Quantitative mass spectrometry methods for pharmaceutical analysis.

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Quantitative mass spectrometry methods for pharmaceutical analysis Glenn Loos, Ann Van Schepdael and Deirdre Cabooter

Review Cite this article: Loos G, Van Schepdael A, Cabooter D. 2016 Quantitative mass spectrometry methods for pharmaceutical analysis. Phil. Trans. R. Soc. A 374: 20150366. http://dx.doi.org/10.1098/rsta.2015.0366 Accepted: 25 May 2016 One contribution of 19 to a theme issue ‘Quantitative mass spectrometry’. Subject Areas: analytical chemistry Keywords: mass spectrometry, matrix effects, hyphenated techniques, sample preparation, pharmaceutical analysis, internal standards Author for correspondence: Deirdre Cabooter e-mail: [email protected]

KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, Herestraat 49, 3000 Leuven, Belgium DC , 0000-0001-5502-5801 Quantitative pharmaceutical analysis is nowadays frequently executed using mass spectrometry. Electrospray ionization coupled to a (hybrid) triple quadrupole mass spectrometer is generally used in combination with solid-phase extraction and liquid chromatography. Furthermore, isotopically labelled standards are often used to correct for ion suppression. The challenges in producing sensitive but reliable quantitative data depend on the instrumentation, sample preparation and hyphenated techniques. In this contribution, different approaches to enhance the ionization efficiencies using modified source geometries and improved ion guidance are provided. Furthermore, possibilities to minimize, assess and correct for matrix interferences caused by co-eluting substances are described. With the focus on pharmaceuticals in the environment and bioanalysis, different separation techniques, trends in liquid chromatography and sample preparation methods to minimize matrix effects and increase sensitivity are discussed. Although highly sensitive methods are generally aimed for to provide automated multi-residue analysis, (less sensitive) miniaturized set-ups have a great potential due to their ability for in-field usage. This article is part of the themed issue ‘Quantitative mass spectrometry’.

1. Introduction Electronic supplementary material is available at http://dx.doi.org/10.1098/rsta.2015.0366 or via http://rsta.royalsocietypublishing.org.

Since the introduction of mass spectrometry (MS) in analytical chemistry, multiple adjustments have been made to improve its performance. Numerous

2016 The Author(s) Published by the Royal Society. All rights reserved.

(a) Mass analyzers Because UV detection is a cheap, very accessible, robust and straightforward technique, it still plays a key role in pharmaceutical analysis [8,9]. Molecules without chromophores can, however, not be detected and its low specificity is a major drawback when complex matrices are considered. For this reason, MS became a major player in pharmaceutical sciences giving rise to an exponentially increasing number of publications in the field of analytical chemistry. The performance and operation of the various mass spectrometers available on the market have consequently already been described in detail in the literature. A number of comprehensive reviews compare the advantages and disadvantages associated with the use of specific instruments and provide a clear overview that can be consulted before selecting an apparatus to perform specific experiments [2,10–12]. To be clear, every mass spectrometer has its advantages and limitations and comparing different instruments is therefore difficult. In contrast with (U)HPLC-UV, the results obtained with MS are not congruent, but rather instrument dependent and can be distinct when one sample is analysed with different types of mass spectrometers.

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2. Instrumental advances

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rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150366

techniques have been developed to ionize, scan, focus, fragment and detect chemical structures [1]. In the early days of MS, the ability to detect individual precursor–product ion pairs mainly allowed the identification of different structures by fragmenting molecules into smaller building blocks. Nowadays, analytes can also be identified based on very accurate masses obtained by high-resolution mass spectrometry (HRMS) [2,3]. New developments have led to more sensitive, selective, robust and repeatable analyses. The enhanced accuracy and repeatability of the new generation of mass spectrometers allows using these instruments not only for the identification but also for the quantitation of analytes. In this way, MS has evolved into an established value within e.g. pharmaceutical, (bio)chemical, (bio)medical, biological and environmental sciences. A mass spectrometer is often wrongfully seen as merely an alternative to UV/VIS, flame ionization, fluorescence and electrochemical detection. Owing to its detection principle based on analysing specific mass-to-charge ratios, a mass spectrometer can also be used as an independent separation technique [4]. However, the stand-alone use of a mass spectrometer remains extremely challenging because the complexity of samples in emerging fields such as environmental, toxicological and biomarker discovery studies demand highly sensitive and selective measurements to avoid interferences. For example, the analysis of trace elements in complex matrices such as waste water, blood or urine remains a major challenge [5,6]. To obtain high sensitivity or to avoid injecting extremely dirty samples, it is recommended to perform a sample preparation step prior to analysis. Examples of frequently used sample preparation strategies are liquid/liquid extraction (LLE), protein precipitation, solid-phase extraction (SPE) and all derived forms hereof. Alternatively or additional to sample preparation, an extra separation step is typically added to the methodology. Gas chromatography (GC), capillary electrophoresis (CE) and liquid chromatography (LC) are the most commonly used techniques to ensure not all molecules enter the ionization source simultaneously. As a result, the signal is less subjected to matrix effects (MEs) leading to an increased sensitivity [7]. A major challenge is the development of repeatable sample preparation methods that give acceptable and reliable recoveries to guarantee the correct representation of the obtained result. For that reason, the use of internal standards should be considered. This review gives an overview of equipment and techniques used to quantify pharmaceuticals in complex samples. Furthermore, various sample preparation and standardization procedures to validate quantitative analytical methods are discussed. The advantages and limitations of every method are carefully considered. Finally, a brief summary of recent applications demonstrates the current quantitation possibilities for pharmaceuticals in complex matrices.

