Pharmaceutical applications of ion mobility spectrometry

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Trends in Analytical Chemistry, Vol. 27, No. 1, 2008

Pharmaceutical applications of ion mobility spectrometry Ryan M. OÕDonnell, Xiaobo Sun, Peter de B. Harrington The applications of ion mobility methods (e.g., ion mobility spectrometry (IMS), differential mobility spectrometry (DMS), and field asymmetric waveform IMS (FAIMS)) to quality assurance and process monitoring by the pharmaceutical industry have been burgeoning. Specifically, the uses of IMS and FAIMS for cleaning verification of manufacturing equipment, direct analysis of formulations, and maintenance of worker health and safety can help save money and increase overall efficiency of production. We review ion mobility methods currently employed in pharmaceutical companies and research that could further these methods. ª 2007 Elsevier Ltd. All rights reserved. Keywords: Differential mobility spectrometry; DMS; Field asymmetric waveform ion mobility spectrometry; FAIMS; IMS; Ion mobility spectrometry; Pharmaceutical; Quality assurance; Quality control; Worker health and safety

1. Introduction Ryan M. OÕDonnell, Xiaobo Sun, Peter de B. Harrington* Ohio University, Center for Intelligent, Chemical Instrumentation, Clippinger Laboratories, Athens, OH, USA 45701-2979

*

Corresponding author. Tel.: +1 740 994 0265; Fax: +1 740 593 0456. E-mail: Peter.Harrington @OHIO.edu

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Pharmaceutical companies require quick, efficient, and low-cost tools for quality control (QC) and quality assurance (QA) of their products. During pharmaceutical manufacturing, chemical monitoring is critical for QC. Cleaning verification is related to the screening of active pharmaceutical ingredients (APIs) on manufacturing equipment from production, which could contaminate future pharmaceutical products [1]. Routinely used techniques for pharmaceutical QC, such as high-performance liquid chromatography (HPLC) and total organic carbon (TOC), suffer the shortcomings of low speed and limited accuracy [2,3]. Ion mobility spectrometry (IMS) techniques, which include linear or low-field IMS, differential mobility spectrometry (DMS), and field asymmetric waveform IMS (FAIMS), are being explored as alternatives for pharmaceutical QC and QA. Cohen and Karasek first introduced IMS in the 1970s [4,5]. Since then, IMS has been applied to diverse fields (e.g., detection of trace explosives [6–8], screening of chemical-warfare agents [9–

12], environmental monitoring [13–18], and screening of illicit drugs [19–26]). The use of IMS for pharmaceutical QC is increasing. IMS is usually subdivided into three techniques. Typically, IMS refers to lowfield (e.g., 100 V/cm) linear measurements. The technique is linear in that the ions travel at a constant velocity through a linearly decreasing field. DMS and FAIMS are both high-field (e.g., 10 kV/cm or greater), non-linear ion measurements [27–29]. In the literature and this review, IMS collectively refers to all three techniques or specifically to the linear measurement. In linear IMS, ion formation is initiated at atmospheric pressure by one of several sources: radioactive, photoionization, and corona discharge are the most prevalent. An electric shutter grid is opened briefly (e.g., 100 ls) to allow the ions into the drift tube and initiate the timing sequence. The drift tube is typically 5–10 cm in length and has a decreasing electric field (100 V/cm). The electric field causes the ions to traverse the drift tube at constant velocities. A counter-current of clean drift gas (usually purified air) keeps the drift region free of neutral molecules to hinder the formation of cluster ions. The ions are detected at the distal end of the drift tube with a Faraday-plate detector. Ionic species with different cross-sections and charges will separate by differing velocities and arrive at the detector at different times. Fig. 1 is a schematic of a generic IMS drift tube that shows ion separation. The current detected with respect to time comprises the ion mobility spectrum. A typical spectrum (Fig. 2) would be collected in 5–25 ms, depending on the drift-tube length, pressure, temperature, and applied electric field.

0165-9936/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2007.10.014


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Figure 1. Drift tube for ion mobility spectrometry (IMS). A voltage gradient is applied to the ions, as illustrated by the triangle (A). (A) Two different samples are introduced into the ionization region of the IMS instrument. (B) The two samples are ionized. (C) The ions enter the drift region when the shutter grid opens, flowing against the drift gas to reach the detector. Note that neutral samples do not enter the drift region (Adapted from [27]).

in which vd is the velocity of the ions and E is the potential drop of the applied electric field. Standardized ion mobilities, referred to as reduced mobility constants (K0), are converted to standard conditions, as expressed in Equation (2):

Water 0.25

0.2 Intensity (V)

ð1Þ

K ¼ vd =E

Nicotine Chemical Agent Monitor Positive Spectra

K 0 ¼ KðP1 =P0 ÞðT 0 =T 1 Þ

0.15 Nicotine Monomer

Ammonia 0.1

Nicotine Dimer

0.05

0 4

6

8

10

12

14

Drift Time (ms)

Figure 2. Ion mobility spectrum of nicotine obtained using a Chemical Agent Monitor.

