites of emodin were first

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266 found.

267 Anderson’s group [121, 122] introduced an in situ metathesis IL-DLLME method. In this

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268 approach, a hydrophilic IL is completely dissolved in the aqueous sample solution to promote

269 interaction between the IL and analytes. Then, an ion-exchange reagent is introduced to carry out

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270 the in situ metathesis reaction. A turbid solution with fine IL micro-droplets was formed, and a

271 hydrophobic IL was produced, which can be directly analysed by HPLC. A significant advantage

272
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of this method lies in that the metathesis reaction and extraction are accomplished in one step,

273 making the method very rapid and amendable to high-throughput analysis.
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274 Elimination of the dispersion solvent is an approach that has been developed in DLLME and

275 applied in TCMs analysis, because the solvent can decrease the partition coefficient of the analytes
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276 into the extraction solvent. Ultrasound is frequently used to assist the extraction to form an

277 appropriate oil-in-water emulsion that would disperse the extraction solvent into the aqueous
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278 phase. The approach called ultrasound assisted DLLME (USA-DLLME) increases the interfacial

279 area between DP and AP without the aid of a dispersive solvent. Yan et al. [123] developed an
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280 USA-DLLME coupled with HPLC and introduced it for the extraction and analysis of

281 anthraquinone compounds like aloe-emodin, rhein, emodin, chrysophanol and physcion in TCMs
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282 samples. The most favourable conditions, such as an AP of 60 mg of [HMIM][PF6], DP of pH 3.0,

283 ultrasound at 40ºC for 7 min, and centrifugation at 2500 rpm for 6 min, were obtained. Under the

284 optimal conditions, good linearities of the five anthraquinone compounds were obtained with

285 correlation coefficients higher than 0.9939; the LODs ranged between 0.01 to 0.09 μg L–1; the

286 RSDs (n = 3) were less than 9.8% and the EFs were in the range of 80 to 197 fold. In addition,

287 temperature-assisted DLLME [109] has also been proposed in 2010 for the determination of

288 anthraquinones in Radix et Rhizoma Rhei samples.

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289 Afterwards, Tian [107] and Wang [124] respectively analysed and discussed the extraction

290 mechanism of IL–DLLME. Wang et. al thought that in the IL–DLLME, [HMIM][PF6] as AP was

291 first diffused and orderly arranged in the DP, and then formed the IL molecular ordered organized

292 assembly (MOOA), which consisted of hydrophilic cations (imidazole group) in the DP and a

293 hydrophobic alkyl chain constituting the core (Fig. 2A). In the acid medium, conjugated electrons

294 in phenylpropionic acids move to the carboxyl because of a carboxyl electron-withdrawing

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295 inductive effect, thus making the carboxyl electron-rich. When extracted by IL–DLLME, the

296 phenylpropionic acids encounter imidazole cation in IL’s MOOA, and the electron-rich carboxyl

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297 easily transfers electrons to the imidazole cation and forms a more steadily and highly ordered

298

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carboxyl-imidazole charge-transfer supramolecular (CICTSM). Thus, the phenylpropionic acids

299 were included in IL’s MOOA and extracted by IL (Fig. 2B). To verify the CICTSM extraction

300

301
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mechanism, the author compared and analysed the ultraviolet spectrum of phenylpropionic acids

before and after IL-DLLME. The results showed that the absorbances of the target analytes after

302 IL-DLLME are significantly higher than before IL-DLLME, and the maximum absorption
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303 wavelength underwent a blue shift by 10 nm.

304 In addition, Cabala [125] et al. developed a new microextraction technique for equilibrium,
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305 non-exhaustive analyte preconcentration. The key point of the method is the application of a

306 specially designed, optimised bell-shaped extraction device. The technique has been applied to the
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307 preconcentration of selected volatile and semi-volatile compounds from aqueous solutions into

308
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organic solvents lighter than water and determined by GC/MS in spiked water samples.

309 A novel automated approach, low density solvent based/solvent demulsification DLLME

310 coupled to analysis by GC/MS, was developed [126]. In this procedure, all extraction steps and
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311 analysis were continuously carried out repetitively, completely and automatically with the use of a

312 CTC CombiPAL autosampler.

313 Another kind of DLLME named solidification of floating organic drop microextraction

314 (SFOME) (Fig. 1D) was introduced by Khalili-Zanjani [127] in 2007. To date, the method has

315 been further expanded [128-132]. A solvent droplet with a melting point (M.P.) of 10ºC to 30ºC

316 and a density lower than that of water is added (DP), and extraction is performed. After extraction,

317 the sample vial is placed in an ice bath or a refrigerator freezer, and the AP solidifies rapidly on

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318 the DP surface. After the solid is removed and melted at room temperature, the analyte enhanced

319 in the AP is determined [28]. 1-undecanol (M.P. 13ºC-15ºC) [128, 133], 1-dodecanol (M.P.

320 22ºC-24ºC) [134], hexadecane (M.P. 18ºC) [135], undecanoic acid [30] etc. are often used. In

321 addition, 1-bromo hexadecane (M.P. 17ºC-18ºC), 1,10-dichorodecane (M.P. 14ºC-16ºC),

322 2-dodecanol (M.P. 22ºC-27ºC) and 1-hexadecanethiol (M.P. 18ºC-20ºC) are also reported.

323 Toraj and his worker [136] employed SFOME combined with HPLC/UV to determine the

t
ip
324 low concentration of the complex matrix of real samples taken from addicted persons and patients

325 under morphine and codeine treatment. Xue [137] et al. introduced SFOME combined with HPLC

cr
326 for the determination and evaluation of five low abundance lignan compounds in Schisandra

327

us
Chinensis (Turcz.) Baill from different origins. The researches also believed that in SFOME, the

328 extraction solvent n-dodecyl diffused rapidly in water under a certain stirring speed and orderly

329

330
an
arranged to form dodecanol MOOA. In the MOOA, the hydrophilic -OH pointed to the external

water system and hydrophobic alkyl group gathered to constitute the hydrophobic inner core. The

331 analyte molecules with different polarities, which either were distributed in different positions or
M
332 entered into the hydrophobic inner core of the dodecanol’s MOOA, were extracted. Under the

333 condition of below freezing point of the extraction solvent, the dodecanol’s MOOA forms fruity
ed

334 and dense solid supermolecular aggregation by hydrogen bond and float on the top of the aqueous

335 sample phase.

pt

336 Recently, Zhang et al. [138] combined two DLLMEs of both low- and high-density
ce

337 extraction solvents in one step, developed a novel LPME technique termed ionic

338 liquid-water-organic solvent three phase microextraction (IL-W-OS-3p-ME) and introduced the
Ac

339 method for the simultaneous preconcentration and determination of flavonoids and anthraquinones

340 in TCMs. The procedure was performed in one step using a syringe and two extraction solvents

341 (the low- and high-density APs are not only insoluble but also non-emulsified in DP; however,

342 both APs are immiscible). Firstly, 3.0 mL of the DP was placed in a 5 mL syringe. Next, 100 µL of

