Forensic Chemistry 10 (2018) 5–14 Contents lists available at ScienceDirect Forensic Chemistry journal homepage: www.elsevier.com/locate/forc Development and validation of fast liquid chromatography high-resolution mass spectrometric (LC-APCI-QToF-MS) methods for the analysis of hexamethylene triperoxide diamine (HMTD) and triacetone triperoxide (TATP) Lisa Dunn ⇑, Hamda Sultan Ali Al Obaidly, Saif Eldin Khalil General Department of Forensic Science and Criminology, Dubai Police General Headquarters, Dubai, United Arab Emirates a r t i c l e i n f o Article history: Received 7 September 2017 Received in revised form 26 June 2018 Accepted 26 June 2018 Available online 30 June 2018 a b s t r a c t Two semi-quantitative, fast liquid chromatography-mass spectrometry methods have been developed using an atmospheric pressure chemical ionisation source in conjunction with an accurate mass detector (LC-APCI-QToF-MS) for the analysis of traces of the peroxide explosives hexamethylene triperoxide diamine (HMTD) and triacetone triperoxide (TATP). A comprehensive validation was conducted on each method and is presented herein. The limits of detection (LOD) for HMTD and TATP using these methods were determined to be 0.5 ng and 10 ng on column, respectively. The high mass accuracy and narrow mass detection window offer high selectivity with <2 ppm mass difference between measured and calculated values for HMTD. This paper supports recent work performed using ESI-TOF and Orbitrap that demonstrates that the 207.0614 ion observed during the analysis of HMTD is in fact [TMDDD + H]+, and not [M-1]+. Ó 2018 Elsevier B.V. All rights reserved. 1. Introduction Hexamethylene triperoxide diamine (HMTD) and triacetone triperoxide (TATP) are peroxide explosives, Fig. 1. Both HMTD and TATP can be made from readily available precursor materials; the principal ingredients are usually hydrogen peroxide and acetone (for TATP), or hexamine (for HMTD). Preparation is done in the presence of an acid catalyst, typically: citric, sulphuric or hydrochloric acid. Detailed instructions and videos are available on the internet. Although these explosives are relatively easy to make, the process is hazardous since these primary high explosives are very sensitive to initiation and are relatively powerful; HMTD and TATP have TNT equivalences of around 60% and 88%, respectively [1–3]. TATP was first encountered in the 1980s in Israel, and in the early 1990s in the UK [4,5]. Terrorist use of peroxide explosives has not waned in recent years; in fact, the use of TATP has continued to be used across much of the world [6–8]. HMTD and TATP are not used commercially or by the military due to their high sensitivity and poor stability; this means that traces of these explosives would not be expected to be encountered in the general environment. In any case, both explosives exhibit low persistence in the environment and in the case of TATP, persistence is very ⇑ Corresponding author. E-mail address: ldunn@dubaipolice.gov.ae (L. Dunn). https://doi.org/10.1016/j.forc.2018.06.003 2468-1709/Ó 2018 Elsevier B.V. All rights reserved. low because it readily sublimes, so any microscopic residue remaining after an explosion would be rapidly lost. This means that the presence of nanogram quantities of HMTD and TATP in both pre-blast and post-blast trace samples can be highly significant; its detection can aid in establishing links between a suspect and an explosives incident [9]. Thus, there is a need for reliable and sensitive analytical methods that can unambiguously detect these peroxide explosives. Analysis of HMTD and TATP is relatively straightforward for visible quantities of sample. Methods are well-documented, and predominantly focus on techniques such as presumptive colour tests, thin layer chromatography (TLC), FTIR and Raman spectroscopy. However, there are limitations associated with these methods, particularly when analysis of trace amounts of sample is required. Commercially available presumptive colour tests designed to detect peroxide explosives generally lack specificity and can give false indications if interferents are present in the sample; hydrogen peroxide itself can give positive results for these tests. The LODs tend to be in the region of 100 ng/mL for HMTD and TATP; this is insufficient for most trace analysis casework. Published TLC methods mainly focus on using visualisation reagents comprising either 1% diphenylamine in sulphuric acid or 1% thymol in sulphuric acid. The methods are time consuming and the LODs achievable are in the region of 30–50 ng for both analytes; although an improvement on colour tests, TLC is not adequately sensitive for most trace 6 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Fig. 1. Structure of (a) TATP, (b) HMTD and (c) TMDDD. analyses. Additionally, TLC results need to be confirmed via another technique due to its poor