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Therefore, the inter-laboratory transfer of a certain methodology is a complex procedure, which demands a thorough validation prior to use. It is thus of major importance that the types of both ionization and mass spectrometer are described. Further, the choice for a specific type of mass spectrometer depends particularly on the type of research that will be conducted. There is no point in comparing a triple quadrupole (QQQ) that has a high scan rate and low resolution with a time-of-flight (TOF) instrument with the opposite specifications, because they are mainly used to study different things. Because these devices are rather complementary, they should be used together or alternately in an ideal scenario [13,14]. Nevertheless, the performance of different mass spectrometers is often compared to determine the optimal analysis conditions for certain compounds [15,16]. Comparing the quantification of opioid drugs in human plasma using a QQQ and QTOF instrument, Viaene et al. [15] for example showed that the best performing instrument in terms of selectivity, MEs, repeatability, accuracy and sensitivity is compound and even concentration dependent. Remarkably, the QTOF proved to be more sensitive than the QQQ for most drug compounds in this experiment. The authors indicated that this was mainly due to the choice of the ions that were selected for quantitation. In the QTOF experiment, opioids were quantified using the precursor ions while the QQQ measurements required product ions, which are less abundant [15]. Because a more recent QTOF was compared with a QQQ from a previous generation, the higher sensitivity of the QTOF could be related to the improvements made to this new instrument. Given the high cost of a mass spectrometer, many research laboratories lack the financial resources to purchase various state-of-the-art devices. Moreover, the cumbersomeness of using different instruments to analyse one sample is preferably avoided. The recent development of hybrid devices combining the benefits of multiple instruments, therefore, allows researchers to use the same tool for various purposes [17,18]. Two interesting examples are the QTrap and the QTOF, which are in fact triple quadrupoles wherein the last quadrupole is replaced by a linear ion trap or a TOF tube, respectively. As a result, the high speed and sensitivity of a conventional QQQ is combined with a higher resolution in the case of a QTOF or with MSn capability in case of a QTrap, respectively. When comparing these two instruments, it should be noted that both devices are extremely suitable for both identification and quantification [17,19,20]. The QTOF can therefore be used in HRMS, but its slightly lower scan speed limits the duty cycle when multiple analytes have to be quantified. Although orbitrap mass analysers have a reduced acquisition speed, they are increasingly used in pharmaceutical industry owing to their very high resolution. The resolving power up to 500 000 full width at half maximum (FWHM) with an isotopic fidelity up to 240 000 FWHM at m/z 200 that can be obtained with the newest generation is mainly used to elucidate proteomic and metabolomic pathways [21]. Recently, Lin et al. published a clear overview of the different types of hybrid HRMS and their characteristics [10]. Although the main focus of manufacturers seems to be on the development of more accurate, faster and robust instruments with an ultimate sensitivity and resolving power, there is also an evolution towards miniaturization (electronic supplementary material, figure S1). Despite the reduced sensitivity and resolving power due to the smaller residence time in miniaturized mass analysers, there are currently portable devices on the market that can be used in the field [22–24]. For most applications, however, the limited sensitivity is an insuperable problem. Another major concern is to get an appropriate vacuum which is necessary to obtain accurate, sensitive and repeatable measurements [25,26]. Furthermore, in comparison with laboratory conditions, these portable set-ups are exposed to varying environmental parameters such as temperature and humidity, which are detrimental for the accuracy of the measurements (particularly important for TOF tubes) [2]. Nevertheless, portable devices are an important development, which deserves special attention. They have a great future ahead when improvements and new techniques will be developed to overcome current issues. These miniaturized instruments will, for example, have great potential in clinical diagnostics, where fast and simple techniques are required to perform on-site analysis [22,27].

(b) Ionization methods

Instrument manufacturers realized that a gain in sensitivity can mainly be achieved by optimizing the ion formation and treatment. Therefore, some manufacturers optimized the design of the ionization source. Periat et al. varied the mobile phase conditions in HILIC and RPLC

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(c) Ion formation and guidance


The resolving power and speed is related to the type of mass spectrometer and, in particular, the type of mass analyser used. Using HRMS or working in multiple reaction monitoring (MRM) mode can drastically decrease the background noise of a spectrum and will therefore have a positive influence on the signal-to-noise ratio which often leads to an increased sensitivity [28]. However, sensitivity remains particularly related to the improved formation and guidance of analyte ions [10,29]. During ionization, only a certain fraction of the analytes is ionized and only part of them will subsequently reach the mass analyser [30]. To perform a reliable quantification in MS experiments, it is of great importance that there is no aberration in the fraction of ionized analytes during different analytical runs. Depending on the type of research and sample, different ionization sources are used. A new trend is the use of ambient ionization techniques, which allows direct sample analysis with minimal or no sample pre-treatment. The major advantage is the speed and simplicity with which the measurements can be carried out. Ions can be directly created from gaseous, liquid or solid samples in open air. A comprehensive overview of ambient (plasmabased) ionization techniques such as desorption electrospray ionization (DESI), direct sample analysis in real time (DART) and paper spray ionization are given by Huang et al., Ding & Duan, and Monge et al. [31–33]. Besides the working mechanisms, they also describe some applications in which these techniques are used. Although ambient ionization MS can be used quantitatively for point-of-care diagnostics, sensitivity and primarily reproducibility remain an issue compared to chromatography-based MS [32,34]. Therefore, atmospheric pressure chemical ionization (APCI), atmospheric pressure photo-ionization (APPI) and, in particular, electrospray ionization (ESI) are still the ionization methods of choice in pharmaceutical analysis. These types of ionization can easily atomize the mobile phase when hyphenated with LC, even in highly aqueous conditions and at high-flow rates [29]. Although multiple charged ions can occur, these soft ionization techniques mainly result in singly charged ions [28]. The inferior ionization of certain pharmaceuticals can therefore result in a reduced sensitivity and/or unreliable results. Various molecules can demand different ionization modes. Acidic functional groups easily lose a proton and are thus more likely ionized in negative mode. However, pharmaceutical analyses are generally performed in positive mode, because most drugs are weak bases and thus easily protonated [35,36]. Because the ions produced by an APCI and/or APPI interface are not necessarily the same as the ones formed in an ESI source, these techniques are alternately used depending on the type of analytes. For the analysis of rather apolar/volatile compounds, ions are preferably produced by an APCI source as they can evaporate in the ESI spray without being charged [37]. Therefore, Waters (ESCi) and later also AB Sciex (IonDrive DuoSpray) came up with a multimode ionization source which can alternately switch between ESI and APCI to ionize every analyte in the sample [10,38,39]. This allows the successful analysis of both polar and apolar compounds. The simultaneous use of APCI and ESI has recently been improved by Cheng et al. [40] with the development of a concentric ESI + APCI dual ionization source (figure 1) which can be operated in ESI only, APCI only and ESI + APCI mode. Polar pharmaceuticals are mainly ionized using ESI [38,41]. The desolvation efficiency during ESI depends on the mobile phase, the matrix, wherein the analyte is dissolved and the ionization source design as demonstrated by Periat et al. [29]. High concentrations of organic solvents used in hydrophilic interaction liquid chromatography (HILIC) separations, for example, can easily evaporate and will promote ionization relative to the highly aqueous mobile phases used in RPLC [29,42].