The gas-phase ions are identified and separated by their mobilities. The mobilities (K) of different ionic species can be obtained from the relationship in Equation (1):

ð2Þ

for which P0 is the standard pressure in Torr, T0 is the standard temperature in Kelvin, and P1 and T1 are the pressure and the temperature for the experiment, respectively. DMS is related to IMS, with the exception that ions separate by their change in mobility with respect to high and low fields applied perpendicularly to a carrier gas that is conveying the ions between two electrodes. The device has two parallel electrodes spaced 0.5–3 mm apart. A carrier gas will convey the ions between the two electrodes, at which an asymmetric electric field is applied comprising a shorter, high-field pulse (e.g., 10 kV/ cm) followed by a longer, low-field pulse of opposite polarity (e.g., –100 V/cm). The asymmetric waveform is http://www.elsevier.com/locate/trac

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Figure 3. Motion of an ion between the two electrodes that apply a high field asymmetric waveform, shown as V(t) (distance not to scale) (Adapted from [30]).

applied at 100 MHz. When ions exhibit the same differential mobility, they will migrate towards one of the two electrodes where, upon making contact with the electrodes, the ions will be neutralized and rendered undetectable. Fig. 3 illustrates the effect of an asymmetric field on the flight path of an ion in a DMS instrument. This instrument is scanned by superimposing a DC compensation voltage that corrects the paths of the ions with the same differential mobility so they will pass between the two electrodes. Typically, two or more parallel electrodes are located past the separation electrodes for detection of positive and negative ions. The main advantages of DMS over IMS are: higher throughput, in that there is no shutter grid, so more ions are analyzed; and, both positive and negative ions can be separated simultaneously. A similar method, called FAIMS, uses the same separation principle as DMS, but differs in instrumental design. FAIMS instruments typically utilize electrospray ionization (ESI) sources, coaxial electrodes (cylindrical, dome, and cube electrodes), and are used for ion separation prior to mass spectrometry (MS) analysis. DMS instruments typically use radioactive or photoionization and in some cases ESI sources, planar electrodes, and MS for ion detection. DMS has the advantage of faster scanning speeds and the ability to simultaneously separate positive and negative ions; whereas FAIMS has a higher resolution because the cylindrical fields can focus ions of a single polarity [30]. 46

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This article reviews the applications of IMS to QC and QA of pharmaceuticals. IMS instruments are low-cost, portable and sensitive, and have fast responses.

2. Cleaning verification of manufacturing equipment The use of IMS instruments for cleaning verification of manufacturing equipment offers several advantages over methods currently used by pharmaceutical manufacturers. IMS instruments meet Food and Drug Administration (FDA) standards, specifically 21 CFR Part 11, which regulates electronic data collection for the industry, and 21 CFR Part 211.67, which offers guidelines and suggestions for cleaning verification [1,3,31,32]. The low levels of quantification for APIs and contaminants using IMS are in the range of 0.4 mg– 10 ng, which are comparable to HPLC and TOC methods [33–35]. However, IMS provides increased specificity during analysis by identifying compounds, whereas TOC finds all organic carbon present, which is a common source of false positives [1,3]. IMS substantially shortens the time for the cleaningverification process. Standard HPLC cleaning verification generally requires 9–20 min per sample analyzed and 18–48 h total. Analyses require only 5–60 s per sample analyzed and 3–4 h total using IMS [1,3,36–40]. The speed advantages of IMS compared with HPLC are also realized in the times for instrument set-up, method development, and re-analysis of potentially false


positives. Set-up for HPLC instruments comprises mobilephase preparation and column equilibrium and requires twice the time needed for IMS-instrument set-up [1]. The method-development process aims to challenge accuracy, reproducibility, sensitivity, costs of analysis in time and resources, and specificity of existing protocols for cleaning verification. New analytical methods are optimized in accordance with 21 CFR 211.165(e), which requires companies to establish and to document cleaning-verification methods. The relatively faster analysis afforded by IMS (i.e., compared with HPLC, GC, and TOC) shortens the time for repetitive testing in the method-verification process and facilitates reanalysis of dirty samples to reduce false positives during cleaning verification [1,31,37,39]. This ability ensures efficient cleaning verification by eliminating, and thus avoiding, needless cleaning of the processing equipment [36,38]. IMS instruments are easy to use, as demonstrated by their widespread employment in military and aviation security applications. Unlike HPLC, IMS does not require solvents or column materials, thereby reducing the cost of materials and avoiding analysis problems associated with faulty or dirty columns [1–3,37]. For IMS, volatile samples are introduced by sampling the headspace of open containers or vapor streams from processing lines. Less volatile particulates are collected by wiping surfaces with an inert material followed by its thermal desorption directly into the instrument. Because sampling is accomplished without solvents or derivatization, non-scientists can perform the measurements [36,38,39]. The ease of use and the portability of IMS instruments allow workers to verify the cleaning process immediately (e.g., Forest Laboratories initiated the use of IMS in their evaluations and found it to be more efficient and effective than their previous methods [39]). IMS-MS instruments are useful in the laboratory for characterizing compounds and confirmation of the ionic species under study. However, it is unlikely that an IMSMS set-up would be employed for on-line analyses in a manufacturing facility due to the maintenance and costs associated with the MS detector. With IMS instruments deployed on-line with manufacturing equipment, pharmaceutical companies can significantly increase their productivity and efficiency while decreasing costs associated with the cleaning-verification process.