343 heptanol (AP1) and 100 µL of [HMIM][PF6] (AP2) were injected separately into the sample

344 solution with a syringe. A cloudy emulsion was formed after 25 s of manual shaking. The

345 emulsion was allowed to stand for 3 min. Soon afterwards, the emulsion readily separated into

346 three clear phases: the AP1 mainly contained the flavonoids floating on the surface of the DP, the

Page 13 of 59
347 aqueous sample DP and the AP2 that mainly contained the anthraquinones settling at the bottom of

348 the syringe. With the syringe held pointing upward, the syringe plunger was pressed to transfer the

349 upper layer AP1 into a small EP tube. By rotating the syringe so that it pointed downward and

350 allowed to settle for 1 min, the lower AP2 was recovered into the above-mentioned EP tube from

351 the syringe tip by slightly pressing the plunger. Next, the solution was diluted with 20 µL of

352 HPLC-grade methanol. Then, the mixed solution was injected into the HPLC system for analysis.

t
ip
353 Under optimized conditions, the EFs of the flavonoids were ranged between 102 and 230, and

354 those of the anthraquinones were from 102 to 211, the LODs were below 0.05 ng mL−1, and the

cr
355 precisions and recoveries were 5.2% to7.8% and 80.1% to 105.8%, respectively.

356

us
In addition to the above mentioned, DLLME and SFOME has been widely supplied in vivo

357 and in vitro from the following natural product, such as phenylpropionic acid compounds [124],

358

359
an
anthraquinones [123, 138], flavonoids [138], furocoumarin [139], oleanolic acid and ursolic acid

[140] in TCMs, as well as volatile constituents in tea [141], essential oil constituents of the plant

360 Oliveria decumbens vent [142], auxins in plants [143], endogenetic plant growth regulators in
M
361 common green seaweeds [144], emodin and its metabolites in urine samples [55] and opium

362 alkaloids in human plasma [136]. In addition, several metal compounds have also been analysed,
ed

363 such as total and water soluble copper [145] and vanadium [28]. All the specific parameters are

364 listed in Table 2.

pt

365 The main advantages of the technique include simplicity, low cost, short extraction time,
ce

366 simple apparatus and minimum organic solvent consumption [69]. However, the extraction solvent

367 is susceptible to contamination by sample impurities and the matrix because of its exposure to the

368
Ac

sample solution during extraction. In addition, the precision of analytical result is limited, and the

369 two can be mentioned as the technology’s drawbacks.

370 2.3 Hollow fibre liquid-phase microextraction

371 To enhance single drop stability and reduce AP pollution from impurities or substrate in DP

372 in the above mentioned SD-LPME, hollow fibre liquid-phase microextraction (HF-LPME) was

373 introduced in 1999 by Pedersen-Bjergaard and Rasmussen as a simple and effective LPME [46].

374 Based on the AP in/on hollow fibre (HF) type, the HF-LPME can be classified into two-phase

Page 14 of 59
375 HF-LPME (2p-HF-LPME) [146, 147] and three-phase HF-LPME (3p-HF-LPME) [46, 148, 149].

376 In 2p-HF-LPME (Fig. 1E, Fig. 1F), the organic solvent is immobilize in the pores and filled in the

377 HF lumen, and the analytes are extracted by passive diffusion from the DP into the organic AP in

378 the HF lumen [150]. A weak acid in acidic DP medium, weak alkali in alkaline DP medium or

379 neutral substances compounds with high solubility in non-polar organic solvent AP can be

380 extracted by a two-phase system. In the 3p-HF-LPME (Fig. 1G), three liquid phases participate in

t
ip
381 analyte extraction: aqueous sample DP containing the target analyte, the water-immiscible organic

382 extraction phase immobilised in the wall pores of the HF and the aqueous AP in the HF lumen

cr
383 [149]. The target analytes in DP are first extracted by an organic solvent immobilised in the HF

384

us
pores, and then further extracted into the aqueous AP in the HF lumen. Acid, alkali or strong

385 dielectric compounds with poor solubility in organic solvent can be back-extracted to the aqueous

386

387
an
AP of the three-phase system [25]. The enriched-target analytes in organic AP or aqueous AP are

directly or indirectly detected by UV, GC, AAS, HPLC, CE [151, 152], UHPLC/MS and

388 HPLC/MS [153].

M
389 In HF-LPME, extraction solvent is also crucial for achieving good selectivity and high EE of

390 the target compound. The extraction solvent should have enough dissolving capacity for the
ed

391 analyte, similar polarity to the fibre and no reaction with any of the compounds in the sample

392 solution. Only one kind of extraction solvent is used in general, but mixed solvent is used at times
pt

393 to obtain the best EE [154, 155] is used. When Xi et Al. [154] studied the effect of 20 organic
ce

394 solvents on the extraction capacities of four hyoscyamines compounds in TCMs, the group found

395 that 7:3 (v:v) of xylene and n-heptanol mixed solvent had the best extraction effect on the four
Ac

396 hyoscyamines.

397 HF is another important factor for achieving optimal extraction and concentration of the

398 target analytes. In addition to serving as carrier to protect the AP and micro-strainer to purify

399 sample solution [156, 157], HF also participate in target analyte extraction and improve the

400 analyte EE or EF [158]. Wang et al. [158] used HF-LPME combined with HPLC for the

401 preconcentration and quantitation of phenylpropionic acid active constituents in TCM preparations.

402 While investigating the different HFs as carriers to extract phenylpropionic acids, they found that,

403 under the same condition, polyvinylidene difluoride (PVDF) had the highest phenylpropionic

Page 15 of 59
404 acids EEs, so the researchers discussed and analysed the HF-LPME mechanism based on PVDF.

405 In the paper, they proposed that a strongly electronegative fluorine (F) exists in the PVDF

406 structure, making the F electron-rich in PVDF surface. Meanwhile, the benzene ring in

407 phenylpropionic acids is electron-deficient given its conjugated with the attractive electronic

408 carbanyl group. In the extraction process, the electron-deficient benzene ring in the target analyte

409 and electron-rich PVDF surface easily form the orderly charge-transfer supramoleculars (Fig. 3),

t
ip
410 which make the phenylpropionic acids concentration increases on the HF surface and enhance

411 their EE or EF.

cr
412 Zhou [159] and his colleagues developed a 2p-HF-LPME with magnetofluid coupled to

413

us
HPLC with ultraviolet detection, successfully applied it to separate and determine four

414 phenylethanoid glycosides (PhGs) (echinacoside, tubuloside B, acteoside and isoacteoside) in rat

415

416
an
plasma after oral administration of Cistanche salsa extract. Under optimised conditions, the EFs

for PhGs exceeded 625. The calibration curve for PhGs was linear in the range between 0.1 and

417 100 ng mL−1, with correlation coefficients greater than 0.9996. The intra-day and inter-day
M
418 precisions (RSDs) were below 8.74%, and the LODs for the four PhGs ranged between 8 and 15

419 pg mL−1. To date, 2p- or 3p-HF-LPME have been successfully employed for analysing and
ed