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(a)

(b)

stainless steel tube

APCI-only

glass tube ESI + APCI

fused capillary (i.d.100 mm, o.d. 375 mm)

ring electrode (AC high voltage) APCI plasma

copper rod (DC high voltage)

ESI plume

Figure 1. Scheme (a) and photograph (b) of the concentric ESI + APCI dual ionization source. Reprinted with permission from [40]. (a)

(b)

grounded nebulizer

HV target 1–3 mm

flow streamlines

7 mm

ion inlet 5 mm

Figure 2. Sideview (a) and frontview (b) of the UniSpray ionization source. Reprinted with permission from [44]. (Online version in colour.) to study the effect of different ESI sources on the obtained sensitivity [29]. Only a limited number of instruments were compared, but from these experiments, it was concluded that the Turbo V source from AB Sciex, the new Jet Stream thermal gradient focusing technology from Agilent and the optimized Z-spray source from Waters are more robust than classical ESI sources. The evaporation efficiency in the newly developed ionization sources was higher, especially for mobile phases containing a large percentage of organic modifier, and allowed the use of much higher flow rates compared to ESI sources from previous generations [29]. The gain in sensitivity related to mobile phase evaporation and the impact of new-generation ionization sources have also been confirmed by Grand-Guillaume Perrenoud and Novakova et al. by comparing the sensitivity of UHPLC with ultra-high-performance supercritical fluid chromatography (UHPSFC). Owing to the higher desolvation efficiency of the MeOH surrounded with compressed CO2 in the UHPSFC mobile phase, a gain in sensitivity was observed for the less retained drugs which elute under aqueous conditions in UHPLC [36,43].

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acidic methanol solution

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ESI-only


nebulizing gas inlet (N2)

(a) Ion suppression and enhancement With the introduction of new high-resolution mass spectrometers, molecules can be analysed with a very high accuracy. These instruments are often used with minimal or even without prior sample treatment because interfering masses can be separated owing to the impressive resolving power of the mass analysers [50,51]. Indeed, the high specificity of current equipment will lower the MEs caused by equivalent masses. Unfortunately, ion suppression and/or enhancement introduced during the sample ionization are not always visible in the chromatogram. Therefore, Taylor called MEs the ‘Achilles heel’ of quantitative MS [52]. Over the years, many studies have been performed and numerous reviews published to evaluate MEs in atmospheric pressure ionization MS which is still considered to be the standard for quantitative pharmaceutical analysis. In these articles, different hypotheses have been postulated; however, the exact mechanism of ion suppression or enhancement remains unresolved. MEs are influenced by multiple factors such as analyte characteristics, type of matrix, sample preparation procedure, chromatographic conditions, type of ionization and mass spectrometer settings as described in table 1 [7,19,52–56]. It is very likely that these features have a synergic effect on the ionization; however, it cannot be ruled out that MEs can be allocated to only one cause [55]. In APCI, molecules are transferred to the gas phase followed by chemical ionization. In ESI, the analytes become ionized when they escape from a charged droplet during evaporation. Therefore, ESI is assumed to be more prone to ion suppression, especially for polar, hence less volatile compounds that remain trapped in the matrix droplets [37,53]. Reactions can moreover neutralize some of the ions in the gas phase [55]. For ESI, it is generally known that co-eluting matrix components have a deleterious effect on the ionization efficiency. In particular, less or non-volatile co-eluting solutes will hamper droplet formation and hinder solvent desolvation. An undesirable competition between pharmaceuticals and co-eluting substances for the excess of charge to get ionized can arise as well. Therefore, MEs highly depend on the structure and thus physico-chemical properties of both the analytes and matrix components [37,53].