3. Direct formulation analysis Due to its quantitative nature and ability to identify a broad range of substances, IMS can perform direct formulation analyses of pharmaceutical products for use in clinical trials or authentication purposes. The responsibility for determining the composition of the drug, whether it is a placebo or an active pharmaceutical, lies with the manufacturer. Current determination tech-

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niques (e.g., HPLC and gas chromatography (GC)) suffer several shortcomings, namely lengthy analysis times and use of solvents. Peterson et al. conducted a blind study using IMS to determine the absence or the presence of a drug, baclofen, in tablet samples. Placing wipes into high-density polyethylene bottles containing either active pharmaceuticals with 10 mg of baclofen or placebos and analyzing the wipes using IMS yielded a 100%-accurate determination. The applicability of their method with solid dosage forms (e.g., capsules and coated tablets) will require further research [41]. Due to the large quantity of counterfeit drugs manufactured and sold over the Internet, pharmaceutical companies and other organizations require methods to determine whether a drug is an authentic pharmaceutical product or a counterfeit. One method of determining the authenticity of a substance is to identify its components and their relative proportions. Pharmaceutical QC also benefits from the use of IMS due to its speed, convenience, and inexpensive nature. Lawrence published two papers in the late 1980s characterizing prescription and illicit drugs using IMSMS. LawrenceÕs first paper demonstrated the general use of IMS to separate and to identify compounds (e.g., codeine, diazepam, and morphine) [20]. LawrenceÕs second paper characterized several benzodiazepines by fragment ions and assigned reduced mobilities [22]. Table 1 is a comprehensive listing of the reduced mobilities, ionic species, and methods used to identify the pharmaceutical compounds mentioned in this article. Examination of Table 1 shows that opiates are the most widely studied pharmaceuticals using IMS methods. Stand-alone IMS is the most prevalent method for pharmaceutical characterization, with more than 50 different ionic species characterized, followed by ESI-IMS-MS and secondary ESI (SESI)-IMS-MS, with a combined total of 47 ionic species characterized. In Table 1, many of the pharmaceutical compounds form multiple ionic species, which all have characteristic reduced mobility constants, increasing the selectivity of IMS methods. Eatherton et al. developed two hyphenated IMS methods for drug identification, one using capillary GC and the other supercritical fluid chromatography (SFC). They characterized several steroids, opiates, and benzodiazepines with N2 or an N2/CO2 mixture as the carrier gas [21]. Eiceman et al. characterized substances such as aspirin, caffeine, and acetaminophen using IMS. Their study examined binary mixtures of common APIs, made to resemble over-the-counter (OTC) drugs, which yielded spectra useful for qualitative purposes [42]. To determine the amount of parabens in a pharmaceutical formulation, Lokhnauth and Snow developed a solid-phase microextraction (SPME)-IMS method. Found in topical drugs as preservatives, the five parabens http://www.elsevier.com/locate/trac

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Table 1. Reduced mobilities of pharmaceutical compounds identified in the literature Compounda

Reduced mobility constant (K0)b

2-phenylethylamin 3-phenyl-1-propylamine 6-monoacetyl codeine 6-monoacetyl codeine 6-monoacetyl codeine 6-monoacetyl morphine 6-monoacetyl morphine 6-monoacetyl morphine acetylcodeine acetylcodeine alprazolam AM AM AM AM benzylparaben bromazepam bromazepam butylparaben cannabinol chlordiazepoxide chlordiazepoxide chlordiazepoxide chloroephedrine chloromethylephedrine chlorophentermine cocaine codeine codeine codeine codeine codeine codeine codeine diazepam diazepam diazepam diazepam diazepam dimethylamphetamine ephedrine ephedrine ephedrine estrone estrone ethamphetamine (EA) ethylamphetamine ethylparaben flurazepam flurazepam flurazepam heroin heroin heroin heroin heroin heroin heroin hydromorphone lorazepam lorazepam

1.592 1.685 0.99 0.99 1.10 1.01 1.01 1.14 1.09 1.21 1.15 1.62 1.676 1.665 1.66 1.1382 1.144 1.24 1.2204 1.06 1.091 1.18 1.19 1.433 1.381 1.466 1.150 1.27 1.29 1.04 1.07 1.10 1.18 1.21 1.29 1.28 1.123 1.21 1.21 1.591 1.572 1.5848 1.5843 1.27 1.25 1.53 1.586 1.3569 1.06 1.09 1.03 0.94 0.98 1.11 1.04 1.14 1.037 1.135 1.32 1.085 1.118

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Ionic speciesc

[M + Na]+ [MH]+ [M CH3CO2] + [M + Na] + [MH] + [M CH3CO2]+ [M]+ [M CH3CO2]+ [MH]+

[M + H]+ [MH]+ [MH]+ [M]+ [M]+ [MH]+ [MH]+ [M H]

[M + H]+

[M + Na]+ [MH]+ [M H2O]+ [M]+ [M H2O]+ [MH]+ [M]+ [M]+

[MH]+ [MH]+ [M + Na]+ [M CH3CO2]+ [M]+ [M CH3CO2]+ [M + H]+ [M CH3CO2]+ [MH]+ [M H2O]H+

Method

Ref.