420 researching the amounts of compounds in natural product samples. 2p-HF-LPME has used for

421 analysing and researching the anthraquinones compounds in Radix Polygoni Multiflori [160],
pt

422 emodine and its metabolites in rat urine and plasm [161], protein binding properties of
ce

423 furocoumarins [162] and flavonoids compounds [163] to bovine serum albumin, osthole

424 pharmacokinetics in cerebral ischemia hypoperfusion rat plasma [164], and permeable
Ac

425 biomembrane ingredients in TCMs [165, 166]. 3p-HF-LPME has been employed to

426 preconcentrate and determine oxymatrine and matrine [167], phenylpropionic acids [158],

427 cinnamic acid and its derivative [168], valerenic acid [169], flavonoids [151], magnolol and

428 honokiol [156], aristolochic acid [170], anthraquinones [171] in Rhubarb, studies on protein

429 binding rates [172], extraction mechanism [174, 173], the preferred conformation of ephedrine and

430 pseudoephedrine [174], as well as correlativities between the EF of the target analyte and its pKb

431 [175] or pKa [176].

432 The presence of charged compounds used in liquid extraction procedures led several authors

Page 16 of 59
433 to propose the use of electrical fields to enhance and manipulate HF-LPME [177-184]. For the

434 first time in 2006, Pedersen–Bjergaard and Rasmussen [185], proposed electromembrane

435 extraction (EME). In essence, the method is similar to a 3p-HF-LPME [186], but migration in

436 EME system through an organic solvent immobilised in the HF wall (e.g. supported liquid

437 membrane, SLM) is forced by an electrical field generated from two electrodes, one that is placed

438 outside the HF (DP) and the another inside the HF lumen (AP). To ensure efficient electrokinetic

t
439 mobility in the EME system, pH must be adjusted to provide total ionisation of the analytes in the

ip
440 two aqueous solutions. In a two-phase EME recently described by Davarani and co-workers [187],

cr
441 the researchers discovered that the application of an electrical potential could significantly

442 increase mass transfer and reduce extraction time [188].

us
443 In various fields, an increasing number of applications of carbon nanotubes (CNTs) have

444 been presented because of CNT’s high selectivity and good extraction efficiency in case of organic

445
an
analytes extracted from aqueous samples [189]. These features present a potential use for CNTs as

446 adsorbing material in reinforcing LPME. Es’haghi et al [190] succeed in promoting the HF-LPME
M
447 technique by inserting multi-walled CNTs (MWCNTs) into the pores of a HF in the measurement

448 of caffeic acid in echinacea purpurea herbal extracts. In the test, the MWCNTs dispersed in the
ed

449 organic solvent were held in the pores of a porous HF supported by capillary forces and sonication.

450 The CNTs then remained in contact with the aqueous DP and the aqueous AP. The analyte from
pt

451 the DP diffuses into the MWCNTs dispersed in the organic solvent and filled the HF pores, and

452 was then back-extracted into a small volume of aqueous AP and enriched. The method showed
ce

453 good linearity (0.1 ng L−1 to 50 μg L−1), repeatability, LOD (0.05 ng L−1) and excellent enrichment

454 (EF=2108). Chen et al [173] had applied MWCNTs reinforcing LPME to the separation and
Ac

455 determination of three cinnamic acid derivatives, coffee acid, ferulic acid and cinnamon acid in

456 pollen. The inter-day and intra-day precision values of the experiment were less than 9.8% (n = 9),

457 the average recoveries ranged from 93.8% to 115.2% and the EFs of the three analytes ranged

458 between 514 and 1084. In addition, Chen and his group also discussed the mechanism of

459 CNT-reinforcing HF-LPME and thought that hydroxylation CNTs, which are rich in hydroxyls on

460 ports and possess larger specific surface area, are excellent adsorbent; octanols, which not only

461 being rich in hydroxies and having proper polarity, are a good extraction solvent. In a

Page 17 of 59
462 CNTs/octanol dispersed system, each CNT constitutes a SPME unit, and each octanol forms a

463 LPME unit. When the micropore in the HF wall was inlaid or full of CNTs/octanol dispersive

464 solution, each micropore constitutes a CNTs/octanol solid-liquid microextraction (SLME) array or

465 unit beam. The multipath or multiply extraction mode improves the adsorption and extraction

466 capability of the analyte, so the group proposed a HF-CNTs/octanol solid-liquid synergistic

467 microextraction (HF-CNT-O-SLSME) mechanism and defined the synergistic microextraction

t
ip
EFS/L
468 coefficient (SMEC)： RSMEC  . EFS/L , EFS and EFL were the EF of analyte in
EFS  EFL

cr
469 HF-CNT-O-SLSME, in CNTs-SPME and in octanol-LPME, respectively. In the study, the SMEC

470 of coffee acid, ferulic acid and cinnamon acid were 4.2, 2.7 and 1.9, respectively.

us
471 Another useful LPME techniques based on HF is known as HF solvent bar microextraction

472 (HF-SBME) (Fig. 1F), which was first proposed by Huang [191] in 2012 and has been applied to

473
an
separate and concentrate phthalate esters from aqueous matrices. Ma et al. [192] have recently

474 used an improved HF-solvent bar (HF-SB), in which HF of PVDF (1.0 cm) was wraped by
M
475 octanol (about 2 µL) on its outside surface and coupled with HPLC to extract, preconcentrate, and

476 simultaneously determine lipid soluble active ingredients and water–soluble ingredients in Radix
ed

477 Salvia miltiorrhiza. Under the most favourable conditions, the EFs of the analytes were 0.7 to 612,

478 and the LODs were below than 1.11 ng mL–1. Hao and her partener [140] use the improved
pt

479 HF–SBME combined with HPLC to rapidly determine oleanolic acid (OA) and ursolic acid (UA)

480 in TCMs, investigate the protein-binding rates between OA or UA and human serum albumin
ce

481 (HSA), and calculate and obtain the numbers of binding site and binding constants of OA and UA.

482 Compared with HF-LPME or the conventional HF-SBME, the improved HF-SBME did not
Ac

483 require injecting and removing the AP using a microsyringe before and after the extraction, as well

484 as prevented sealing both ends of HF-SB. However, the method has certain limitations, such as

485 susceptibility ofthe AP to pollution by sample impurities or matrix and limited precision because

486 the system is unprotected.

