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Identication and semi-quantitative analysis of parabens and UV lters in cosmetic products by direct-analysis-in-real-time mass spectrometry and gas chromatography with mass spectrometric detection
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Manuela Haunschmidt,*a Wolfgang Buchberger,a Christian W. Klampa and Robert Hertsensb

Received 29th September 2010, Accepted 12th November 2010 DOI: 10.1039/c0ay00588f A method based on direct-analysis-in-real-time mass spectrometry (DART-MS) for the qualitative and semi-quantitative analysis of eight organic UV lters and four parabens in twelve cosmetic products with substantially different formulations (as cream, milk, lotion, oil, lipstick) was developed. All tested substances could be identied unambiguously in the investigated samples without any sample pretreatment. Direct analysis of cosmetic products allows semi-quantitative determination of parabens. For UV lters no satisfactory results were obtained by direct analysis but all analytes could be quantied by simply dissolving the samples in methanol, addition of an internal standard and subsequent measurement of the solution by DART-MS without further pre-treatment. The results obtained using DART-MS were conrmed by a more established method namely gas chromatography with mass spectrometric detection (GC-MS).

Introduction
During the last decade, the popularity of cosmetics has increased rapidly. While in earlier times cosmetics were originally developed to add colour or make a fashion statement, modern products also aim to repair damaged skin, reverse visual signs of aging or to provide ultraviolet protection. Cosmetics and skin care products are generally safe and well tolerated. Because of intensive testing of the products before release in the market, most cosmetics do not cause any unwanted reactions in most people. However, some substances which are added to provide preservation or to protect the skin from UV radiation can trigger allergic reactions1,2 or inuence the human body in an adverse way.3 UV lters, mainly organic substances, are often classied as derivatives of cinnamate, anthranilates, benzophenones, camphors, p-aminobenzoates, salicylates and dibenzoylmethanes. These substances can absorb UV light and protect the skin against sunburn, hyperplasia, solar keratosis, photocarcinogenesis and photoaging. Unfortunately, some UV lters can provoke undesirable dermatological side effects like urticaria or allergic reactions of photocontact origin.1 Parabens, esters of p-hydroxybenzoic acid, have a broad antimicrobial spectrum, relatively low toxicity, good stability and low-volatility and are therefore used as preservatives in

a Institute of Analytical Chemistry, Johannes Kepler University Linz, Altenbergerstrasse 69, A-4040 Linz, Austria. E-mail: manuela. haunschmidt@jku.at; Fax: +43 732 2468 8679; Tel: +43 732 2468 8720 b JEOL (Europe) BV, Leuvensesteenweg 542, B-1930 Zaventem, Belgium

cosmetic products. The toxicity of the parabens is still under discussion. They are suspected to act as endocrine disrupting substances and provoke breast cancer.4,5 For all these reasons, the analysis of cosmetic products is an important necessity, especially with respect to safety and health issues. Accordingly the main focus lies on the development of rapid and simple analytical methods and screening techniques for this purpose. In the past, high performance thin layer chromatography (HPTLC) was a widely used method68 for the determination of UV lters in cosmetic products. Over the last few years, several methods based on gas chromatography (GC) and liquid chromatography have been implemented. Although UV lters have relatively high boiling points, making them less suited for GC analysis, several successful examples for their identication913 and quantitation12,13 using this technique have been described. GC was also found to be suited for the determination of parabens (after derivatisation) in cosmetic products.1416 However, high performance liquid chromatography (HPLC) is usually the preferred method for quantitative analysis of these two groups of substances, whereby UV-vis detection is commonly used for both UV lters1720 and parabens.15,2123 Focusing on alternative analytical techniques, some electroseparation methods such as micellar electrokinetic chromatography24 and microemulsion electrokinetic chromatography25,26 have also been employed for this purpose. Despite the fact that these methods provide quantitative results they are affected with one main drawback: they are commonly quite time- and labour-consuming. Sample preparation steps are necessary and the separation often takes more than
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30 minutes per run. Often e.g. for the screening of cosmetics a qualitative or at least semi-quantitative analysis of UV lters and parabens would be enough. For this reason methods that can provide the requested information with a reduced effort regarding time and labour would be highly desirable. Direct-analysis-in-real-time mass spectrometry (DART-MS) is a relatively new analytical technique allowing the measurement of solid, liquid and gaseous samples directly without further sample pre-treatment.27 Coupled with a mass spectrometer providing sufcient resolution (like a time-of-ight instrument), spectra with exact masses are obtained within a few seconds, allowing the unambiguous identication of the analytes in samples with different matrices. Up to now DART-MS has been employed for the determination of a variety of substances in diverse types of samples. Focusing on the classes of compounds discussed in the present paper, DART-MS was found useful for the determination of UV lters in environmental water samples after an enrichment procedure by stir bar sorptive extraction.28 Main aim of the present work is to introduce a rapid and simple method for direct analysis of a wide range of different cosmetic products (like lotion, cream, suntan oil, make-up and lip care product) with respect to the presence of eight widely used UV-lters and four parabens. A major advantage of this approach employing DART-MS over previously described methods for the analysis of cosmetic products is the fact that even for semi-quantitative determination no (for parabens) or only very little (for UV lters) sample pretreatment is required.