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3. Matrix effects

6


Besides sensitivity issues, source design modifications can also result in more robust, repeatable and therefore more reliable data. Very recently, Lubin et al. [44] compared a Unispray ionization source, wherein a highly charged metal rod is added between the grounded/neutral ESI nebulizer and the ion inlet of the mass spectrometer (figure 2) with a conventional ESI source for the analysis of prostaglandins and thromboxanes. Analysing diverse sample matrices, an equivalent or better linearity and repeatability could be demonstrated for the Unispray combined with an increase in sensitivity up to a factor 5. Considering the use of a charged rod positioned at a small distance from the nebulizer to ionize the analytes, this source should be capable of ionizing more volatile compounds compared with a Z-spray ESI source from Waters. However, the ionization principle still has to be characterized [44]. In addition to the ionization source geometry, improvements to the ion guidance are implemented to guarantee an optimal introduction of analytes in the mass analyser(s). Very recently, Lin et al. [10] published an overview of tandem high-resolution MS wherein they described how different manufacturers applied various techniques to augment the ion guidance from the source towards the analyser. These data are compiled in electronic supplementary material, table S1 to provide a comprehensive summary of the principal ion guidance mechanisms [10,21,45,46]. Adjustments to optimize the ion guidance have a positive influence on the sensitivity and repeatability of measurements. Moreover, with the introduction of ion mobility separators, ions of similar mass-to-charge ratio but different mass or structure can be separated. Therefore, this technique is frequently employed in drug discovery and development studies to identify structural changes, antibody–drug conjugates, protein–ligand bindings, isomers and metabolites [47–49].

Table 1. Overview of different factors that can have a disadvantageous or beneficial influence on matrix effects [52–58].

electrospray ionization

optimized source geometry

presence of large molecules

alternative ionization principle e.g. APCI

positive ionization mode

negative ionization mode

high-flow rates

small flow rates or flow splitting

aqueous mobile phase conditions

miniaturization

co-eluting substances:

enhanced chromatographic separation

.......................................................................................................................................................................................................... .......................................................................................................................................................................................................... .......................................................................................................................................................................................................... .......................................................................................................................................................................................................... .......................................................................................................................................................................................................... ..........................................................................................................................................................................................................

ionic species e.g. salts

high content organic modifier in mobile phase

highly volatile analytes

small injection volumes

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hydrophilic contaminants

optimized sample preparation

similar organic molecules

adjusted MS settings

competitive internal standards

reduced matrix/analyte ratio (dilution)

mobile phase additives

matrix effect correction:

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e.g. ion-pairing agents, buffers, acids

matrix-matched standardization

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standard addition method

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post-column infusion

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echo-peak method

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stable isotopically labelled standards

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(b) Method validation The variation in ion suppression or enhancement between samples can influence the reliability of the analysis. Highly complex matrices may cause interferences that can lead to incorrect determinations and even false positive or negative results. Therefore, every LC-MS methodology should be validated to obtain reliable quantitative results, even when actions are taken to compensate for MEs [55,57]. Concerning this topic, the group of Matuszewski made a large contribution. They composed assays to determine precision, accuracy, recovery, cross-talk, absolute and relative MEs [58–60]: Precision: covariance calibration curve slopes for replicate analysis (n = 5) Accuracy: [(mean observed concentration)/(spiked concentration)] × 100% Recovery: ratio between mean peak areas of analytes spiked before and after extraction Cross-talk: cross-contamination between IS and analytes can be examined by subsequent injection of a sample containing (i) an IS and (ii) the analyte at the highest concentration of the standard curve and respectively monitor the MS/MS response for the drug (first injection) and the IS (second injection). — Absolute ME: response difference analytes spiked in extracted matrix and solvent samples — Relative ME: relative standard deviation of absolute ME in samples from different sources — — — —

Because ion suppression or enhancement can differ between similar samples from different lots, Bonfiglio et al. [61] came up with an alternative post-column infusion technique to assess MEs. In this approach, the analytes are continuously post-column infused using a syringe pump to get a representation of the retention-time related matrix effect. Co-eluting matrix substances will influence the constant detector response and can thus be used to correct for suppression or enhancement [61]. Post-extraction spiking and post-column infusion matrix

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positive effect


negative effect

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To avoid co-elution of different molecules and thus MEs, preliminary chromatographic separations are often applied. Hyphenation of for example CE, GC and LC with a mass spectrometer will drastically decrease the simultaneous introduction of interfering components in the source.

(i) State-of-the-art chromatography Although recent reviews by El Deeb et al. [66] and Breadmore et al. [67] show that extensive efforts have been made to improve the sensitivity of CE, CE-MS remains mostly applied in proteomics, metabolomics and enzymatic studies. The quantification of pharmaceutical compounds is less common; however, due to its selectivity CE-MS can be used to differentiate and quantify enantiomers. Liu et al. [68] for example developed an assay to quantify the enantiomers of venlafaxine and O-desmethylvenlafaxine in the determination of drug–drug interactions. Because of the small sample volumes required and the low operating cost, CE-MS has a large potential for bioanalytical studies. The small injection volumes in CE, however, also results in a low sensitivity (high to mid microgram per litre range) even when combined with pH-mediated stacking or SPE to enhance the sensitivity [68,69]. In general, CE is hyphenated to MS using an ESI source. The background electrolyte solution is thus subjected to numerous limitations in order to obtain reliable quantitative results. The electrolyte salts must be volatile and have low surface affinity to avoid excessive MEs. Consequently, this will limit the possibilities to obtain optimal resolution, selectivity and sensitivity [69]. Finally, it is known that CE has an inferior repeatability compared with LC and can mainly be used to analyse charged molecules. A less common separation technique is high-performance thin-layer chromatography (HPTLC). Its advantages such as high selectivity and efficiency, low detection limits, no carry-over

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(c) Hyphenation with separation techniques