specificity. Since HMTD and TATP lack chromophores, direct analysis by HPLC-UV is not possible so UV absorption cannot be used as another identification criterion. HMTD and TATP have characteristic FTIR and Raman spectra. However, interpretation of spectra can become complex when samples also contain other FTIR and Raman active components; this is the case for post-blast samples which typically comprise complex matrices. For such samples, analytical methods must exhibit a high degree of selectivity to enable the analyte of interest to be distinguished from other substances present in the sample. For analysis of some analytes, gas chromatographic (GC) separation prior to FTIR analysis could simplify interpretation of results, whilst simultaneously providing additional analyte confirmation in the form of retention time. However, analysis of peroxide explosives by GC methods is difficult to achieve because of thermal decomposition and activation of the column stationary phase; in the case of TATP, this can happen rapidly [10–20]. On the other hand, LC/MS is well suited for analysing peroxide explosives since thermal decomposition of the analytes is less likely to occur. In general, the greater the number of characteristic ions seen, the greater the level of confidence in the analyte being correctly identified. Analysis of these analytes using LC/MS and LC/MS/MS with APCI+ ionisation is well-documented [20–23]. Of the two techniques, LC/MS/MS analysis is preferred due to increased sensitivity and the ability to monitor selected reactions. LC/MS analysis for HMTD results in the formation of many characteristic ions that typically include m/z 209.0768 and 207.0975, corresponding to [M + H]+ and [C7H15O5N2]+, respectively [10,22– 26]. In contrast, TATP does not form stable ions under APCI conditions, thus a chemical such as ammonium acetate or formate is often added to the mobile phase to facilitate the formation of stable adduct ions [20,21]. TATP has few characteristic ions, typically m/z 240.1441 and 89.0597, corresponding to [TATP + NH4]+ and [C4H9O2]+ [10,20,21,24,26]. To achieve a high degree of confidence for TATP identifications, it is common for forensic laboratories to analyse samples in full scan and MS/MS mode for the positive identification of TATP [21,24]. The downside to performing LC/MS and followed by LC/MS/MS analysis is the increased analysis time required. Advancements in LC/MS have led to liquid chromatography time-of-flight mass spectrometry (LC-QToF-MS) instruments. High resolution analysis of organic and peroxide explosives has been reported using quadrupole time-of-flight mass spectrometers and using Orbitrap instruments [24–26]. LC-QToF-MS analysis allows analysts to gain more information about analytes due to the high resolution that offers greater ability to separate the target mass from interfering masses. Since mass information is accurate to within 3 ppm, the number of potential compounds is limited and therefore greater confidence in analyte identification is achieved as the possible number of candidate compounds is considerably lower than with conventional mass spectrometry systems [27]. Additionally, the feature of all-scan, all-the-time TOF data also allows retrospective data analysis to search for analytes that may be present, but which were not originally sought. This could be useful for historical searching for other analytes that are not routinely screened for at this laboratory, such as diacetone diperoxide (DADP) and methyl ethyl ketone peroxide (MEKP), in cases where it is later suspected that they might have been manufactured or used. This is a significant advantage over traditional LC/MS/MS, which only acquires data for specific ion transitions. The aim of this work was to develop fast and accurate methods for the analysis of HMTD and TATP using an ultra-performance liquid chromatography (UPLC) column in conjunction with an Agilent 6540 Ultra High Definition Accurate-Mass QToF Mass Spectrometer. This paper presents two separate methods developed and comprehensively validated for the semi-quantitative analysis of HMTD and TATP. This paper supports recent work performed using ESITOF and Orbitrap that demonstrates that the 207.0611 ion observed during the analysis of HMTD is in fact [TMDDD + H]+, and not [M-1]+, as widely reported [28,29]. The authors believe that this paper is the first to confirm the presence of this TMDDD ion using accurate mass with APCI-TOF. 2. Materials and equipment 2.1. Materials Explosive standards of hexamethylene triperoxide diamine (HMTD) and triacetone triperoxide (TATP) were obtained from AccuStandard Inc., (New Haven, USA). Both standards (M-8330ADD-25 and M-8330-ADD-24) were supplied as 100 ng/mL solutions in acetonitrile. HMTD and TATP standards were diluted using LC-MS CHROMOSOLVÒ acetonitrile (Fluka Analytical, 34967-2.5L) to obtain the desired concentration of analyte in solution. The mobile phases were prepared using LC-MS CHROMOSOLVÒ methanol (Fluka Analytical, 34966-2.5L) and deionised water (>18. 