Experimental
Standards and samples The names and the structures of the tested UV lters and parabens are summarised in Fig. 1. All UV lters, the two internal standards benzyl cinnamate (BC) and 4-hydroxybenzoic acid (4-HBA) and methanol (of chromatographic analysis grade) were obtained from Merck (Darmstadt, Germany). The parabens were purchased from Sigma-Aldrich (Steinheim, Germany). All used chemicals were of analysis grade. Two stock solutions were prepared in methanol: one containing UV lters at a concentration level of 1 mg mL1 and a second one containing parabens at a level of 0.1 mg mL1. These stock solutions were stored at 4  C and protected from sunlight. The standard solutions were prepared daily directly before use by dilution of the stock solutions with methanol to the nal working concentrations. Internal standard solutions were prepared by dissolving 50 mg BC in 50 mL methanol, or 5 mg 4-HBA in 50 mL methanol. To demonstrate the suitability of DART-MS for the direct detection of UV lters and parabens in sun protection products, model samples were prepared by weighing specied amounts of the tested substances to a commercially available cream (blank cream), which did not contain any of the analytes (this was previously checked by GC-MS). The compositions of these samples were: sample I (HMS, EHS, OD-PABA, OC), sample II (BP-3, BM-DBM, 4-MBC, EHC) and sample III (methyl-, ethyl-, propyl-, butylparaben) with each UV lter added to a concentration of about 5% (250 mg to 5 g cream) and with each paraben added to a concentration of 0.3% (1.5 mg to 5 g cream). After homogenisation the model samples were directly measured by DART-MS. For establishing calibration curves, again three different types of model samples corresponding to I, II and III; (see above) with concentration ranges of 1.0 to 10% UV lters and 0.05 to 5.0% parabens (representing the relevant range for real samples) were prepared. As internal standards 5% BC and 0.5% 4-HBA were added. In addition to the model samples, real samples such as suntan cream, lotion, milk, oil, make-up and lipstick were analysed. For the qualitative and semi-quantitative analysis by DART-MS the samples were just spiked with the internal standards (5% for BC and 0.5% for 4-HBA) and directly measured without further pretreatment. For analysis of dissolved samples by DART-MS and GC-MS 100 mg of the sample were treated with 5 mL methanol by positioning the ask in an ultrasonic bath for 10 min. Not all components of the sun protection products were soluble in methanol (e.g. titanium dioxide, other pigments). Therefore, samples had to be ltrated through a 0.45 mm membrane lter before GC-MS measurements, whereas for DART-MS measurements no ltration was needed. For quantication 50 mL of internal standard were added to 100 mL of the sample solution and lled up to 1 mL with methanol. The solution was then ready for analysis.

Instrumentation
DART-MS
Fig. 1 Structure of the UV lters, parabens and the internal standards included in this study.

