Analytical method for the determination and a survey of parabens and their derivatives in pharmaceuticals Cristina Moreta a,b , María-Teresa Tena b , Kurunthachalam Kannan a,c,n a Wadsworth Center, New York State Department of Health, Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Empire State Plaza, P.O. Box 509, Albany, New York 12201-0509, USA b Department of Chemistry, University of La Rioja, C/Madre de Dios 51, E-26006 Logroño, La Rioja, Spain c Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia article info Article history: Received 24 June 2015 Received in revised form 20 July 2015 Accepted 21 July 2015 Keywords: Parabens Pharmaceuticals Liquid chromatography Mass spectrometry Human exposure abstract Exposure of humans to parabens is a concern due to the estrogenic activity of these compounds. Para- bens are widely used as preservatives in some personal care products, foodstuffs and pharmaceuticals owing to their low cost, high water solubility and broad spectrum antimicrobial properties. Despite this, little is known on the occurrence of parabens in pharmaceutical products. In this study, a method based on solid–liquid or liquid–liquid extraction (SLE or LLE), and high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (QqQ or MS/MS) was developed for the determination of six most frequently used parabens and four paraben derivatives (methyl- and ethyl- protocatechuates, and mono- and di-hydroxybenzoic acids) in pharmaceuticals. A sample-purification step involving solid phase extraction (SPE) was optimized for the analysis of solid and lipid-rich phar- maceuticals. To our knowledge, this is the first comprehensive report on the occurrence of parabens in pharmaceuticals. The developed method was applied for the analysis of 128 liquid/syrup, cream, solid, prescription or over-the counter (OTC) drugs collected from the USA and a few other countries in Europe and Asia. Although majority of the drugs analyzed in the study did not contain parabens, concentrations as high as 2 mg/g were found in some drugs. Methyl- and propyl- parabens were the frequently detected compounds. 4-Hydroxybenzoic acid was the major metabolite found in pharmaceutical products. & 2015 Elsevier Inc. All rights reserved. 1. Introduction Parabens are alkyl esters of 4-hydroxybenzoic acid (4-HB) and are widely used as preservatives in consumer products including processed foodstuffs (Liao et al., 2013a,b), cosmetics (Guo and Kannan, 2013; Guo et al., 2014; Baranowska et al., 2014), toiletries (Guo and Kannan, 2013; Guo et al., 2014; Baranowska et al., 2014), paper products (Liao and Kannan, 2014) and pharmaceuticals (Baranowska et al., 2014) due to their low cost, effectiveness over a wide range of pH, high stability, water solubility and a broad spectrum antimicrobial activity. In particular, preservatives are added to pharmaceuticals to prevent any microbial growth and/or degradation of the drug (i.e., to increase the shelf-life). Studies have shown that parabens possess a weak estrogenic activity (Routledge et al., 1998). The most commonly used parabens are methyl-, ethyl-, propyl-, butyl-, benzyl- and heptyl- parabens and the estrogenic activity of these compounds increases with the length of the alkyl chain (Routledge et al., 1998). Parabens are considered as endocrine disrupting compounds. Some studies have associated a decrease in sperm production or an increase in the incidence of breast cancer and malignant melanoma to para- ben exposures (Oishi, 2002a, 2002b; Darbre et al., 2004; Darbre and Harvey, 2008; Witorsch and Thomas, 2010). Concomitant with an increase in the understanding of tox- icological properties of parabens, the European Union has lowered allowable maximum concentrations of propyl- and butyl- para- bens in cosmetics from 0.4% when used individually and 0.8% when mixed with other esters, to 0.14% when used individually or in mixture (Bernauer et al., 2013). In addition, the use of propyl- and butyl- parabens is banned in cosmetics intended for children under three years of age (Angerer et al., 2011). Human exposure to parabens is a concern, and sources of hu- man exposure to parabens are not fully characterized. A few stu- dies have reported the occurrence of parabens in consumer pro- ducts including processed foods and personal care products (Liao and Kannan, 2014; Guo et al., 2014; Baranowska et al., 2014; Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/envres Environmental Research http://dx.doi.org/10.1016/j.envres.2015.07.014 0013-9351/& 2015 Elsevier Inc. All rights reserved. n Corresponding author at: Wadsworth Center, New York State Department of Health, Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Empire State Plaza, P.O. Box. 509, Albany, NY 12201-0509, USA. Fax: þ1 518 473 2895. E-mail address: kurunthachalam.kannan@health.ny.gov (K. Kannan). Environmental Research 142 (2015) 452–460