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assessment procedures are generally accepted to validate LC-MS methods and are therefore used in numerous bioanalytical studies and summarized by e.g. Van Eeckhaut et al. and Peters & Remane [54,56]. The high selectivity of a chromatographic separation combined with mass spectrometric detection allows the multicomponent analysis of difficult samples. Besides previously described validation parameters also robustness, quantification limits, linearity range, quality control and sample stability can be tested. In general, robustness can be verified using columns from different batches or manufacturers. Small alterations in mobile phase composition, column temperature and injection volume can furthermore be evaluated. Finally, validation experiments can be performed by a different operator to assess robustness [62]. Acceptance criteria for bioanalytical method validation can be different depending on the used guidelines. A large number of internationally or nationally accepted guidelines such as the International Conference on Harmonisation (ICH) guidelines are provided by numerous organizations, such as the International Organization for Standardization (ISO), International Union of Pure and Applied Chemistry guidelines (IUPAC), Bureau International de Poids et Mesures (BIPM), US Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), American Association of Pharmaceutical Scientists (AAPS) and European Medicines Agency (EMA) [56,63,64]. An overview of these agencies is reviewed by Wille et al. and Gonzalez et al. [63,64]. The variation on sample precision, accuracy, recovery and MEs should always be below 15% or 20% when working against the limit of quantification (LOQ) [63]. The most widely used guidelines are those proposed by the FDA, AAPS, IUPAC and EMA and although acceptance criteria show many similarities, some of them are open for interpretation. The LOQ determination is for example based on the signal-to-noise ratio which has to be more than 5 or more than 10. The assessment of the signal-to-noise ratio is, however, not defined and can therefore be interpreted and applied differently depending on method requirements. When working in MS/MS mode or in HRMS the noise may be filtered out. LOQ values are sometimes statistically calculated using the 95% confidence limit of the mass error or using the (relative) standard deviation of the signal at low concentrations [65].

Considering most pharmaceutical compounds are non-volatile, LC remains the most prominent technique to separate complex samples prior to mass spectrometric analysis. Extensive research

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(ii) Trends in liquid chromatography

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effects, limited or no sample preparation requirements, low mobile phase consumption, fast separation times and the possibility to analyse multiple samples simultaneously make HPTLC a very simple, fast and cheap technique for pharmaceutical analysis [70,71]. The potential of HPTLC in combination with MS to identify drugs and metabolites in urine was already demonstrated in 1999 by Tames et al. [72]. Over time, the evolution of this technique declined, making HPTLC a bit of a forgotten technique wherein only a limited number of groups were specialized. However, the group of Morlock revived HPTLC-MS by converting an inkjet printer to an autosampler, which allows an automated and precise dosing of the sample on the plate [73]. With this development, HPTLC-MS might have a promising future for the quantitative analysis of nonvolatile pharmaceuticals in environmental, food and biological samples because MEs are limited and highly reproducible and very sensitive measurements can be performed [70,74,75]. Another revived chromatographic technique is supercritical fluid chromatography (SFC). The introduction of new UHPSFC equipment with minimal dead volumes, higher backpressure limits and more stable flow rates together with optimized MS interfaces has eliminated the main issues long associated with this technique [43]. Using supercritical CO2 in combination with small amounts of organic modifiers, the mobile phases in UHPFSC are environmental friendly, nonviscous and volatile. Therefore, longer and thus more efficient columns can be used to separate complex samples at high linear velocities. The group of Guillarme further demonstrated that UHPSFC-MS is more robust than UHPLC-MS because it is less susceptible to small changes in ionization parameters. Owing to the more volatile mobile phases in comparison with those in UHPLC, UHPSFC-MS can moreover be more sensitive and less prone to MEs, especially for polar analytes. Because of the different selectivities and retention mechanisms, UHPSCF-MS is considered as an alternative or complementary approach to UHPLC-MS. Owing to its high potential applicability in the field of bioanalysis and enantioselective separations, SFC-MS is increasingly used to analyse pharmaceuticals in biological samples [36,76–79]. A more frequently used separation technique in pharmaceutical analysis is GC. Although GCMS is limited to the measurement of volatile or semi-volatile compounds, it is regularly used in environmental studies and to a lesser extent in bioanalysis and impurity profiling [80–83]. Because pharmaceuticals are in general polar, non-volatile molecules, derivatization reactions are required to make them suitable for GC analysis. To simplify and make this laborious process less time consuming, derivatization is sometimes conducted simultaneous with the sample preparation [81]. In order to enable multi-residue analysis, Kumirska et al. [84] introduced a derivatization approach, which allows the simultaneous analysis of pharmaceuticals from six different drug classes in the nanogram per litre range. Because most GC-MS experiments are performed using electron ionization (EI) and many analysts are not aware of the signal drift that can occur using this type of ionization, the reliability of some results may be questionable. D’Autry et al. [85] demonstrated that when stainless steel was used in the EI source, the MS signal decreased in consecutive runs. This error could be countered with an internal standard, but experiments showed a various drift pattern for different homologous compounds. The use of isotopically labelled internal standards therefore seems insufficient to correct for signal drift when high accuracy levels are required to perform quantitative analysis. It was demonstrated that conventional EI sources should rather be modified by applying a gold coating to obtain reliable data [85]. Alternatively, a different ionization source can be used. Although Raro et al. [86] demonstrated that the peak areas using EI were generally more repeatable, APCI was successfully used to screen androgenic anabolic steroids in urine samples. Detection limits obtained with APCI were 5–20 times lower than those obtained with EI. However, it should be noted that due to the impossibility to interchange both sources, the APCI and EI interfaces were coupled to different mass spectrometers. This could have had an influence on the final sensitivity [86].