2 MXcm), purified using a Millipore Milli-Q Gradient A10 system. Ammonium acetate with a purity >99% (Fluka Analytical, 73594100G-F) was used as a buffer for the TATP method mobile phase. A Waters Acquity UPLC HSS C18, 1.8 mm, 2.1 x 50 mm column (www.waters.com, product code: 186003532) was used for both methods. The internal reference mass solution was prepared using an API-TOF reference mass solution kit (Agilent G1969-85001) and solvents as follows: LC-MS CHROMOSOLVÒ acetonitrile (95 mL), deionised water (5 mL), HP-121 (200 mL) and HP-921 (80 mL). Real samples were collected using cotton swabs obtained from the Forensic Explosives Laboratory (UK), previously analysed and proven to be free from explosives traces. A solution comprising analytical grade ethanol and deionised water in the ratio 50:50 was used for swab sampling and extraction. The sample extracts were then cleaned-up using Biotage ISOLUTEÒ ENV + 200 mg/6 m L solid phase extraction cartridges (www.biotage.com, product code: 915-0020-C). 2.2. Instrumental An Agilent 1260 series liquid chromatograph was used in conjunction with an Agilent 6540 Ultra High Definition AccurateMass Quadrupole Time of Flight Mass Spectrometer. Agilent Mass Hunter Software, version B.06.01, enabled data processing. The MS operated in 4 GHz, high resolution, low mass mode. Full scan L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 mode was used with a mass range of m/z 60–1000 and an acquisition time of 1000 ms/spectrum. 3. Method development A series of experiments were carried out to obtain the optimum method parameters for the detection of HMTD and TATP. Each parameter was independently varied, while the remaining parameters remained constant. Responses were compared as a function of peak area (m/z 209.0766 for HMTD and m/z 240.1443 for TATP). The results of these experiments are discussed in detail below. 3.1. HMTD analysis The proportion of methanol in the mobile phase was varied from 10% to 30% (v/v), in increments of 5%. The optimum HMTD response was obtained when the mobile phase comprised 80:20 water/methanol; at this ratio the HMTD response was 16% better compared with a mobile phase comprising 30% methanol. Decreasing the methanol content further did not have any significant effect on the HMTD response, though the retention times were markedly increased, as would be expected. With regards to the MS conditions, several key parameters were observed to affect the HMTD response, including: the vaporiser and gas temperatures, the nebuliser and drying gas flows and the skimmer voltage, Fig. 2. From the figure, it can be seen that the HMTD response increased significantly as the nebuliser flow was increased from 20 psig to 45 psig. The strongest HMTD response (45 psig) was 147% greater than the weakest response (20 psig). The strongest HMTD response was obtained at a vaporiser temperature of 300 °C; a 50% increase in response was observed at the optimum vaporiser temperature (300 °C) compared with the weakest response (350 °C). The optimum drying gas setting was determined to be 5 L/min; the response was improved by 47% at the optimum value compared with the weakest response (7 L/min). The skimmer voltage was varied between 40 V and 65 V, with the strongest response for HMTD obtained with a skimmer voltage of 50 V; this response was 39% greater than the weakest response (60 V). The gas temperature was varied between 180 °C and 320 °C. Comparison between 7 the strongest response (240 °C) and weakest response (300 °C) showed that a 19% increase in response was observed at the optimum gas temperature. Fine tuning was then performed and the greatest HMTD response was found to occur with a gas temperature of 250 °C. The fragmentor voltage was varied between 50 V and 110 V; the HMTD response was a little lower at 40 V compared with the other values, but was relatively consistent between 60 V and 110 V, with the relative standard deviation (RSD) for the response being 3.5% across this voltage range. Similar experiments were carried out with the capillary and octopole RF voltages (1500 V to 2700 V, and 240 V to 260 V); it was found that varying these parameters resulted in relatively insignificant improvements in HMTD response. 