IMS IMS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS IMS IMS IMS ESI-IMS-MS IMS SESI-IMS-MS IMS SPME-IMS ESI-IMS-MS IMS SPME-IMS IMS ESI-IMS-MS IMS IMS IMS IMS IMS SESI-IMS-MS CGC-IMS CSFC-IMS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS IMS IMS CGC-IMS CSFC-IMS ESI-IMS-MS IMS IMS IMS IMS IMS SPME-IMS CGC-IMS CSFC-IMS ESI-IMS-MS IMS SPME-IMS CGC-IMS CSFC-IMS IMS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS IMS IMS SESI-IMS-MS SESI-IMS-MS CSFC-IMS ESI-IMS-MS ESI-IMS-MS

[23] [23] [46] [46] [46] [46] [46] [46] [20] [20] [22] [47] [23] [26] [20] [43] [48] [22] [43] [20] [48] [22] [22] [23] [23] [23] [26] [21] [21] [46] [46] [46] [20] [20] [21] [21] [48] [20] [22] [23] [23] [59] [59] [21] [21] [47] [23] [43] [21] [21] [22] [46] [46] [46] [20] [20] [26] [26] [21] [48] [48]


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Table 1 (continued ) Compounda


Ionic speciesc

Method

Ref.

lorazepam lorazepam lysergic acid diethylamide (LSD) lysergic acid diethylamide (LSD) MA MA MA MA MA MDA MDA MDA MDEA MDEA MDMA MDMA MDMA mescaline methoxyphenamine methylephedrine methylparaben methyprylon morphine morphine morphine morphine morphine morphine morphine morphine morphine morphine morphinee morphinee N-acetylamphetamine nicotine nitrazepam nitrazepam nitrazepam nitrazepam N-methylbenzylamine norcodeine norcodeine norephedrine normorphine normorphine normorphine noscapine o6-monoacetylmorphine o6-monoacetylmorphine oxazepam oxazepam oxazepam oxazepam phenfluramine phentermine phenylcyclidine phenylcyclidine phenylcyclidined phenylcyclidined phenylcyclidined phenylcyclidined

1.19 1.22 1.028 1.070 1.59 1.61 1.63 1.640 1.630 1.45 1.487 1.49 1.37 1.4201 1.42 1.449 1.4733 1.328 1.528 1.538 1.4412 1.52 1.31 1.32 1.07 1.11 1.14 1.164 1.195 1.214 1.254 1.33 1.22 1.26 1.53 1.54 1.29 1.29 1.22 1.23 1.781 1.07 1.10 1.617 1.10 1.12 1.16 1.65 1.13 1.26 1.138 1.184 1.23 1.28 1.342 1.601 1.255 2.010 1.27 1.63 2.01 2.23

[M]+ [M H2O]+ [M + Na]+ [M + H]+

IMS IMS SESI-IMS-MS SESI-IMS-MS ESI-IMS-MS IMS IMS IMS SESI-IMS-MS ESI-IMS-MS IMS IMS ESI-IMS-MS IMS ESI-IMS-MS IMS IMS IMS IMS IMS SPME-IMS IMS CGC-IMS CSFC-IMS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS SESI-IMS-MS SESI-IMS-MS SESI-IMS-MS SESI-IMS-MS IMS IMS IMS IMS IMS CGC-IMS CSFC-IMS IMS IMS IMS ESI-IMS-MS ESI-IMS-MS IMS ESI-IMS-MS ESI-IMS-MS ESI-IMS-MS IMS IMS IMS ESI-IMS-MS ESI-IMS-MS IMS IMS IMS IMS SESI-IMS-MS SESI-IMS-MS IMS IMS IMS IMS

[22] [22] [26] [26] [47] [19] [20] [23] [26] [47] [23] [20] [47] [24] [47] [23] [24] [23] [23] [23] [43] [20] [21] [21] [46] [46] [46] [26] [26] [26] [26] [53] [20] [20] [20] [19] [21] [21] [22] [22] [23] [46] [46] [23] [46] [46] [46] [53] [20] [20] [48] [48] [22] [22] [23] [23] [26] [26] [20] [20] [20] [20]

[MH]+ [M + H]+

[M]+

[M H]+, [MH]+

[M + Na]+ [MH]+ [M H2O]+ [M + Na]+ [M + O + H]+ [M + H]+ [M H2O + H]+ [M]+ [M H2O]+ [MH]+

[MH]+ [M] [MH]+ [M H2O]+ [M + Na]+ [MH]+ [M H2O]+ [M]+, [M H2]+ [M CH3CO2]+ [MH]+ [M H2O]H+ [M H]+ [M H2O]+

[M + H]+ [M C12H16 + H]+ [M]+ [1 phenylcyclohexene]H+ [piperidine]H+ [pyridine]H+

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Table 1 (continued ) Compounda


progesterone progesterone propyl methamphetamine carbamate propylparaben pseudoephedrine psilocin psilocybin testosterone testosterone tetrahydrocannabinol (THC) tetrahydrocannabinol (THC) thebained triazolam triazolam a-methylbenzylamine

1.16 1.16 1.35 1.285 1.558 1.4452 1.4452 1.21 1.23 1.05 1.040 1.14 1.13 1.13 1.592

Ionic speciesc

[M]+ [M + H]+ [M H]+, [MH]+ [M H]+, [MH]+

Method

Ref.