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has been carried out and numerous reviews have been published concerning new trends and developments in LC [87–90]. In the last decade, LC has evolved into ultra-high pressure liquid chromatography (UHPLC) to obtain a higher throughput. To prevent or minimize co-elution and hence MEs in LC-MS, the highest possible peak capacities are pursued by increasing the efficiency of the columns. Currently, this is mainly done by decreasing the particle size (less than 2 µm) of the stationary phase as demonstrated by Jakimska et al. [91]. Because smaller particles result in higher backpressures, a new generation of UHPLC equipment is required to carry out the chromatographic runs under these demanding conditions. A comparison of the most recent UHPLC instruments on the market can be found in De Vos et al. or Nazario et al. [89,92,93]. Alternatively, using core–shell particles with a solid core and a porous shell, the backpressure can be reduced with similar or better efficiencies [94,95]. Another option to reduce the backpressure is the use of monolithic columns, which have a stationary phase made of one single rod of porous silica-based or polymer material. Therefore, this material can be used at high-flow rates to elevate the sample throughput or in longer dimensions to increase the efficiency. Despite these benefits, monoliths are not commonly used. The limited number of available selectivities and column geometries, low maximum backpressures (200 bar) and problems with the structural homogeneity of the rod should first be overcome before these columns can compete with currently available sub-2 µm and core–shell particles. Further research is thus necessary to improve the production process and provide a wide selection of monoliths with repeatable performances [96,97]. With numerous improvements in stationary phase material and a better understanding of the retention principles in HILIC, the use of HILIC for the analysis of polar pharmaceuticals in bioanalysis has increased drastically in the last decade [13,98–100]. Because HILIC separations require organic solvent rich mobile phases, the use of HILIC can moreover be advantageous in terms of sensitivity and MEs as previously discussed. A clear overview of commercially available HILIC stationary phases can be found in Kohler et al. [101]. As can be seen in recently published reviews, HILIC columns are much less frequently used in environmental studies. Most water analyses are still done using reversed-phase (RP) stationary phases and in particular C18 columns [91,102–104]. However, to allow the simultaneous analysis of polar and apolar compounds, both RP and HILIC columns can be combined. In this way, highly polar substances are subjected to an improved separation and interferences will be spread more resulting in reduced MEs [104]. The coupling of orthogonal stationary phases is usually done with a T-piece or switching valves and a second pump to dilute the mobile phase of the first dimension post-column to make the eluate compatible with the second dimension separation [104–106]. Although it has not yet been used to analyse real water or biological samples, an alternative approach to couple HILIC and RP columns in series has recently been proposed [107,108]. Because of the high potential for on-site and high-throughput applications, downscaling dimensions is also a trend in LC instrumentation. Several reviews give an overview of the advances made in both column sizes and LC modules [87,93,109,110]. The major advantage of miniaturized LC set-ups is the enhanced sensitivity due to higher efficiencies, lower flow rates and minimized void volumes, which will have a positive influence on the ionization efficiency and the peak shapes [111]. Additionally, the run time and solvent consumption are reduced which results in more environmental friendly and economic analysis. Therefore, conventional HPLC systems have evolved into capillary or micro-LC and even nano-LC devices. The recent development of microfluidic chromatography and micro-chip-based systems such as the Agilent Chip Cube or Waters IonKey wherein an optimized MS interface is incorporated, offers the possibility to perform automated, robust and very sensitive LC-MS analysis with a limited amount of sample [87]. More information about microfluidic LC can be found in Rainville et al., Wang et al. and Šesták et al. [110,112,113]. Advances made in hand-portable LC instrumentation will moreover allow its use on-site and therefore have a huge potential in environmental and bioanalysis [114].

(d) Sample preparation

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As previously described, co-elution of matrix substances can have negative effects on the ionization. To avoid ion suppression or enhancement and to obtain reliable quantitative results in mass spectrometric analysis, additional separation techniques are performed prior to MS introduction. Furthermore, sample preparation methods can be applied to clean-up the sample and minimize co-elution of different molecules. Although sample preparation can significantly reduce matrix interferences, its main purpose in environmental or bioanalysis is to preconcentrate the analytes of interest to enhance the sensitivity. Numerous methodologies can be applied to extract the analytes of interest. However, in general only a small number of techniques based on the partitioning between two phases are frequently used. Another popular sample preparation technique is dried blood spots (DBSs) wherein small drops of whole blood are collected and air-dried on filter paper. These DBSs can cost-effectively be shipped and stored at room temperature, while only small solvent volumes (5 µl) are required to extract the analytes. Using an inox desorption cell, desorption can be performed online, allowing the direct analysis of a DBS in combination with LC-MS [115]. For quantitative analysis, liquid– liquid extraction (LLE) with an aqueous and organic solvent used to be the standard. Over the years different advances, such as working at elevated temperatures and pressures in pressurized liquid extraction (PLE), miniaturization in liquid–liquid micro-extraction (LLME) and the use of a disperser solvent in dispersive liquid–liquid micro-extraction (DLLME) have been made to improve the extraction efficiencies. Nevertheless, LLE based extraction procedures lost ground in favour of the generally more efficient SPE. The higher selectivity, capacity and thus sensitivity are the main reasons why SPE is now commonly used as a sample preparation method to analyse pharmaceuticals in aqueous samples [91,116]. Furthermore, this technique allows combining sorbents with different selectivities to enlarge the range in which multi-residue analysis can be performed [104,117]. Because large sample amounts are available in environmental studies, starting volumes up to 1000 ml are often used to obtain very high sensitivities [84,118]. However, in contrast with the study of Nannou [118] wherein the highest recoveries were obtained for the largest sample volumes, it has also been shown that the absolute recovery can decrease when sample volumes are too high [119,120]. Moreover, it is more convenient and faster to sample and extract smaller volumes. Therefore, solid-phase micro-extraction (SPME) is used more and more frequently [121]. Because of the smaller sample volumes required and its reduced solvent consumption, lower cost and high-performance characteristics, SPME is also very suitable for the analysis of biological samples [51,122]. A detailed summary of key features of SPME, SPE and LLE can be found in Boyaci et al. [123]. To prevent clogging of precipitates, filtration prior to sample preparation is often applied. Alternatively, stir-bar sorptive extraction (SBSE), a technique which is less susceptible to clogging, can be used to extract different compounds [124,125]. When analytes are captured in or adsorbed onto for example soil, manure, food, plant cells or biological tissues, the analytes first need to be extracted from the solid material. Therefore, ultrasound or microwave-assisted extraction can be used prior to an additional enrichment step such as LLE, SPE or SPME [80,126–128]. Another option is to use Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) extraction salts. This combination of different extraction procedures provides a high-throughput sample preparation with high recovery rates for a wide range of pH dependable analytes [129,130]. In the fields of both water and biological analysis, efforts are made to increase the sensitivity, recovery and repeatability. For this reason and because it is often difficult to obtain large sample amounts in bioanalysis, advances have been made in online SPE-LC-MS methodologies [131,132]. While in conventional SPE procedures only a small fraction of the eluate is injected onto the column, the entire sample is injected when using online SPE. Therefore, similar sensitivities in the low to sub-nanogram per litre range can be obtained with only 1–5 ml of sample instead of the 200–500 ml that are needed when offline SPE is applied [117,133–137]. Furthermore, sample preparation is fully automated making this set-up more robust in comparison with offline SPE.