487 A novel microporous membrane/solvent microextraction (MPMSME, as Fig. 1H to Fig. 1J)

488 was recently developed [193, 194] and introduced for extraction and preconcentration of active

489 compounds in TCMs. In this approach, filter paper (or membrane) scrap was cut into small square

Page 18 of 59
490 pieces (1 cm2), which was immersed into the extraction solvent for 10 seconds. Then, the filter

491 paper were removed from the solvent using forceps and placed on absorbent paper to remove the

492 excess extraction solvent on the membrane surface. Afterwards, a solvent-impregnated membrane

493 piece was attached to a clean microsyringe needle that was pre-inserted vertically through the

494 centre of a rubber stopper. The rubber stopper was placed on a vial containing DP, and the

495 membrane was submerged in the DP. Extraction was performed using a magnetic bar at 900 rpm.

t
ip
496 After extraction, the membrane was removed from the needle and placed in double-distilled water

497 for 5 s to wash the impurities or sample matrix. The enriched analytes on the membrane were

cr
498 dissolved in methanol, and the eluate was analysed. Xing et al. [193] selected the cinnamic acid

499

us
derivatives as model analytes to evaluate and assess MPMSME (Fig.1H). Parameters affecting

500 MPMSME, such as type of extraction solvent, membrane area (or volumes of extraction solvent),

501

502
an
pH and ionic strength in DP, extraction stirring rate and time, and DP volume were investigated

and optimized. Under optimized conditions, the EFs of cinnamic acid derivatives ranged from 43

503 to 144, and good linearities were obtained between 4 and 4000 ng mL–1 for all analytes, with
M
504 regression coefficients of between 0.9956 and 0.9977, limits of quantifications were below 0.4 ng

505 mL–1, and the satisfactory recoveries (93% to 106%) and precisions (0.37% to 13%) were also
ed

506 achieved. Soon afterwards, multiple-solvent simultaneous microextraction (MSSME, Fig. 1I)

507 [194], or MPMSME based on two solvents, was presented and introduced to pre-concentrate
pt

508 flavonoids and anthraquinones from TCMs simultaneously. This technique was performed in a
ce

509 single step by using two different solvents (immiscible with each other, but both miscible with

510 methanol) carried respectively by two filter membranes (1 cm2), which were used as extraction
Ac

511 devices. HPLC/UV was subsequently conducted. The variables influencing MSSME were

512 investigated and optimised. The EFs of flavonoids and anthraquinones extracted by two solvents

513 in MSSME were defined, and the formulas were derived. Under optimized conditions, the EFs of

514 the flavonoids ranged from 81 to 104, whereas those of the anthraquinones were from 68 to 132.

515 In addition, the LODs were <0.96 ng mL−1, satisfactory recoveries of 80.1% to 119.2% and

516 precisions of 2.2% to 8.8% were achieved. In MPMSME, the wide exchange surface and low

517 solvent consumption, as well as multiple solvents simultaneous extraction, made this sample

518 pretreatment technology highly compelling.

Page 19 of 59
519 To sum up, LPME techniques based on HF, e.g. HF-LPME, EME, HF-SBME, improved

520 HF-SBME or MPMSME, can not only be employed to extract and concentrate the trace

521 compounds in complex samples but also have the potential for researching the protein-binding of

522 active ingredient in TCMs. Although samples may be stirred or vibrated vigorously without any

523 loss of extracting liquid because of mechanical protection [69], relatively long extraction times

524 and low selectivity are perhaps the major disadvantages of the mentioned [24].

t
ip
525

cr
526 3. Concluding remarks and future prospects

us
527 LPME is a high-potential sampling and sample preparation technique, because of its inherent

528 advantages over conventional procedures, such as simple operation, low cost, low solvent

529

530
an
consumption, speed and high enrichment. LPME coupled to different instrument configurations

(UV, AAS, GC, GC/MS, HPLC, LC/MS, UHPLC, UHPLC /MS) has been widely used in the
M
531 analysis of organic or inorganic compounds in complex samples. In particular, these methods have

532 been applied with success to the analysis of trace or ultra-micro-levels active ingredients in
ed

533 complex TCM samples. Despitethe complex samples generally requiring a prior extraction

534 procedure with a suitable solvent to make the analytes available in a liquid matrix, the overall

535 procedure is still simple, fast and with good EF, and thus high sensitivity or low LOD can be
pt

536 achieved. Among different modes of LPME, HF-LPME has been applied in a higher number of
ce

537 occasions to natural product analysis, possibly considering that method performance is easier than

538 that of SD-LPME, in which drop stability is a crucial step, and offers higher precision than
Ac

539 DLLME, which involves higher contamination by sample impurities in the natural product.

540 Most of these applications have been focused on the extraction of organic analytes in vivo

541 and in vitro, particularly those related to active ingredients in TCMs. However, the applications of

542 the LPME technique in fingerprint and pharmacokinetic studied of TCMs are relatively rare, and

543 few works have been reported about these applications. In addition, inorganic or heavy metal

544 compounds in TCM samples, as another important index of TCM quality control, have been less

545 studied, although the technique has already found a good application area in inorganic analyte

546 extraction from other matrices.

Page 20 of 59
547 From a detailed revision of the literature, a good number of organic solvents are available for

548 LPME applications, thereby extending the potential of the technique. However, for current natural

549 product analysis applications, the growing application of ILs as a new class of solvents has been

550 considered. In fact, a relatively small number of ILs has been proposed in LPME, and exploring

551 their ability to extract the target analytes from such complex samples has potential for further

552 study. In the forthcoming years, the technique may be increasingly applied in numerous analytical

t
ip
553 fields, especially in TCM analysis. In particular, efforts should be focused on the study and

554 development of the use of new extractants. In addition, the establishment of novel LPME or

cr
555 multiclass LPME methods through the combination of different solvents or techniques (like the

556

us
proposed use of EME, MSSME, ILWOS-3p-ME and HF-CNT-O-SLSME) to simultaneously

557 analyse and research different types of active compounds in TCMs that are of particular

558

559
an
importance both in vivo and in vitro is needed, because the multi-component synergy and

integration effect arecharacteristic of the TCM effect on the body. Further improvements in

560 performance, mainly dealing with automation [196-199] or especially adapted instrumentation, are
M
561 also predicted in attempts to fully exploit its potential. Finally, availability of commercialised

562 LPME equipment in the future is likely and highly available.

ed

563
pt

564 Acknowledgments

565 This study was supported by the National Nature Science Foundation of China (No.
ce

566 81041084), the Young Scientists Fund of the National Natural Science Foundation of China

567 (No.81302734), and the Nature Science Foundations of Shanxi Province, China (No.
Ac

568 2011011035-2, 2012011007-4).

569

570 Renference

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931 graphite furnace atomic absorption spectrometry, Anal. Chim. Acta 623 (2008) 163–167.

932 [130] M.S. Bidabadi, S. Dadfarnia, A.M.H. Shabani, Solidified floating organic drop microextraction

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934 graphite furnace atomic absorption spectrometry (GFAAS), J. Hazard. Mater.,166 (2009) 291–296.

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t
940 HPLC with fluorescence detection, Clean 42 (2014) 364–370.

ip
941 [133] R.E. Rivas, I. López-García, M. Hernández-Córdoba, Microextraction based on solidification of a

cr
942 floating organic drop followed by electrothermal atomic absorption spectrometry for the

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946

947
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ed

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951 [136] T. Ahmadi–Jouibari, N. Fattahi, M. Shamsipur, M. Pirsaheb, Dispersive liquid–liquid

952 microextraction followed by high–performance liquid chromatography–ultraviolet detection to

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953 determination of opium alkaloids in human plasma, J. Pharm. Biomed. Anal. 85 (2013) 14–20.
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954 [137] X. Xue, H.F. Zhang, X.H. Bai, Y. Yue, Solidification of superamolecule ordering assembly

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964 microextraction coupled with HPLC-UV as a sensitive and efficient method for the extraction and

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t
970 [142] H. Sereshti, Y. Izadmanesh, S. Samadi, Optimized ultrasonic assisted extraction–dispersive

ip
971 liquid–liquid microextraction coupled with gas chromatography for determination of essential oil of

cr
972 Oliveria decumbens Vent, J. Chromatogr. A1218 (2011) 4593–4598.