All DART-MS measurements were performed with an ion source from IonSense, Inc. (Saugus, MA, USA) coupled to
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a JMS T100 LP (AccuTOF-LC-plus) time-of-ight mass spectrometer (JEOL, Peabody, MA, USA). The analysis of the UV lters was performed in the positive ion mode and the following voltages were applied to the ion source: orice 1, 10 V; orice 2, 5 V; and ring electrode, 10 V. For the parabens the negative ion mode and the same voltages as for the UV lters were used. Orice 1 was always operated at a temperature of 120  C to avoid contamination and the ion guide potential was set to 600 V. For operation of the DART source helium gas (4.6) was employed, whereas nitrogen gas was used in the standby mode. Optimum alignment of the DART orice and the MS orice was achieved by monitoring the signal intensity for the water cluster (m/z 37.0290). Mass calibration in the positive ion mode was carried out employing polyethylene glycol 600 (PEG 600) from Baker (Deventer, The Netherlands) as a solution of 50 mL PEG in 10 mL methanol/dichloromethane, 50/50. In the negative ion mode a mass calibration mix containing the following substances was used: benzoic acid (m/z 121.0295), 2,4-dihydroxybenzoic acid (m/z 153.0193), veratric acid (m/z 181.0506), and 1,3,5-benzenetricarbonic acid (m/z 209.0092) (all purchased from Sigma Aldrich) dissolved in methanol. Measurements were performed by dipping a Dip-IT glass rod (IonSense) into the respective solution and placing it into the DART source. Data acquisition was performed for both ion modes in a range from 100 to 400 m/z for all analytes. To achieve reproducible positioning of the glass rods in the ion source a lab-made modied Dip-IT holder was used. GC-MS The GC-MS measurements were carried out with a 6890N Network gas chromatograph coupled to a 5973 Network MSD mass spectrometer from Agilent (Waldbronn, Germany). The injection was performed in the splitless mode for the UV lters and in split mode (split: 1 : 20) for the parabens. The separation was carried out on an HP-5ms fused silica column (30 m 0.25 mm i.d.; 0.25 mm lm thickness, Agilent) in constant ow mode. The temperature program of the oven started at 70  C (held for 2 min), then the temperature was increased in a rst step to 160  C at 20  C min1 and in a second step to 280  C at 8  C min1. Helium was used as a carrier gas with a column ow rate of 1 mL min1. The mass spectrometer was operated in the selected ion monitoring (SIM) mode at the following m/z for the UV lters: 120.00, 138.00, 181.00, 251.00 (0 to 11.5 min); 120.00, 138.00, 261.00 (11.5 to 12.5 min); 131.00, 151.00, 227.00, 254.00 (12.5 to 15.5 min); 148.00, 165.00, 277.00 (15.5 to 17.0 min); and 204.00, 249.00, 360.00 (17.0 min to end of the run). The following m/z were selected for the parabens: 93.00, 121.00, 138.00, 152.00, 166.00 (5 to 10.0 min); 93.00, 121.00, 138.00, 180.00, 194.00 (10.0 to 15.0 min); and 131.00, 191.00, 238.00 (15.0 to end of the run). The bold numbers given above indicate the m/z ratios used for quantitative analysis.

methanol and directly measured by dipping a Dip-IT glass rod into the solution and subsequently positioning it into the helium gas stream of the ion source. The following parameters were investigated in order to achieve the highest signal intensity: temperature of the gas heater on the ceramic tube (50450  C in 50  C steps); helium gas ow; needle voltage (20004000 V in 500 V steps); discharge electrode and grid electrode voltages (50300 V in 50 V steps). Optimum parameters were: needle voltage 3500 V, discharge electrode and grid electrode voltages 100 V and 50 V respectively. The optimum heater temperature was 200  C. Due to their different chemical structures, UV lters provided higher intensities in the positive ion mode (detecting [M + H]+) whereas for parabens the negative ion mode (detecting [M H]) was favored. The conditions elaborated with solutions were also rechecked for the UV lters and the parabens spiked into a cosmetic cream. Comparing results from these experiments for UV lters and parabens respectively indicate that the optimal conditions for DART-MS are the same for both groups; only the ionisation mode has to be changed from positive to negative. A list of all analytes together with measured exact masses in the positive/negative ion mode is provided in Table 1.

Direct analysis of model samples and real samples After the optimisation of the DART parameters the suitability of this novel technique for direct identication of UV lters and parabens in real samples was checked by measuring model samples IIII (see Experimental section). For this purpose, a Dip-IT glass rod was dipped into the model sample, gently wiped off with a lint-free cloth and directly placed into the DART ion source. All tested substances could be detected in the cream and no interferences from the matrix occurred. In the next step twelve sun protection products of different formulations like suntan oil, suntan cream, milk, lotion, lipstick
Table 1 Summary of measured masses, calculated masses and error of masses for UV lters and parabens measured under the optimised DART conditions (see Instrumentation) [M + H]+ Analyte EHS HMS BP-3 4-MBC OD-PABA OC BM-DBM EHC Empirical formula C15H22O3 C16H22O3 C14H12O C18H22O C17H17NO2 C24H27NO2 C20H22O3 C18H26O3 Calculated mass 251.1642 263.1612 229.0895 255.1685 278.2148 362.2214 311.1653 291.1975 [M H] Analyte MP EP PP BP Empirical formula C8H8O3 C9H10O3 C10H12O3 C11H14O3 Calculated mass 151.0401 165.0557 179.0714 193.0870 Measured mass 151.0403 165.0548 179.0725 193.0872 D 0.0002 0.0009 0.0011 0.0002 Measured mass 251.1652 263.1627 229.0877 255.1714 278.2131 362.2165 311.1648 291.1965 D 0.0010 0.0015 0.0018 0.0029 0.0016 0.0050 0.0006 0.0010