CGC-IMS CSFC-IMS IMS SPME-IMS IMS IMS IMS CGC-IMS CSFC-IMS IMS SESI-IMS-MS IMS IMS IMS IMS

[21] [21] [19] [43] [23] [25] [25] [21] [21] [20] [26] [20] [20] [22] [23]

a

Abbreviations used in table can be found in text. cm2/V/s. c Reported if substance was identified by mass. d Drugs are in the hydrochloride-salt form. e Drugs are in the sulfate-salt form. b

studied were extracted from a 3-mL sample using a divinylbenzene/carboxen/polydimethylsiloxane (DVB/ CAR/PDMS) fiber for 15 min with no pH adjustments. This SPME-IMS method allowed for rapid detection and quantification of parabens and provided a basis for developing and validating SPME-IMS methods for other pharmaceutical preservatives [43]. Weston et al. developed a hyphenated IMS instrument that incorporated desorption ESI (DESI) and time-of-flight MS (ToF-MS). Their DESI-IMS-ToF-MS instrument is capable of analyzing OTC and prescription drugs without sample pretreatment or chromatographic separation, giving analysis times of 2 min. This method can analyze hard or soft pharmaceutical formulations and is highly selective for APIs compared to excipients. They analyzed a Zantac 75 tablet, an Arimidex tablet, a Nicorette patch, and a Germolene antiseptic cream, which contained APIs of ranitidine, anastrozole, nicotine, and chlorhexidine gluconate, respectively. Tablets of paracetamol and codeine were also analyzed [44]. Budimir et al. developed a hyphenated IMS method using LC and nano-ESI for pharmaceutical analysis. Using caffeine, they found an R2 of 0.9982 for linearity and reproducibility with RSD of 2.3%, n = 6. This method allowed quantitative analysis of a Prontalgine tablet, which contained APIs of caffeine, codeine, and paracetamol [45]. Matz and Hill published three papers, of which each evaluated the separation of a different drug class using ESI-IMS-MS. The first paper examined opiates and their metabolites. Their work identified the compounds morphine, normorphine, codeine, norcodeine, 6-monoacetyl 50


morphine, 6-monoacetyl codeine, and heroin by their different ionic species, found in Table 1. They demonstrated the separation of metabolic isomers by their characteristic mobilities, which have important implications for pharmacokinetic studies [46]. The second paper evaluated the separation of amphetamines (i.e. amphetamine (AM), methamphetamine (MA), ethylamphetamine (EA), methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), and methylenedioxyethylamphetamine (MDEA)). Limits of detection (LODs) were in the range of 15.4– 71.8 ppb with limits of quantification (LOQs) in the range of 51.3–239 ppb. The R2 correlation coefficient was at least 0.99 for all six compounds [47]. The third paper evaluated separation of benzodiazepines, namely bromazepam, chlordiazepoxide, diazepam, lorazepam, and oxazepam. LODs were in the range 52.8– 305 ppb for these compounds. The ESI-IMS-MS method employed was sensitive for all five benzodiazepines with good separation. With analysis times of around 70 s for the ESI-IMS-MS method that Matz and Hill developed, its application as a rapid analysis method for drug analysis is obvious [48]. Wu et al. characterized several illicit drugs using an ESI-IMS-MS method and a similar hyphenated method using SESI-IMS-MS. Amphetamine, cocaine, heroin, lysergic acid diethylamide (LSD), MA, morphine, phencyclidine (PCP), and tetrahydrocannabinol (THC) were characterized individually, and a mixture of these compounds excluding PCP and heroin, was separated and identified [26]. McCooeye et al. demonstrated that flow-injection-ESIFAIMS-MS (FI-ESI-FAIMS-MS) could separate and


quantify the stereoisomers of ephedra alkaloids. LODs, in ng/mL, were 0.1, 0.1, 0.2, 2.0, 1.0, and 3.0, for ephedrine (E), pseudoephedrine (PE), norephedrine (NE), norpseudoephedrine (NPE), methylephedrine (ME), and methylpseudoephedrine (MPE), respectively. Evaluation of the FI-ESI-FAIMS-MS method showed good agreement with the conventional LC-ultraviolet (LC-UV) method [49]. In 2003, Cui et al. used ESI-FAIMS-ion-trap MS (ESIFAIMS-ITMS) to separate and to quantify cisplatin, a platinum-based chemotherapeutic drug for cancer, and its mono- and dehydrated complexes. Their method sizably reduced the amount of material required for an analysis, compared to nuclear magnetic resonance (NMR) spectroscopy, and dramatically improved the signal-to-noise ratio for cisplatin, compared to ESI-MS. The LOD for cisplatin was 0.7 ng/mL and there was a linear calibration curve over the concentration range 10–200 ng/mL with an R2 value of 0.9995. They investigated the effects of modifying the carrier gas by adding different amounts of carbon dioxide and helium to the nitrogen used as carrier gas in their method and concluded that a three-gas system provided the best analytical sensitivity [50]. Kapron et al. also used FAIMS to increase the selectivity of analysis by creating an LC-FAIMS-tandem MS (LC-FAIMS-MS2) method to separate an unspecified amine drug and its co-eluting N-oxide metabolite. Their method required sample preparation and handling procedures no different from LC-MS2 methods currently in use. Adding the on-line FAIMS increased the accuracy of the analysis while it retained a level of precision that did not significantly differ from the LC-MS2 method [51]. Guevremont and Kolakowski developed an LC-FAIMSMS method for separation and quantitative analysis of two isobaric, co-eluting caffeine metabolites: theophylline and paraxanthine. Their method was linear over the tested range 0.1–10 ng/lL of theophylline. Accurate measurements of the theophylline concentration, held constant at 0.250 ng/lL, were obtained in samples where the paraxanthine concentration was in the range 0–250 ng/lL [52]. A method for quantifying morphine and noscapine developed by Khayamian et al. used corona-discharge IMS with ammonia as the reagent gas. The LODs of their method were 56 pg morphine and 67 pg noscapine with R2correlation coefficients greater than 0.994 for each [53]. Ochoa and Harrington illustrated that IMS could detect methamphetamine in the presence of nicotine using propyl chloroformate as a derivatization agent [19]. Characterizations of compounds, including cocaine, psilocybin, psilocin, heroin, GHB, and ketamine, by IMS have also been performed by Keller et al., Buryakov and Kolomiets, and Geraghty et al. [25,54–56].