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974 using dispersive liquid−liquid microextraction followed by high-performance liquid

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976

977
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978 dispersive liquid–liquid microextraction method, Plant Physiol. Biochem. 49 (2011) 1259–1263.

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980
ed

liquid-liquid microextraction followed by capillary electrophoresis for the analysis of total and

981 water soluble copper in Rhizoma coptidis, Chin. Chem. Lett. 24 (2013) 506–508.

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983 a simple in-vial liquid-phase microextraction device for drug analysis compatible with capillary gas
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984 chromatography, capillary electrophoresis and high-performance liquid chromatography, J.

985 Chromatogr. A 873 (2000) 3–11.

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999 liquid-phase microextraction with sweeping techniques in micellar electrokinetic chromatography

t
1000 for the determination of Strychnos alkaloids in human urine, Chin. Chem. Lett. 18 (2007) 316–318.

ip
1001 [152] C. Wang, C.R. Li, X.H. Zang, D.D. Han, Z.M. Liu, Z. Wang, Hollow fiber-based liquid-phase

cr
1002 microextraction combined with on-line sweeping for trace analysis of Strychnos alkaloids in urine

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1005 determination of nine flavonoids in Polygonum hydropiper L. samples using nanomagnetic powder

1006

1007
an
three-phase hollow fibre-based liquid-phase microextraction combined with ultrahigh performance

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M
1008 [154] G.C. Xi, X. Chen, X.H. Bai, F. Huang, Application of hollow fiber cooperative liquid phase

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1014 Chinese medicine of Magnolia officinalis and its preparations by liquid phase microextraction-back

1015 extraction combined with high performance liquid chromatography, J. Chinese Pharm. Sci. 17

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(2008) 163–166.

1017 [157] L.S. de Jager, A.R.J. Andrews, Preliminary studies of a fast screening method for cocaine and

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1019 Analyst 126 (2001) l298–1303.

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1021 in the analysis of phenylpropionic acids, Chinese J. Anal. Chem. 37 (2009) 35–40.

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1024 B, acteoside and isoacteoside in rat plasma after oral administration of Cistanche salsa extract by

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t
1030 phase microextraction, Chinese J. Chromatogr. 30 (2012) 507–514.

ip
1031 [162] S. Hu, Y.J. Zhang, X.H. Bai, Rapid and simultaneous study on drug–protein binding of four

cr
1032 furocoumarins by hollow fiber liquid phase microextraction, Chromatographia 74 (2011) 503–506.

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us
1034 six flavonoids drugs by hollow fiber liquid phase microextraction, Chinese J. Anal. Chem. 39 (2011)

1035 857–862.

1036

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1038 osthole pharmacokinetics in cerebral ischemia hypoperfusion rat plasma, J. Chromatogr. B 879

1039 (2011) 2304–2310.

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1041 screening and fishing membrane permeation ingredient of coumarins and lignans in traditional

1042 Chinese medicine, Chinese J. Anal. Chem. 41 (2013) 337–343.

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1043 [166] X. Chen, X. Zhang, J. Tian , X.H. Bai, Preliminary screening and analysis of biomembrane
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1044 permeable compounds in herbal medicines: Hollow fiber liposome microscreening combined with

1045 HPLC, Chromatographia 75 (2012) 1395–1403.

1046
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1047 liquid-phase microextraction with back extraction coupled with high performance liquid

1048 chromatography, Chinese J. Anal. Chem. 36 (2008) 182–186.

1049 [168] J. Wang, X. Chen, X.H. Bai, H. Li, Concentration enrichment and chromatographic analysis of

1050 cinnamic acid and its derivatives,a group of low-to-moderately abundant active ingredients in

1051 traditional Chinese medicine by liquid-phase microextraction, Chinese remed. clin. 10 (2010)

1052 625–629.

1053 [169] M. Mirzaei, H. Dinpanah, Three phases hollow fiber LPME combined with HPLC–UV for

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1054 extraction, preconcentration and determination of valerenic acid in Valeriana officinalis, J.

1055 Chromatogr. B 879 (2011) 1870–1874.

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1057 liquid-phase microextraction combined with high-performance liquid chromatography, Biomed.

1058 Chromatogr. 24 (2010) 1350–1355.

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t
1060 liquid-phase microextraction-high performance liquid chromatography, Chinese remed. clin 9

ip
1061 (2009) 375-377.

cr
1062 [172] G.C. Xi, S. Hu, X.H. Bai, Simple and rapid hollow fiber liquid phase microextraction followed

1063 by high performance liquid chromatography method for determination of drug-protein binding,

us
1064 Chem. Res. Chinese U. 27 (2011) 764–768.

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1066

1067
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solid-liquid synergistic microextraction, Chinese J. Anal. Chem. 40 (2012) 510–516.

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M
1068 determination of the concentration of ephedrine and pseudoepedrine based on hollow fiber

1069 liquid-phase microextraction, Chinese J. Chromatogr. 28 (2010) 1144–1149.

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1073 microextraction for analysis of hydroxybenzoic acids, Chinese J. Chromatogr. 27 (2009) 769–775.
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1075 membranes of amphetamine-type stimulants from urine samples followed by high performance

1076
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liquid chromatography analysis, J. Chromatogr. A 1218 (2011)3958–3965.

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1084 104–111.

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1086 Lee, Electromembrane extraction and HPLC analysis of haloacetic acids and aromatic acetic acids

1087 in wastewater, Talanta 86 (2011) 109–113.

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t
1090 [183] M. Ramos–Payán, M. Villar–Navarro, R. Fernández–Torres, M. Callejón-Mochón, M.A.

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1091 Bello–López, Electromembrane extraction (EME)—an easy, novel and rapid extraction procedure

cr
1092 for the HPLC determination of fluoroquinolones in wastewater samples, Anal. Bioanal. Chem. 405

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1096

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1098 Chromatogr. A 1109 (2006) 183–190.

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1100
ed

Callejón-Mochón, Analytical applications of hollow fiber liquid phase microextraction (HF-LPME):

1101 A review, Anal. Lett. 45 (2012) 804-830.

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1103 electromembrane extraction followed by gas chromatography-mass spectrometry analysis, J. Sep.

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1104 Sci. 36 (2013) 736–743.

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1106
Ac

supported liquid membranes forced by pH gradients and electrical fields, J. Chromatogr. A 1157

1107 (2007) 38–45.