Results and discussion

Optimisation of DART-MS parameters for the analysis of standard solutions and model samples To nd the best DART parameters for the determination of UV lters and parabens, solutions of the analytes were prepared in
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and make-up were measured directly. The measurement was performed in the same way as done for the model samples. By obtaining exact masses for the components, an unambiguous identication was possible for all tested analytes. A DART-MS spectrum of suntan oil #2 is depicted in Fig. 2 (UV lters, detected in the positive ion mode) and for the suntan lotion in Fig. 3 (parabens, detected in the negative ion mode). As can be seen from these gures, the selected cosmetic products could be analysed directly and all UV lters and parabens present in these samples were unambiguously identied based on the exact masses. The results were conrmed by GC-MS measurements, whereby pre-treatment of the samples was necessary hereby (dissolving and ltration of the sample). To investigate the applicability of DART-MS also for the analysis of samples with rather low content in UV-lters and parabens, the lowest detectable concentrations of these compounds in cosmetic products were determined. They were found to be between 2.5 mg g1 (BP-3) and 460 mg g1 (OC) for UV lters and between 0.14 mg g1 (methylparaben) and 0.3 mg g1 (butylparaben) for the parabens. This can be seen as sufcient with respect to concentrations expected in real samples.29 Furthermore investigations on the possibility of semi-quantitative analysis of cosmetic products with respect to their

content in UV-lters and parabens were performed. For reproducibility of results, the positioning of the Dip-IT glass rod in the DART source is the most crucial point. Unfortunately, no autosampler was available for this work and the use of a Dip-IT holder did not allow a sufciently exact positioning. Therefore an internal standard was used for area correction. Best choice as an internal standard for UV lter determination was BC, being well ionised in the positive ion mode; for parabens 4-HBA, which is accessible in the negative ion mode, was used. Spiked samples with concentration ranges from 1 to 10% for UV lters (plus 5% BC as internal standard) and from 0.05 mg mg1 to 5 mg mg1 for parabens (plus 0.5 mg mg1 4-HBA as internal standard) were prepared. These samples were directly measured as described above. For the parabens quite good correlation coefcients (R > 0.98) were achieved with an acceptable repeatability better than 40% relative standard deviation (n 5). These results indicate that although DART-MS without a dedicated autosampler (that might improve reproducibility) cannot provide quantitative results at least semi-quantitative analysis is possible. Due to their low volatility, UV lters are much slower desorbed from the glass rod and ionised than parabens. Whereas parabens usually give a very sharp signal immediately upon placing the rod in the ion source (indicating a quantitative desorption from the glass rod), UV lters yielded a broader and smaller peak, making quantitation less reliable. For this reason only qualitative results could be obtained for UV lters. For parabens, the concentrations found by DART-MS were in the same order of magnitude as those from GC-MS measurements. Analysis of dissolved samples In order to improve the quality of the (semi-) quantitative determination of the selected compounds in cosmetic products, a simple sample pre-treatment procedure, namely solution of the products in methanol, was tested. As in this case standard solutions of the UV-lters and parabens prepared in pure methanol are used for comparison, eventual suppression effects caused by the matrix of the cosmetic products investigated had to be evaluated rst. Therefore, standard solutions at concentrations of 100 mg mL1 (for UV lter) and 10 mg mL1 (for parabens) were prepared by diluting the standard stock solution. Subsequently, 500 mL of each standard solution were mixed with 50 mL internal standard (BC and 4-HBA respectively) and 0, 100, 200, 300, 400 or 500 mL of a solution of cosmetic cream (100 mg blank cream in 5 mL methanol) and nally lled up with methanol to 1 mL. The results showed that peak areas were independent on the content of cream, so matrix effects could be regarded negligible. In the next step the calibration for the UV lters was performed at concentrations of 10, 25, 50, 75, 100 mg mL1 of each UV lter (with 50 mg mL1 of BC as internal standard) and 0.1, 0.5, 1.0, 2.5, 5.0, and 10 mg mL1 of each paraben (with 5 mg mL1 of 4-HBA as internal standard). Each concentration level was measured four times. The calibration curves were calculated by plotting the ratio of the analyte signal area/internal standard signal area versus concentration. Correlation coefcients R > 0.975 (for UV lters) and R > 0.995 (for parabens) were achieved, which seems to be sufcient for semi-quantitative analysis.
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Fig. 2 DART-MS spectrum of suntan oil #2 measured directly without further sample pre-treatment (positive ion mode). For signal assignments see Fig. 1 and conditions see Experimental.