3.2. TATP analysis The optimum mobile phase composition was determined to be 60:40 methanol/water. As the methanol content was decreased from 70% to 60%, the TATP response increased by approximately 6%. The TATP response increased as the ammonium acetate concentration in the mobile phase was increased from 4 mmol to 10 mmol, until the ammonium acetate concentration reached 10 mmol; at this concentration the TATP response decreased by 22%. The column temperature was observed to have an effect on the TATP response; temperatures ranging 15 °C to 25 °C were evaluated and it was observed that the TATP response was 11% greater when the column temperature was 15 °C compared to 25 °C. With regards to the MS conditions, several parameters were observed to significantly affected the TATP response, including: the vaporiser temperature, the nebuliser and drying gas flows, and the capillary and fragmentor voltages, Fig. 3. It was observed that the capillary voltage had the most significant effect on the TATP response. The capillary voltage was varied between 900 V and 2500 V; an increase of 1259% was observed at a voltage of 1000 V compared with 900 V. At voltages >1000 V, the TATP response gradually decreased with increasing voltage; there was a reduction in response of 39% between the optimum response (1000 V) and the response at the highest voltage (2500 V). The vaporiser temperature also significantly affected TATP response; as the vaporiser Fig. 2. Optimisation of HMTD method parameters. (Duplicate measurements performed for each parameter setting and the average value plotted). 8 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Fig. 3. Optimisation of TATP method parameters. (Duplicate measurements performed for each parameter setting and the average value plotted). temperature was increased from 100 °C to 340 °C, there was little change in TATP response until 220 °C, above which the response increased markedly with increasing temperature. The maximum response (300 °C) was 430% greater than the weakest response (100 °C). The drying gas was varied between 2 L/min and 7 L/min, with the strongest TATP response (5 L/min) being 257% greater than the weakest response (2 L/min). The strongest TATP response was obtained with a nebuliser flow of 25 psig; at this setting, the response was 117% greater than the weakest response (15 psig). Improvements in response of 21% and 9% were achieved by optimising the fragmentor and skimmer voltages, respectively. Varying the gas temperature and octopole RF made little difference to TATP response, with the RSD of TATP response across the ranges tested being <3% and 5%, respectively. It was observed that the degree of contamination of the corona pin and APCI source significantly affected the TATP response. To examine this in further detail, a sequence comprising 14 consecutive TATP standards was analysed, Fig. 4. As can be seen in the figure, the TATP response decreases rapidly for the first few analyses, and then decreases more slowly as the run progresses. The TATP response drops by 47% over the run. This effect was not observed for the HMTD response. The TATP response was also observed to be substantially affected when the internal reference mass solution flowed continuously into the APCI source. Reference mass solutions comprising various proportions of HP-121 and HP-921 were tested and all were found to reduce the TATP response to approximately one third of the response obtained without the reference mass solution. Given the effect of the reference mass solution on Fig. 4. Monitoring response for consecutive TATP standards (50 ng/mL). L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Table 1 HMTD and TATP method parameters. Parameter HMTD method TATP method Solvent 20:80 MeOH:H2O Run time/min Gas temperature/°C Vaporiser temperature/°C Drying gas/L/min Nebuliser/psig Fragmentor voltage/V Skimmer voltage/V OCT1RF/V Capillary voltage/V Corona/mA Reference mass(es) 4 250 310 5 40 85 50 250 1700 12 121.0509, 922.0098 60:40 MeOH:H2O, with 8 mM ammonium acetate 8 100 300 5 25 155 60 260 1000 12 149.0233 the TATP response, it was decided that a stable background ion should be used instead. An ion with mass of 149.0233 was identified as being suitable reference mass for this method; this ion is due to phthalic anhydride contamination in the system. 3.3. Optimised methods Both optimised methods for HMTD and TATP utilised isocratic elution at a flow rate of 200 mL/min, with autosampler and column chamber temperatures set to 15 °C. A 1 mL injection volume was injected from an insert vial. Sample ionisation was achieved using Atmospheric Pressure Chemical Ionisation (APCI) in positive ion mode. Method specific parameters are given in Table 1. For the HMTD method, the continuous flow of the internal reference mass solution to the APCI source enabled the monitoring of two reference masses (121.0508 and 922.0098). As discussed in section 3.2, no reference solution was used for the TATP method. On completion of TATP analysis, the column was flushed with nonbuffered mobile phase for a minimum of 30 min. 4. Validation 4.1. Validation methodology The validation assessed the selectivity, limits of detection and quantification, linearity, repeatability and reproducibility of the methods. The limit of detection (LOD) and limit of quantitation (LOQ) were determined (for 10 replicates) at a signal-to-noise ratio (S/N) of 3 and 10, respectively. The characteristic ions evaluated were m/z 209.0766 and 207.0973 for HMTD, and m/z 240.1443 for TATP. Standards of concentrations ranging from the LOD to 100 ng/mL were analysed in triplicate to determine the linearity of the methods. The standards were analysed in a random order to help eliminate any bias effects. Retention time, peak area and accurate mass values were used for determining the repeatability, reproducibility and robustness of the methods. Peak area was used for quantitation. All standards and samples were interspersed with blanks comprising acetonitrile to assess whether any HMTD or Table 2 Identity of real samples collected for validation study. Sample ID Description 1 2 3 4 Post explosion debris Desk, monitor and keyboard Laboratory floor Laboratory bench 9 TATP carryover occurred. The repeatability was assessed using 10 replicates analysed within 1 day for each of three concentrations (HMTD: 5 ng/mL, 40 ng/mL and 100 ng/mL, TATP: 30 ng/mL, 50 ng/mL and 100 ng/mL). The reproducibility and ruggedness data was acquired by different analysts conducting analyses over an extended time period (HMTD 11 weeks, TATP 14 weeks). The RSD was calculated to provide some measure of the reproducibility of the method, factoring in any effects of inadvertent changes, such as, cleanliness of the source, exact composition of the mobile phase, and contamination of the LC column and capillary. 4.2. Preparation and analysis of real samples The selectivity of the method was assessed using real samples spiked with explosives. Cotton swabs moistened with ethanol/ water were used to swab a variety indoor and outdoor surfaces to obtain samples expected to contain a matrix similar to what might be encountered in real casework samples, Table 2. Swabs were extracted twice with 5 mL ethanol/water, and the combined extract of 10 mL then cleaned-up by elution through an Isolute ENV+ cartridge. Adsorbents were removed from the cartridge using acetonitrile (1 mL) [5,26,30]. Sample extracts were then passed through a 0.2 mm filter. Each acetonitrile sample extract was spilt into two portions; one aliquot was left unchanged, whilst the remaining aliquot was spiked with standards to give a concentration of approximately 10 ng/mL HMTD and 40 ng/mL TATP. The acetonitrile sample extracts were then analysed in triplicate. A calibration curve comprising 6 standards was analysed immediately prior to sample analysis. Additionally, a standard was injected after every three sample injections (10 ng/mL HMTD, 50 ng/mL TATP). Since the purpose of the spiked samples was to monitor the effect of the sample matrices on signal suppression, mass accuracy error and retention time shift, and given that the authors have not yet fully validated the clean-up method, the explosives were added post-clean-up so as not to distort the results. Validation of the clean-up method will be performed in due course. The recovery of analytes in casework samples varies according to the sampling, extraction and clean-up methods used in processing the evidence. This is in addition to any losses that may occur at the scene prior to, or during, evidence packaging. Many forensic laboratories only report that explosives were found on evidence, not the actual quantity. Quantitation in explosives trace analysis is generally used as an indication as to whether evidence is likely, or unlikely, to have been in recent direct contact with an unwrapped quantity of explosive, or materials contaminated with explosive. The authors wanted to determine whether semiquantitation using a 1-point calibration would be sufficient for this purpose. Certainly, performing a 1-point calibration is markedly quicker than performing a full calibration prior to each set of casework samples. Thus, quantitation was performed using two methods; the concentration of analyte in the sample was calculated from the calibration curve and it was also determined using a 1point calibration using the nearest preceding standard. 5. Results and discussions 5.1. HMTD HMTD was resolved from the solvent front (0.9 min) and eluted at around 1.8 min. HMTD was detected using seven ions, Table 3. The ions with m/z 209.0766 and 207.0973 were considered to be characteristic ions for HMTD; these were required to be present to confirm the presence of HMTD in a sample. It is widely reported in the literature that the identity of the heavier ion is [M + 1]+. The 10 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Table 3 Accurate mass values for characteristic ions. Analyte HMTD TATP Calculated m/z 209.0768 207.0975 179.0662 145.0608 118.0499 90.0550 88.0393 240.1441 89.0597 Identity + [HMTD + H] [C7H15O5N2]+ [C5H11O5N2]+ [C5H9O3N2]+ [C4H8O3N]+ [C3H8O2N]+ [C3H6O2N]+ [TATP + NH4]+ [C4H9O2]+ lighter ion is considered to be a reaction product between HMTD and methanol, [C7H15O5N2]+ [10,22–26]. An ion with