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1111 nanotube reinforced hollow fiber solid/liquid phase microextraction: A novel extraction technique

1112 for the measurement of caffeic acid in Echinacea purpurea herbal extracts combined with

1113 high–performance liquid chromatography, J. Chromatogr. A 1217 (2010) 2768–2775.

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1117 with high performance liquid chromatography for preconcentration and determination of

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t
1120 preconcentration of cinnamic acid derivatives in rhizoma typhonii, Chromatographia 77 (2014)

ip
1121 553–559.

cr
1122 [194] L.S. Zhang, R.R. Xing, S. Hu, X. Chen, X.H. Bai, Novel multiple–solvent simultaneous

1123 microextraction for flavonoid and anthraquinone preconcentration in traditional Chinese medicine,

us
1124 Anal. Methods 6 (2014) 1076–1081.

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1126

1127
Methods 5 (2013) 4549–4557. an
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1128 injection system for electrothermal atomic absorption spectrometric determination of trace metals,

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1133 liquid phase microextraction to assess the distribution of organophosphate esters in the pearl river
ce

1134 estuaries, Sci. Total Environ. 470–471 (2014) 263–269.

1135 [199] B. Li, N.J. Petersen, M.D.R. Payán, S.H. Hansen, S. Pedersen–Bjergaard, Design and

1136
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implementation of an automated liquid–phase microextraction–chip system coupled on–line with

1137 high performance liquid chromatography, Talanta 120 (2014) 224–229.

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1141 (2014) 7285-7293.

1142

1143

Page 40 of 59
1143 Fig.1. A schematic of some of these microextraction modies.

1144 : magnetic stirrers; : stirrer; : sample pool; : centrifuge tube; : extracting solvent; :

1145 sample solution; : hollow fibre tube with water soluble acceptor phase (inside) and extraction solvent

1146 (outside)； and : hollow fibre tube with extraction solvent; : hollow fibre film with extraction

t
1147 solvent； : microinjector; : spoon.

ip
1148
1149

cr
Fig.2. Extraction mechanism of phenylpropionic acids by IL-DLLME.

1150 A, the [HMIM][PF6] molecular-ordered organized assembly; B, the carboxyl-imidazole charge transfer

us
1151 superamolecule.

1152 : [HMIM][PF6]; : Phenylpropionic acid.

1153
1154
an
Fig.3. Schematic of PVDF and phenylpropionic acids forming charge transfer supermolecule.

1155
M
ed
pt
ce
Ac

Page 41 of 59
*Highlights (for review)

Highlights

► Modes and mechanisms of different kinds of LPMEs are discussed and summarized.
► Applications of LPMEs in different natural product matrices analysis are summarized.
► Future developments and applications of the LPMEs in complex sample analysis are
prospected.

t
ip
cr
us
an
M
ed
pt
ce
Ac

Page 42 of 59
Figure 1

i
cr
us
an
M
ed
pt
ce
Ac

Page 43 of 59
Figure 2

i
cr
us
an
M
ed
pt
ce
Ac

Page 44 of 59
Figure 3

i
cr
us
an
M
ed
pt
ce
Ac

Page 45 of 59
Table 1

t
ip
cr
Table 1

us
Applications of SD-LPME in natural product analysis.

Extraction
Extraction Donor Analytical Limit of Recoveries Enrichment

an
Sample Analyte Mode time/ Ref.
solvent phase method detection ( %) factor
temperature

α-Pinene

M
β-Pinene
Artemisia β-Caryophyllene
the sample
capillaris (E)-β-Farnesene HS-LPME Dodecane 4 min GC/MS - - - [45]

d
(2.0 g)
Thunb Capillene
Cubenol
β-Eudesmol
te
ep
Pharmaceuticals
iodized salt aqueous sample
Total iodine SD-LPME iso-Octane 15 min GC/MS 10 ng L−1 96.5–107.0 - [70]
milk powder solution
c

vegetables
Ac

4.0 mL
Palmatine 0.5 ng mL−1 88.5–95.0 3556
sample solution 5 min α −1
Human urine Berberine SD-LPME n-Octanol MEKC 0.2 ng mL 105.5–107.7 2114 [71]
containing 500 /30ºC −1
Tetrahydropalmatine 1.5 ng mL 93.1–115.5 1583
mM NaOH

Page 46 of 59
 t
ip
cr
Single-drop
aqueous sample 0.002

us
Green tea Adenine liquid–liquid–liqui Ethyl acetate 10 min CE 99.4 550 [72]
solution μg mL−1
d microextraction

an
Camphor
10 min
Fructus amomi Borneol HS-LPME Cyclohexane aqueous extract GC/MS - - - [73]
/60ºC
Borneol acetate

M
4-Methyl-1-(1-methylethyl)-
bicyclo[3.1.0]hexene
(E)-3,7-Dimethyl-1,3,6-octatrie

d
100 mg of
Zanthoxylum ne
sample powders
bungeanum
Maxim.
linalool

te
3,7-Dimethyl-2,6-octadien-1-ol
3-Methyl-6-(1-methylethyl)-2-
HS-LPME n-Heptadecane
and 5 mL of
water
10 min GC/MS - - - [74]
ep
cyclohexen-1-one
Terpinyl acetate
c

Syzygium
aromaticum
Ac

(L.) 5-7 min

Essential oil HS-LPME Decane 0.4 g of sample GC/MS - - - [75]
Merr. et Perry /100ºC
Cuminum
cyminum L.

Page 47 of 59
 t
ip
cr
β-Pinene 14.8 pL L−1

us
γ-Terpinene 50 mg of sample 6.67 pL L−1
Cuminum
p-Cymene HS-LPME n-Heptadecane powder and 3 5 min GC/MS 10.1 pL L−1 - - [76]
cyminum L.
Cuminal mL of water -

an
Cuminalcohol -

α-Pinene

M
Limonene
the powdered
Myrtus 1,8-Cineole 30 min
HS-LPME n-Octadecane sample GC/MS - - - [73]
Communis L Linalool /40ºC.
(0.6 g ,30 mesh)
Linalyl acetate

d
β-Myrcene

Limonene
γ-Terpinene te the powdered
ep
Foeniculum Fenchone sample 20 min
HS-LPME Benzylalcohol GC/MS - - - [78]
vulgare Mill Estragole (1.0 g ,120 /70ºC.
trans-Anethole mesh)
c

4-Methoxy-benzaldehyde
Ac

β-Elemene,
Curcuma Curzerene, the powdered
wenyujin Y.H. Curzerenone, sample 20 min
HS-LPME n-Dodecane GC/MS - - - [79]
Chen et C. Germacrone, (4.5 g ,120 /70ºC.
Ling Curcumol, mesh)
Isocurcumenol,

Page 48 of 59
 t
ip
cr
Curcumenol

us
Thymus Thymol 1 g sample in 1.87 mg L−1 89–101
HS-LPME n-Pentadecane 2 min GC/FID −1
- [80]
transcaspicus Carvacrol water 0.23 mg L 95–116

an
β-Pinene
p-Cymene the sample (2.0
Cuminum
γ-Terpinene HS-LPME [OMIM][PF6] g) and water (30 30 min GC/MS - - - [81]
cyminum L.