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IMS can quantify specific compounds in stand-alone instruments or hyphenated methods tailored for specific analyses. This attribute allows high-throughput screening by pharmaceutical companies to determine whether an unknown compound (e.g., in the form of a tablet or a liquid) is an authentic product from their company or another legitimate pharmaceutical company, or a counterfeit.

4. Protection of pharmaceutical workersÕ health and safety Exposure to APIs during the manufacturing process of drugs is an issue for pharmaceutical companies that need to monitor the health and safety of their employees. Several methods currently exist to ensure workplace safety; however, IMS offers viable alternatives with their own associated benefits. Environmental monitoring of the air of a manufacturing facility provides a non-invasive way of maintaining a safe working environment. Eiceman et al. monitored a facility that manufactured nicotine-based transdermal systems. Their study used two portable IMS instruments, an unmodified Chemical Agent Monitor (CAM) and a modified Scrubber-CAM. Air samples taken from individuals wearing personal air-sampling pumps and localized vapor levels for nicotine were determined at regions of interest in the facility. LODs were 0.17 lg/m3and 0.02 lg/m3 for collection times of 1 h and 8 h, respectively, which exceeded OSHA standards of 0.5 lg/m3 for an 8-h collection. Eiceman et al. concluded that small, personal IMS instruments were the preferred method of determining nicotine exposure, rather than area-wide monitors because of location-specific nicotine concentrations. However, throughout the facility, they found elevated isopropanol-vapor concentrations, which could most efficiently be monitored with a stationary IMS instrument [57]. Smiths Detection published an application brief detailing the use of its IONSCAN-LS IMS instrument as an alternative to HPLC for personal air monitoring. The unnamed API studied in the brief is a ‘‘high-potency oncologic agent’’ with K0 of 1.3576. Test results using both IMS and HPLC to quantify exposure levels showed good agreement. LOQs of the API using IMS were 7–8 ng versus 30 ng for the corresponding HPLC method [58]. There are direct methods of determining exposure to APIs from biological matrices. Detection of APIs in a urine matrix offers a non-invasive method to ensure worker safety. Lokhnauth and Snow reported the use of SPME-IMS for analysis of ephedrine in urine. The SPME fiber used in their study was a 50/30 lm DVB/CAR/ PDMS fiber. Reduced mobility constants for all three analyte peaks observed in the study showed very little variation between methods using direct injection and http://www.elsevier.com/locate/trac

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SPME injection. A good linear response was determined for the concentration range of 0.1–10 lg/mL [59]. Wang et al. developed a technique for the determination of verapamil in urine using SPME-surfaceenhanced laser-desorption-ionization-IMS (SPME-SELDIIMS). The LOD for their method was estimated at 2 lg/mL in urine [60]. McCooeye et al. quantified samples of codeine and morphine in a urine matrix using ESI-FAIMS-MS. The study compared results of analysis of ESI-MS with those of ESI-FAIMS-MS and found that the ESI-FAIMS-MS method dramatically reduced background interference that normally results from the large amounts of salt present in the urine matrix. Reported LODs were 20 ng/mL for codeine and 60 ng/mL for morphine in urine [61]. The following year, McCooeye et al. published a paper detailing the quantification of AM, MA, MDA, MDMA, and MDEA in urine using their ESI-FAIMS-MS instrument. Their study found LODs of 7.5 ng/mL urine for AM and 0.6 ng/mL urine for MA with correlation coefficients (R2) of greater than 0.99 for the compounds in this study [62]. The benefits of urine analysis by IMS reside in absence of sample treatment, absence of solvents, and enhanced speed, compared to GC and GC-MS techniques. Analysis of illicit drugs in hair using IMS showed good agreement with GC-MS methods and the application of those IMS methods to worker exposure would guarantee greater safety. Miki et al. developed a method for semiquantitative detection of MA in hair. After digesting MA usersÕ hair in NaOH and adding dibenzylamine (DBA) as an internal standard, the digested hair sample was placed onto a Teflon filter for IMS analysis. The LOD for MA in digested hair samples was 0.5 ng/mg hair, but Miki et al. noted that the LOD may differ depending on the presence of other drugs or substances in the hair that compete with MA and DBA in the ionization process [23]. A study by Keller et al. used the hair-digestion method introduced by Miki et al. but added trihexylamine (THA) as an internal standard for the semi-quantification of MDMA and MDEA in hair [24]. Three other biological matrices that may prove useful to the health and safety of pharmaceutical workers are sweat, breath and saliva. Keller et al. qualitatively analyzed cocaine in the sweat of deceased drug addicts. Saliva collectors wiped in several body regions were pressed on a Teflon membrane filter and inserted into the IMS instrument for analysis [54]. A review by Di Francesco et al. contains examples of breath analysis used to determine occupational exposure to toxic substances [63]. Mercer, Shakleya, and Bell examined a breath-based method for the detection of gammahydroxybutyrate (GHB) that they deemed unfeasible, but suggested saliva as a potential matrix for analysis [64]. 52