11

The determination of the absolute concentration of a component always requires the presence of a standard, whether or not isotopically labelled. The addition of an internal standard moreover allows correcting for instrumental deviations, to ensure that e.g. variations in the injection volume will not affect the repeatability of the analysis. Pharmaceutical standards are usually readily available from distributors of chemicals. Depending on the type of molecule, complexity, availability and principally the purity, the price of such standards can range from tens of euros per gram to several hundred euros for a few milligrams. To determine the concentration of less common metabolites or (biological) degradation products of drugs, analogues can be used to correct for ME [142]. Besides using analogues to reduce costs, an alternative, more expensive, but also more accurate and precise option is to use custom-synthesized standards when no existing standards are available. These custom-made products can additionally be labelled isotopically. Depending on the complexity of this process and the type of isotopes used (mainly 2 H, and/or 13 C, but also 15 N and 34 S), isotopically labelled standards (SIL-IS) can cost hundreds to even thousands of euros for a few milligrams making the analysis cost tremendously more expensive.

(i) Improved label-free quantification When isotopically labelled standards are not available or when their cost is too high (for example in multi-residue analysis), the recovery and interference during ionization must be determined in an alternative way. An option is the use of structural analogues that can be added to the sample. These surrogate analytes may, of course, not already be present in the matrix. To determine the recovery of the sample preparation and to study the effect of a concentrated matrix on the ionization, preferably two separate experiments are carried out in which the standards are added before and after the sample preparation. Based on the analyte/surrogate peak area ratio, Dorival-García et al. [143] suggested a matrixmatched calibration curve in order to compare three extraction methods for the analysis of quinolones in sewage sludge. Because structural analogues differ in functional group(s) and/or backbone structure, this may have an influence on the retention time and/or the ionization of the molecule. For this reason, the calculated recovery may differ from the actual value. Depending on the type of matrix, interference is more likely influenced by the retention time than by compound specificity. In some studies, SIL-IS are continuously added postcolumn to examine when suppression or enhancement occurs [61,144,145]. Otherwise, the principle of standard addition as described in González et al. [145] can be used to determine the analyte concentration. This methodology is often used when the sample matrix already contains trace elements of the analyte prior to spiking. By adding a dilution series, the actual concentration can be calculated by extrapolating the calibration curve to zero [19,146,147]. Sometimes, different samples are pooled together to average interferences or a matrix is searched wherein the analytes are not present or at least below the detection limit [148,149]. When such conditions cannot be found, simulated matrices can be used as an alternative [150,151]. The (slightly) varying composition of the matrix can, however, have a large influence on the final result.

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(e) Internal standards

12


Although recovery rates mainly depend on the type of sorbent, the loading speed is also very important to obtain good recoveries [138]. Ideal recoveries approach 100%, but according to the ICH guidelines, recoveries between 80% and 120% are considered acceptable [63,139,140]. Some compounds, especially in multi-residue analysis, cannot be recovered well during extraction. However, when the recovery rates are reproducible, they can still be acceptable. For example, the 35% extraction recovery of ecgonine methyl ester, a cocaine metabolite, from urine was considered satisfactory [62]. Recoveries are generally determined by comparing the analyte peak areas with those of reference samples after SPE. Alternatively, the sample can be spiked with an (isotopically labelled) internal standard prior to sample preparation [59,129,141].

(ii) Isotopically labelled standards

MS, and in particular LC-MS, has been used in various fields of pharmaceutical research. Quantitative measurements are extremely important in toxicological studies, whether it concerns clinical studies, impurity profiling, doping control analysis or the presence of pharmaceuticals in foods and beverages. Another emerging field wherein pharmaceuticals and their derivatives such as metabolites and degradation products are quantified using MS is environmental science, especially water analysis. Furthermore, MS is also used in pharmacokinetic studies, drug discovery, biopharmacy and radiopharmacy [132,158,159]. In fact, in more than 95% of all cases quantitation of pharmaceutical products is done using MS when complex matrices hinder a reliable spectrophotometric quantification. For this reason, the use of MS for quantitative pharmaceutical analysis is a well discussed subject in the literature. Electronic supplementary material, table S2 provides a general overview of recently published review articles in which different topics are discussed. Because imaging, proteomics and metabolomics are very specific fields of research, their applications are not included. As can be seen from electronic supplementary material, table S3, wherein a selection of different recent applications in quantitative pharmaceutical analysis using MS is provided, environmental studies are mainly focused on multi-residue analysis. Pharmaceuticals are considered emerging contaminants and are therefore analysed together with other pollutants such as personal care products and pesticides. Wode et al. [160] were able to analyse more than 2000 micropollutants (of which only 11 pharmaceuticals) simultaneously using online SPE-UHPLC-HRMS. However, because this method was used for non-target screening, no quantitative data was acquired [160]. To study the influence of these contaminants on the environment and human health, it is also important to perform quantitative measurements.