M
Cuminal mL)
Cuminalcohol
α
Micellar electrokinetic chromatography.

d
te
c ep
Ac

Page 49 of 59
Table 2

t
ip
cr
Table 2

us
Applications of DLLME in natural product analysis.

Extraction
Extraction Disperser Donor Analytical Limit of Recoveries Enrichment

an
Sample Analyte Mode time/ Ref.
solvent solvent Phase method detection ( %) factor
temperature

M
pH=3
Tap Vanadium SFODME 1-Undecanol Acetone aqueous 10 s/270℃ ETAAS 7 ng L−1 96–105 184 [28]
solution

d
1.23
Aloe-emodin, 176

Radix et
Rhizoma Rhei
Rhein,
Emodin,
te
DLLME [HMIM][PF6] Methanol
pH 2.0
H3PO4
10 min/
60±1℃,
HPLC、
DAD
0.50
2.02
1.87
95.2–108.5
174
209 [109]
ep
Chrysophanol， solution 192
1.20
Physcion 213
µg L-1
c

Emodin,
70-400
Ac

Aloe-emodin, CHCl3 THF 87.1–105 90–295

pH=1 pg mL-1
Rhein,
Urine samples DLLME aqueous 4 min HPLC/UV [55]
Danthron,
solution 100-1000
Chrysophanol, [HMIM][PF6] Acetonitrile 94.8–103 63–192
pg mL-1
Physcion

Page 50 of 59
 t
ip
cr
Aloe-emodin,

us
Rhein, pH=2
Radix et 0.01-0.09
Emodin, DLLME [HMIM][PF6] Methanol aqueous 7 min/40℃ HPLC 81.7–110.9 80–197 [123]
Rhizoma Rhei µg L−1
Chrysophanol, solution

an
Physcion

Cinnamic acid，
pH=3,

M
Ferulic acid，
127 g L-1
Caffeic acid, 0.01-0.13
Rhizomatyphonii DLLME [HMIM][PF6] THF NaCl 3 min HPLC/UV 86.9–112.6 56.0–159.3 [124]
p-hydroxycinnamic ng mL-1
aqueous
acid,

d
solution
ferulic acid

Human plasma Morphine，

te pH=9,
1% (w/v)
ep
(persons Papaverine， 0.5-5
SFODME 1-Undecano Acetone NaCl 0.5 min HPLC/UV 88–110.5 110.4–165 [136]
addicted to Codeine， mg L–1
aqueous
opium) Noscapine
solution
c

Psoralen, 2.5%(w/v)
Ac

Oxypeucedan, NaCl 1.00-3.0

Radix Angelicae DLLME CCl4 Acetonitrile 3 min HPLC/UV 97.5–114.8 12 6–38.5 [139]
Imperatorin, aqueous mg L-1
Isoimperatorin, Solution

Page 51 of 59
 t
ip
cr
pH=2,

us
Hedyotis, 10%
Diffusa, Oleanolic acid, (w/v) 0.02 933,
DLLME Chloroform Methanol 2 min HPLC/UV –1
85.7–116.2 [140]
Eriobotrya, Ursolic acid NaCl mg mL 1378

an
Japonica aqueous
solution

M
7.4%
Limonene, (w/v)
21 min/ 0.3
Tea plant Cumaldehyde, DLLME Chloroform Methanol NaCl GC/MS - 4.0–42.6 [141]
32℃ mg L−1
Caffeine aqueous

d
solution

Beta-Pinene,
Beta-Myrecene, te
ep
p-Cymene,
Oliveria
Limonene, Aqueous Room 0.2-29
decumbens DLLME Chlorobenzene Acetonitrile GC 89–93 - [142]
gamma-Terpinene, Solution temperature ng mL−1
Vent
c

Thymol,
Carvacrol,
Ac

Myristicine

Indole-3-acetic pH=4,
Chlorella
acid, 7.5% 0.02-0.1
vulgaris, DLLME CHCl3 Acetone 0.1 min HPLC/FLD 94.7–116 10–60 [143]
Indole-3-butyric (w/v) ng mL-1
Duranta
acid, NaCl

Page 52 of 59
 t
ip
cr
Indole-3-propionic aqueous

us
acid, solution
1-Naphthylacetic
acid

an
pH=4,
7.5%

M
Green Gibberellic acid, (w/v) 0.2-1.0
DLLME CHCl3 Acetone 0.1 min HPLC 80–120 - [144]
seaweeds Abscisic acid NaCl of µg mL-1
aqueous
solution

d
Rhizoma
coptidis
Copper
te
DLLME CCl4 Ethanol
1.0%
(w/v)
NaCl of
A few
seconds
CE
32
ng mL-1
88.3–94.4 - [145]
ep
solution
c
Ac

Page 53 of 59
Table 3

t
ip
cr
Table 3

us
Applications of HF-LPME in natural product analysis.

Extraction
Extraction Donor Acceptor Analytical Limit of Recoveries Enrichment
Hollow fibre

an
Sample Analyte Mode time/ Ref.
Solvent phase Phase method detection (%) factor
temperature

liquid

M
Pine needles sonicated
13 Polycyclic
from the Two Polypropylen Hexane or extract in a 0.01-0.95
aromatic Toluene 20 min GC/MS 64-160 [33]
Pinus pinea -phase e Toluene 20% (v:v) ng g-1
hydrocarbons
L. species acetone
solution

d
1.5
Echinophora
platyloba
DC.,
Morin,
Naringenin,
Quercetin, Three te
Polypropylen
1-Octanol pH 2 pH 9.75 80 min HPLC/UV
6
4
0.5 92–99
293
245
16
[149]
ep
Luteolin, -phase e 311
Mentha 7
Kaempferol, 146
piperita 3
Apigenin 216
ng mL-1
c

Strychnine, Three Polypropylen 0.5 mol L-1 100 mmol L-1 1 ng mL-1 50,
Urine 1-Octanol 40 min CE [152]
Ac

Brucine -phase e NaOH H3PO4 2 ng mL-1 35

Rutin,
50 mL of
Hyperin, 10 mmol L-1
original
Polygonum Isoquercitrin, Three Polyvinylide NaHCO3 0.002–0.054
Ethyl acetate extracting 50 min UHPLC/MS 95.2–99.8 36–83 [153]
hydropiper L. Quercitrin, -phase ne fluoride solution; μg L-1
solution (pH
Catechin, pH 8.5
3.0)
Epicatechin,

Page 54 of 59
 t
ip
cr
Quercetin,

us
Kaempferol,
Isorhamnetin

Anisodamine

an
Hydrobromid
e,
Atropine
Raceanisoda Dimethylben
sulphate, 1.0×10-3 mol
mine tablets, Three Polypropylen zene 5×10-3 molL-1 0.01-0.03 mg 95.0–119,
Scopolamine, L-1 100 min HPLC 11-16 [154]