Due to the risks associated with chronic API exposures, worker health and safety are high priorities for pharmaceutical companies. The quick, non-invasive analyses possible using IMS provide pharmaceutical companies with the tools necessary to provide a safe workplace environment. 5. Conclusions The quick, efficient, portable and inexpensive attributes of IMS instruments make them suitable tools for QC and QA of pharmaceuticals. The results in Table 1 demonstrate that many more pharmaceutical compounds could be characterized using IMS methods. The portability, low LODs and ease-of-use of IMS allow increased speed and efficiency during the cleaning-verification process. The advantages of low LODs, selectivity, low cost and high speed are useful for distinguishing APIs from placebos and authentic pharmaceuticals from counterfeits. Worker health and safety monitoring can be achieved by stationing IMS instruments in the workplace.

References [1] K. Payne, W. Fawber, J. Faria, J. Buaron, R. DeBono, A. Mahmood, Spectroscopy Magazine Online (2005) 24–27. [2] K. Chiarello-Ebner, Pharm. Technol. (2006) 52. [3] Y. Tan, R. DeBono, TodayÕs Chemist at Work (2004) 15. [4] M.J. Cohen, F.W. Karasek, J. Chromatogr. Sci. 8 (1970) 330. [5] C.S. Creaser, J.R. Griffiths, C.J. Bramwell, S. Noreen, C.A. Hill, C.L.P. Thomas, Analyst, Cambridge, U.K., 129 (2004) 984. [6] T.L. Buxton, P.D. Harrington, Appl. Spectrosc. 57 (2003) 223. [7] R.G. Ewing, D.A. Atkinson, G.A. Eiceman, G.J. Ewing, Talanta 54 (2001) 515. [8] M. Tam, H.H. Hill, Anal. Chem. 76 (2004) 2741. [9] K. Tuovinen, H. Paakkanen, O. Hanninen, Anal. Chim. Acta 440 (2001) 151. [10] W.E. Steiner, B.H. Clowers, P.E. Haigh, H.H. Hill, Anal. Chem. 75 (2003) 6068. [11] W.E. Steiner, B.H. Clowers, L.M. Matz, W.F. Siems, H.H. Hill, Anal. Chem. 74 (2002) 4343. [12] P. Rearden, P.B. Harrington, Anal. Chim. Acta 545 (2005) 13. [13] B. Ells, D.A. Barnett, K. Froese, R.W. Purves, S. Hrudey, R. Guevremont, Anal. Chem. 71 (1999) 4747. [14] B. Ells, D.A. Barnett, R.W. Purves, R. Guevremont, Anal. Chem. 72 (2000) 4555. [15] W. Gabryelski, F.W. Wu, K.L. Froese, Anal. Chem. 75 (2003) 2478. [16] G.A. Eiceman, E.G. Nazarov, B. Tadjikov, R.A. Miller, Field Anal. Chem. Technol. 4 (2000) 297. [17] G.A. Eiceman, A. Tarassov, P.A. Funk, S.E. Hughs, E.G. Nazarov, R.A. Miller, J. Sep. Sci. 26 (2003) 585. [18] W. Gabryelski, K.L. Froese, Anal. Chem. 75 (2003) 4612. [19] M.L. Ochoa, P.B. Harrington, Anal. Chem. 76 (2004) 985. [20] A.H. Lawrence, Anal. Chem. 58 (1986) 1269. [21] R.L. Eatherton, M.A. Morrissey, H.H. Hill, Anal. Chem. 60 (1988) 2240. [22] A.H. Lawrence, Anal. Chem. 61 (1989) 343. [23] A.Miki,T.Keller,P.Regenscheit,R.Dirnhofer,M.Tatsuno,M.Katagi, M. Nishikawa, H. Tsuchihashi, J. Chromatogr. B 692 (1997) 319.