m/z 207.0614 was also observed, Figs. 5 and 6. It has been previously reported that the identity of this ion is [M-1]+ [21,25,31]. The need to be able to unequivocally identify analyte ions is important in forensic work as the reported results can have significant implications. Additionally, if significance is reported with regards to the quantity of that analyte present, analysts need to ensure they are using appropriate ions for quantification calculations. If the response of the 207 ions is used for quantification, then an erroneous result could be obtained. Accurate mass experiments performed using ESI-TOF and Orbitrap APCI-MS have indicated that the true identity of this ion is more likely to be [TMDDD + H]+ [28,29]. TMDDD (tetramethylene diperoxide diamine dialdehyde) is itself considered to be an energetic peroxide similar in structure to HMTD, though two aldehyde functional groups replace one of the peroxo groups, Fig. 1 [32]. TMDDD also appears to be a degradation product of HMTD. The calculated m/z for [TMDDD + H]+ is 207.0611; the mass error associated with this ion on this instrument was determined to be 1.45 ppm, thus providing good corroborating evidence that this is the true identity of this ion and that it is not [HMTD-1]+. Measured m/z Mass error/ppm 209.0766 207.0973 179.0661 145.0605 118.0499 90.0548 88.0393 240.1443 89.0597 1.07 1.10 0.83 1.85 0.00 1.71 0.05 4.84 0.06 5.2. TATP TATP eluted at around 6.0 min, being well resolved from the solvent front (0.8 min). TATP was detected using ions 240.1443 and 89.0597, Table 2. The observed ions correspond well with literature values [10,20,21,24,26]. A second peak was present in both of these extracted ion chromatograms; it eluted almost 1 min after the main TATP peak. The peak was present when the TATP concentration exceeded 12 ng/mL. The peak shape and signal to noise ratio was poor, and the peak area was not reproducible. The presence of a second peak in LC chromatograms has been previously observed and it has been reported that it is due to the existence of an alternative structural conformer [20,33]. The presence of this peak in the 240.1443 extracted ion chromatogram (EIC) can be used to provide additional confirmation that TATP is present in a sample. 5.3. Method validation The LOD and LOQ for were determined to be 0.50 ng and 2 ng on column for HMTD, and 10 ng and 25 ng on column for TATP. These values are comparable with other published LC/MS methods [20,21,23,25]. Both methods were observed to exhibit good linear- Fig. 5. HMTD APCI-TOF mass spectrum. 11 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Fig. 6. Zoomed in region of HMTD mass spectrum. Table 4 RSD of mass accuracy, repeatability n = 10, reproducibility n = 64 (HMTD) and n = 70 (TATP). Analyte Measured mass Theoretical mass HMTD 209.0766 207.0973 240.1430 89.0597 209.0768 207.0975 240.1441 89.0597 TATP ity between the LOD and 100 ng/mL (the most concentrated standard commercially available), with R2 > 0.99 (HMTD: 209.0766, 207.0973, TATP: 240.1443). The measured accurate mass values showed good agreement with the theoretical accurate mass values; both identifying ions for HMTD showed around 1 ppm mass error, Table 3. The TATP 240 ion was within 5 ppm of the theoretical value. The TATP conformers exhibited identical accurate mass values. The response repeatability exhibited low RSD values of 7.3% for HMTD and 6.6% for TATP. Other studies have obtained similar repeatability values [24]. The reproducibility was observed to be significantly higher; the RSD values were 32% for HMTD and 31% for TATP. It is the opinion of the authors that the low reproducibility is due to differing degrees of source contamination on the different days that the analyses were performed. It is recommended that samples are always analysed in the same run as appropriate standards. The retention time repeatability was shown to be highly repeatable within one day; the RSD was <1.1% and <0.4% for HMTD and TATP, respectively. The reproducibility was good for both analytes, with a RSD of <4.0% for HMTD and <2.4% for TATP. Accurate mass determination was performed by averaging across the full peak. The results exhibited good precision and appeared stable over a short-timescale, Table 4. Difference/ppm 1 day 7 days 0.06 0.69 4.26 4.88 1.07 1.10 4.84 0.06 5.3.1. Selectivity No HMTD or TATP was detected in any of the unspiked samples, i.e. there were no false positive results. Each mobile phase was shown to be free from interfering background ions with masses within 2 ppm of the exact masses of the analyte of interest. No detectable HMTD or TATP carryover was detected during the validation study. HMTD and TATP were detected in all of the spiked samples. All 7 HMTD ions were observed in all of the samples, with a signal to noise ratio greater than 3. Frequently during TATP analyses m/z 89 channel was extremely noisy, and