M
belladonna -phase e /n-Heptanol HCl L-1 93.0–95.0
Hydrobromid NH3·H2O
tablets127 (V/V=7:3)
e,
Scopolamine,
Butylbromid

d
e

Magnolia
Officinalis
Magnolol,
Honokiol
Three
-phase rile
te
Polyacrylonit
n-Butanol
pH 5 HCl
(25％
methanol)
pH 12 NaOH 30 min HPLC
0.10 µg mL-1,
0.07 µg mL-1
98.3–105.1 [156]
ep
Caffeic acid,
Shuanghuang
Ferulaic acid,
lian peroral
p-Hydroxyci 35.0,
liquid,
c

nnamic acid, Polyvinylide 50.3,

Danggui Three pH 11.7 0 004–0.1
Methoxy ne n-Heptanol pH 3 HCl 60 min HPLC ＜100. 3 79.2, [158]
concentrate -phase NaOH g L-1
Ac

cinnamic fluoride 128,

pellet,
acid, 83.3
Guizhifuling
Cinnamic
pellet
acid

Plasma Echinacoside 8 642

Fe3O4
(after oral , Two Polypropylen 1.5% (w/v) 15 625
n-Octanol magnetofluid 5 min HPLC/UV 93.2–97.6 [159]
administratio Tubuloside -phase e NaCl. 10 631
n-octanol
n of B, 12 637

Page 55 of 59
 t
ip
cr
Cistanche Acteoside, pg mL−1

us
salsa extract) Isoacteoside

Aloe-emodin,

an
21,
Radix Rhein,
Polyvinylide 2 mmol L-1 21,
Polygoni Emodin, Two 0.25–0.30
ne n-Octanol HCl (50％ n-Octanol 60 min HPLC 75.4–111.5 36, [160]
Multiflori Chrysophano -phase μg L-1
fluoride methanol) 44,
praeparata ,
47

M
Physcion

Aloe-emodin,
Rhein, 20 mmol L-1

d
Danthron, Polyvinylide HCl
Plasma, Two 0.1–0.3 12.2
Emodin, ne n-Octanol (plasma), n-Octanol 40 min HPLC [161]
Urine -phase μg L-1 –26.3
Chrysophano fluoride 12 mmol L-1
,
Physcion
te HCl (urine)
ep
analytical
Psoralen,
drug
Oxypeucedan
Traditional containing
in, Two Polypropylen
Chinese 1-Heptanol serum or 60 min HPLC/UV [162]
c

Imperatorin, -phase e
medicines bovine serum
Isoimperatori
albuminsamp
Ac

n,
les

5 m (2 mL HPLC/
Plasma Two Polypropylen 20 min/ 2
Osthole 1-Octanol plasma n-octanol Fluorescence 93.8–96.3 231 [164]
-phase e 25℃ ng mL−1
sample) detection

Page 56 of 59
 t
ip
cr
Sophora

us
Oxymatrine Three Polyacrylonit Isopropyl 1.0
flavescens pH 9 NaOH pH 4 HCl 30 min HPLC ＜9.4 104.3-114.7 [167]
Matrine -phase rile alcohol mg L-1
Ait

Cinnamic

an
acid,
Traditional Hydroxy-cin
Three Polyvinylide 2.0×10-4 0.008 mol L-1 0.08–0.2 94.7–101.3,
Chinese namic acid, Heptanol 60 min HPLC/UV 100 [168]
-phase ne fluoride mol L-1 HCI NaOH pg mL-1 92.1–105.9
medicines p-Methoxy

M
cinnamic
acid

5.0 mL of

d
Valeriana Valerenic Three Polypropylen aqueous 2.5
Dihexyl ethe pH 9.5 30 min HPLC/UV 87–89 446 [169]
officinalis acid -phase e solution with μg L-1

Urine Aristolochic Three

te
Polypropylen
pH 2.5

NaOH
HPLC/
0.01
ep
1-Octanol pH 3.0 40 min photodiode 61–8 230 [170]
acid I -phase e pH 12 μg L-1
array detector

Aloe-emodin,
c

Emodin,
1.5 mL of
Rhizoma Rhein, Three Polyvinylide 1 mmol L-1 2.9–20.0
Hexanol aqueous 50 min HPLC/UV 103.8–106.1 [171]
Ac

Rhei Chrysophano -phase ne fluoride NaOH ng mL-1

solution
l
Physcion

Atropine analytical
Heptanol:
Traditional sulphate, drug 50 mmol L-1
Three Polypropylen Dimethyl
Chinese Scopolamine, containing hydrochloric 5h/37℃ HPLC/UV [172]
-phase e benzene
medicines Hydrobromid serum or acid
(30:70,V/V)
e bovine serum

Page 57 of 59
 t
ip
cr
albuminsamp

us
les

an
Caffeic acid,
Polyvinylide 514,
Ferulic acid, Three pH 2.1 pH 12.7 0.015
Pollen ne n-Octanol 60 min HPLC 93.8–115.2 942, [173]
Cinnamic -phase HCl NaOH μg L-1
fluoride 1084
acid

M
Ephedrine, Polyvinylide
Ephedra Three 5 mol L-1 0.01mol L-1 <1.9 100.6, 38,
Pseudoephed ne n-Hexanol 35 min HPLC [174]
Sinica stapf -phase NaOH H2SO4 μg L-1 103.2 61
rine fluoride

d
Jatrorrhizine,
Rhizoma
Coptidis
Coptisine,
Palmatine,
Berberine
Three
-phase e
te
Polypropylen
n-Octanol
10-4 mol L-1
NaOH
10-2 mol L-1
HCl
60 min HPLC 12.9-67.5 [175]
ep
3,4,5-Trihydr
oxybenzoic
acid ,
c

3,4-Dihydrox
ybenzoic
Ac

acid,
Polyvinylide
2,4-Dihydrox Three 5 mmol L-1 80 mmol L-1 0.09–30
Calyx Kaki ne n-Heptanol 35 min HPLC 93.3–107.1 107.6 [176]
ybenzoic -phase HCl NH3·H2O μg L-1
fluoride
acid,
4-Hydroxybe
nzcic acid,
3,5-Dihydrox
ybenzoic
acid,

Page 58 of 59
 t
ip
cr
2,5-Dihydrox

us
ybenzoic acid

Caffeic acid,
3,4-dihydrox
Echinacea Three Polypropylen NaOH 0.01

an
y 1-Octanol pH 2.5 25 min HPLC/UV 88.9–94.6 51.60 [177]
Purpurea -phase e (pH 11) mg L-1
cinnamic
acid,

M
Dihydrotansh
inone I,
Cryptotanshi
0.07
none, 369
0.05
Tanshinone I, 375

d
Graphene 0.07
Tanshinone 127
Radix Salvia Two Polyvinylide oxide 0.06
IIA, n-Octanol pH 2 30 min HPLC/UV 84.5–107.5 717 [200]
miltiorrhiza
Salvianolic
acid B,
Danshensu,
-phase

te
ne fluoride attached
n-octanol
0.25
0.92
0.12
ng mL-1
905
24
21
ep
Protocatechui
c
aldehyde
c
Ac

Page 59 of 59