Fig. 3 DART-MS spectrum of sun milk measured directly without further sample pre-treatment (negative ion mode). For signal assignments see Fig. 1 and conditions see Experimental.

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Table 2 A comparison of results for UV lters determined by DART-MS and GC-MS for different cosmetic products DART-MS (%)/GC-MS (%) Sample Sun cream 1 Sun cream 2 Sun milk Sun cream 3 Sun lotion Suntan oil 1 Suntan oil 2 Face cream 1 Face cream 2 Make-up 1 Make-up 2 Lipstick
a

EHS 2.4/3.0 2.1/2.4 5.0/4.6

a

HMS 6.9/7.1

BP-3 5.4/4.2

4-MBC 3.7/2.4

OD-PABA

OC 7.5/10.0 8.0/8.3 8.0/8.9 3.3/3.7 1.9/2.3 2.2/1.9

BM-DBM 2.3/2.9 1.2/2.3 2.5/2.4 1.4/1.5 3.4/3.8 3.2/3.9 2.8/2.1

EHC 10.1/7.5 16.7/10.0 8.9/6.1 5.5/2.7 6.8/4.1 13.9/7.8

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not present in the sample.

The repeatability (n 10) was determined for a cosmetic cream containing 5% of each UV lter and 0.05% of each paraben; relative standard deviation ranged from 4% (for EHS) to 30% (for HMS) for UV lters and from 8% (for butylparaben) to 15% (for methylparaben) for parabens. Subsequently recoveries were determined by analysing the model samples IIII; recoveries ranged from 71% (for OD-PABA) to 120% (for EHS) for the UV lters and from 73% (for methylparaben) to 86% (for ethylparaben) for the parabens. As mentioned above, GC-MS measurements were performed in order to conrm the results achieved by DART-MS. For calibration of GC-MS, the same standard solutions as for DART-MS were used. Correlation coefcients of the calibration curves were R > 0.994 for UV lters and R > 0.999 for parabens. For GC-MS the samples were dissolved in methanol and ltrated before injection. It has to be mentioned that such minimised sample pre-treatment is unusual for the analysis of complex and oily matrices like cosmetic products. Generally, isolation of the analytes from the sample matrix is performed to protect the GC system from contamination. In the present case the simple sample preparation did not lead to problems with GC-MS, besides the necessity of a frequent change of the injection liner.

Analysis of real samples Finally, twelve cosmetic products (all providing sun protection) with six completely different formulations were analysed (after dilution with methanol) and their content of UV lters and parabens determined. The concentrations of the UV lters in all tested samples obtained by DART-MS and GC-MS are summarised in Table 2 and those of the parabens in Table 3. Data given in these tables are based on four replicate measurements for DART-MS and single measurements for GC-MS. As can be seen from these tables comparable results were achieved by DART-MS and GC-MS whereby some minor discrepancy was observed for cosmetic products with a high amount of inorganic pigments like make-up samples.

Conclusion
DART-MS has been successfully applied for the detection of UV lters and parabens in various cosmetic products. All eight UV lters and four parabens under investigation could be identied unambiguously in cosmetic matrices by direct measurement without any previous sample treatment. For the parabens also semi-quantitative determination was possible directly from the sample; this could not be realised for UV lters. A simple dissolution of the cosmetic product in methanol and addition of an internal standard also allowed the semi-quantitative analysis of UV lters. The results obtained by DART-MS were comparable to those achieved with GC-MS. As can be seen from this work DART-MS is a suitable tool for the fast and simple characterisation of cosmetic products with respect to their semi-quantitative content in two major classes of ingredients namely UV lters and parabens.

Table 3 A comparison of results for parabens determined by DARTMS and GC-MS for different cosmetic products (DART-MS/mg mg1)/(GC-MS/mg mg1) Sample Sun cream 1 Sun cream 2 Sun milk Sun cream 3 Sun lotion Suntan oil 1 Suntan oil 2 Face cream 1 Face cream 2 Make-up 1 Make-up 2 Lipstick
a

MP a 1.8/1.9 1.3/1.6 1.0/1.4 2.6/2.6

EP 0.9/0.9 n.q.b/0.6 0.9/1.1

PP 1.0/1.2 0.5/0.8 0.4/0.7 0.9/1.2

BP 1.0/1.0 0.8/0.9

Acknowledgements
The authors gratefully acknowledge JEOL (Europe) BV, Zaventem, Belgium for providing the DART-AccuTOF.

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