the peak often exhibited poor peak shape during this experiment. The calibration curves used for determining the concentration of analyte in the spiked samples are given in Figs. 7 and 8. Example chromatograms for the spiked samples are given in Figs. 9 and 10. It was observed that the retention time and accurate mass values for the real samples were stable throughout the analyses, regardless of the presence of common contaminants. There was good agreement between the measured and actual concentration of HMTD for spiked samples 1–3, Table 5 and Fig. 11. The concentration of HMTD in sample 4 was a lower than expected; it is possible that contaminants in the sample either degraded the HMTD or affected the formation of characteristic ions. Both methods for determining the concentration of HMTD in the samples produced similar results. 12 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 Fig. 7. HMTD calibration curve (m/z 209.0766) used for quantitation of spiked samples. (The error bars represent ± one standard deviation, n = 3). Fig. 8. TATP calibration curve (m/z 240.1430) used for quantitation of spiked samples. (The error bars represent ± one standard deviation, n = 3). Fig. 9. Mass spectrum for spiked sample 4 (HMTD), background subtracted. L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 13 Fig. 10. EIC (240.1200-240.1700) for spiked sample 2 (TATP). Table 5 Concentration (mean ± one standard deviation, n = 3) of explosives in spiked samples 1–4: A calculated from calibration curve, B determined from 1-point calibration. Sample HMTD Conc 1 2 3 4 TATP (A) /ppm 9.3 ± 0.8 10.3 ± 0.8 9.9 ± 1.0 8.7 ± 0.7 Conc (B) /ppm 9.1 ± 0.2 10.9 ± 0.2 10.1 ± 0.4 8.2 ± 0.1 Conc (A) /ppm 33.4 ± 2.9 31.9 ± 1.4 30.4 ± 1.9 29.3 ± 2.2 Conc (B) /ppm 37.0 ± 1.3 38.0 ± 3.0 37.7 ± 2.5 42.5 ± 2.5 The concentration of TATP in the spiked samples, as determined by the calibration curve, was observed to be significantly lower than the actual concentration of 40 ppm. From the table it is evident that when the concentration was determined form the calibration curve, the TATP concentration decreased with increasing sample number, i.e. the response for TATP reduced as the run progressed. This was an expected outcome given the observations recorded during the method development phase. In contrast, the TATP concentrations derived using a 1-point calibration based on the peak are of the nearest preceding standard yielded significantly more accurate results. From the results obtained, it was concluded that semiquantitation using a 1-point calibration would be sufficient for determining the concentration of analytes in casework samples to give an indication as to whether evidence is likely to have been in recent direct contact with explosives, or materials contaminated with explosives. Fig. 11. Concentration of explosives in spiked samples 1–4: (A) calculated from calibration curve, (B) determined from 1-point calibration. (The error bars represent ± one standard deviation, n = 3). 6. Conclusions In this paper, the development and validation of fast and robust LC-QToF methods for the trace analysis of HMTD and TATP have been presented. The methods exhibit good chromatography, with 14 L. Dunn et al. / Forensic Chemistry 10 (2018) 5–14 the peroxide analytes being sufficiently retained on the column to prevent solvent peak overlap. Sufficient mass accuracy is achieved to unambiguously confirm the presence of HMTD and TATP. Thorough method validations were performed using real samples to demonstrate good method repeatability and robustness, with complex matrices. As shown from the analysis of spiked samples, the presence of common contaminants had no significant effect on the retention time and accurate mass values of the real samples. The LODs for HMTD and TATP are considered to be practical for forensic applications. The authors determined that semiquantification for TATP achieved via 1-point calibration using the peak area of the nearest preceding standard provides sufficient accuracy for estimating the quantity of explosive in a sample. This paper supports recent work performed using ESI-TOF and Orbitrap that demonstrates that the 207.0614 ion observed during the analysis of HMTD is in fact [TMDDD + H]+, and not [M-1]+. The authors believe that this paper is the first to confirm the presence of this TMDDD ion using accurate mass with APCI-TOF. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements We would like to acknowledge the advice provided during the method development and validation stages of this work by Dr Andrew Crowson (Forensic Explosives Laboratory, UK). The authors wish to acknowledge the strong support of this project from colleagues in the General Department of Forensic Science and Criminology, Dubai Police. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.forc.2018.06.003. 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