Trends in Analytical Chemistry, Vol. 27, No. 1, 2008 [24] T. Keller, A. Miki, P. Regenscheit, R. Dirnhofer, A. Schneider, H. Tsuchihashi, Forensic Sci. Int. 94 (1998) 55. [25] T. Keller, A. Schneider, P. Regenscheit, R. Dirnhofer, T. Rucker, J. Jaspers, W. Kisser, Forensic Sci. Int. 99 (1999) 93. [26] C. Wu, W.F. Siems, H.H. Hill, Anal. Chem. 72 (2000) 396. [27] G.A. Eiceman, Z. Karpas, Ion Mobility Spectrometry, CRC Press, Boca Raton, FL, USA, 1994. [28] R. Guevremont, J. Chromatogr. A 1058 (2004) 3. [29] J. Stach, J.I. Baumbach, Int. J. Ion Mobility Spectrom. 5 (2002) 1. [30] B.M. Kolakowski, Z. Mester, Analyst (Cambridge, U.K.) 132 (2007) 842. [31] US Food and Drug Administration, ‘‘Enforcement Policy: Electronic Records; Electronic Signatures – Compliance Policies Guide: Guidance for FDA Personnel,’’ Federal Register (Notices) 64 (139) (1999) 39,146. [32] US Food and Drug Administration, Analytical Procedures and Methods Validation: Chemistry, Manufacturing, and Controls, Federal Register (Notices) 65 (169) (30 August 2000) 52,776. [33] Smiths Detection, Detection and Quantitative Analysis of Lactose Using Ion Mobility Spectrometry, Application Brief AB-080 (http://smithsdetection-sci.com/). [34] L. Bush, Pharm. Technol. (June 2004) 18. [35] J.D. Carroll, Ion Mobility Spectrometry as an Alternative to HPLC for Cleaning Verification (http://smithsdetection-sci.com/). [36] R. Munden, R. Everitt, R. DeBono, J. Carroll, R. Sandor, Pharm. Technol. Eur. 14 (2002) 66. [37] R. DeBono, S. Stefanou, M. Davis, G. Walia, Pharm. Technol. 26 (2002) 72. [38] R. DeBono, J. Carroll, a2c2 Magazine (July/August 2002) 21. [39] G. Walia, M. Davis, S. Stefanou, Pharm. Process. (September 2003). [40] J. Carroll, T. Le, R. DeBono, Am. Lab. News (February 2004) 32. [41] D.E. Peterson, G.C. Eden, C.R. Apodaca, D.P. Argyres, A.L. Kennedy, J.G. Barnhill, L.A. Felton, AAPS Newsmagazine (2005) 18 (http://www.aapspharmaceutica.com). [42] G.A. Eiceman, D.A. Blyth, D.B. Shoff, P.A. Snyder, Anal. Chem. 62 (1990) 1374.

Trends [43] J.K. Lokhnauth, N.H. Snow, Anal. Chem. 77 (2005) 5983. [44] D.J. Weston, R. Bateman, I.D. Wilson, T.R. Wood, C.S. Creaser, Anal. Chem. 77 (2005) 7572. [45] N. Budimir, D.J. Weston, C.S. Creaser, Analyst (Cambridge, U.K.) 132 (2007) 34. [46] L.M. Matz, H.H. Hill, Anal. Chem. 73 (2001) 1664. [47] L.M. Matz, H.H. Hill, Anal. Chem. 74 (2002) 420. [48] L.M. Matz, H.H. Hill, Anal. Chim. Acta 457 (2002) 235. [49] M. McCooeye, L. Ding, G.J. Gardner, C.A. Fraser, J. Lam, R.E. Sturgeon, Z. Mester, Anal. Chem. 75 (2003) 2538. [50] M. Cui, L. Ding, Z. Mester, Anal. Chem. 75 (2003) 5847. [51] J.T. Kapron, M. Jemal, G. Duncan, B. Kolakowski, R. Purves, Rapid Commun. Mass Spectrom. 19 (2005) 1979. [52] R. Guevremont, B. Kolakowski, Am. Lab. 37 (2005) 11. [53] T. Khayamian, M. Tabrizchi, M.T. Jafari, Talanta 69 (2006) 795. [54] T. Keller, A. Keller, E. Tutsch-Bauer, F. Monticelli, Forensic Sci. Int. 161 (2006) 130. [55] I.A. Buryakov, Y.N. Kolomiets, Anal. Chem. 58 (2003) 944. [56] E. Geraghty, C. Wu, W. McGann, Int. J. Ion Mobility Spectrom. 5 (2002) 41. [57] G.A. Eiceman, S. Sowa, S. Lin, S.E. Bell, J. Hazard. Mater. 43 (1995) 13. [58] Smiths Detection, IMS Detection and Quantification of Active Pharmaceutical Ingredients for Personal Air Monitoring, Application Brief AB-078 (http://smithsdetection-sci.com/). [59] J.K. Lokhnauth, N.H. Snow, J. Sep. Sci. 28 (2005) 612. [60] Y. Wang, S. Nacson, J. Pawliszyn, Anal. Chim. Acta 582 (2007) 50. [61] M.A. McCooeye, B. Ells, D.A. Barnett, R.W. Purves, R. Guevremont, J. Anal. Toxicol. 25 (2001) 81. [62] M.A. McCooeye, Z. Mester, B. Ells, D.A. Barnett, R.A. Purves, R. Guevremont, Anal. Chem. 74 (2002) 3071. [63] F. Di Francesco, R. Fuoco, M.G. Trivella, A. Ceccarini, Microchem. J. 79 (2005) 405. [64] J. Mercer, D. Shakleya, S. Bell, J. Anal. Toxicol. 30 (2006) 539.


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