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4. Applications


A more expensive but simpler and more accurate alternative is the use of isotopically labelled standards. When added to the sample prior to analysis, SIL-IS should behave exactly the same as their non-labelled variant from a physicochemical point of view. This results in a similar retention time and ionization simplifying the quantitation of the targeted analyte. However, it has been demonstrated that not all SIL-IS behave as their non-labelled counterparts [152–154]. During the synthesis of SIL-IS, it is very important to select the correct element and position when labelling the molecule. If deuterium atoms are positioned on an exchangeable site, some of them will be replaced by an H-atom during the sample preparation and/or analysis resulting in unreliable and too high recoveries or concentrations [155]. In addition, it is essential that the mass difference is at least 3 amu to avoid that the peak intensity is affected by the presence of natural isotopes in the analyte [54,154]. The correct use of good isotopically labelled standards guarantees the identification and quantification of components with a high certainty and accuracy. However, when the ionization of both the analyte and SIL-IS is suppressed, it often remains unnoticed and precision or accuracy issues can still occur [53,154]. Moreover, in this way the recovery of the sample preparation and matrix interference during ionization can be taken into account [156,157]. Validation procedures that require matrix effect compensation for each analyte are laborious and the purchase of (isotopically labelled) internal standards for each compound is very expensive. Therefore, González et al. [145] proposed a new approach in which the matrix effect of multiple compounds can be compensated by a post-column infusion of eight different SIL-IS. Based on the ME for every drug/PCI-IS response, the most suitable internal standard was determined and subsequently used to reconstruct the chromatograms for each analyte. As a result, a successful absolute and relative ME compensation was obtained in urine samples. As shown in electronic supplementary material, figure S2, different biofluids could be analysed with this technique without a normalizing factor to correct for MEs in various biological samples. The reconstructed chromatograms after ME compensation were similar for all matrices resulting in an improved precision, accuracy and dynamic range during method validation [145].

13

Despite the development of new high-resolution mass spectrometers, the triple quadrupole remains the standard for the highly sensitive quantification of pharmaceuticals. The use of HRMS for quantitation is mainly advantageous when extra information is required about non-targeted matrix compounds. Although new developments have improved the sensitivity of new-generation mass spectrometers, a significant gain in sensitivity can especially be obtained by improving the ionization efficiency and applying a successful pre-concentration step. Numerous ionization sources can be used, however, for quantitative pharmaceutical analysis APCI and in particular ESI remain the ionization methods of choice. To enhance the efficiency, different adjustments have already been applied to improve the source design and the ion guidance. Additionally, with the development of ambient ionization techniques and miniaturized instruments, these set-ups have a great potential in on-site applications. The ease of use and the ability to perform fast screenings in e.g. clinical analysis are sometimes more important than obtaining an ultimate sensitivity. To obtain reliable quantitative results, method validation is of great importance. The highly complex matrices wherein pharmaceuticals are usually dissolved will in most cases lead to matrix interferences. Ion suppression and enhancement can occur when matrix substances co-elute with the analytes of interest. Different procedures such as post-column infusion and post-extraction

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5. Conclusion

14


Therefore, the aim of multi-residue environmental analysis is to perform a targeted screening, which can be used to quantify as many pollutants as possible. Different methods have already been developed for the analysis of pharmaceuticals in environmental water or sludge samples [136,161–163]. Because the concentration of some drugs is extremely low, very high sensitivities are pursued. Currently, most applications in water research are capable of measuring low microgram per litre concentrations. Some methods can even be used to quantify pharmaceuticals in the picogram per litre range [164,165]. When a large number of pharmaceuticals are quantified together (in combination with other pollutants) matrix effect evaluation and correction can be very time consuming and laborious. For this reason, many bioanalytical methods still focus on a limited number of pharmaceuticals only [68,99,100,166,167]. Although multi-compound analyses are performed, they are not common and mostly limited to analytes of the same drug class [15,18]. Owing to the highly complex matrix and the smaller available sample amounts, the method sensitivity for blood analysis is generally much lower than in environmental analysis. Custom limits of quantification are in the high microgram per litre to nanogram per litre range [18,100,166–168]. When using direct SPME or paper spray ionization, chromatographic separations can be omitted to speed up the analysis (electronic supplementary material, figure S3) [51,122,169]. In combination with miniaturized instrumentation, these ambient ionization techniques have a great potential in bioanalysis and in-field applications [22,109]. To increase the sensitivity and to automate the sample preparation, the use of online SPE is increasing [129,134,170]. In this way, Stravs et al. [171] were able to obtain quantification limits of 0.1–28 ng l−1 for 41 micropollutants in surface water using a minimal sample volume of 88 µl injected on a nano-liquid chromatography HRMS. This was comparable with the extraction of 500 ml water using offline SPE in conventional LC-MS. Furthermore, it was demonstrated that this set-up could not be used to extract and analyse very hydrophilic compounds, because these were not recovered at all despite the use of a multibed SPE cartridge [171]. For the analysis of polar pharmaceuticals and their metabolites alternative hydrophilic interaction LC stationary phases should be used [172]. Finally, electronic supplementary material, table S3, also indicates that for most applications ESI remains the ionization source of choice. Its ease of use, ability to ionize most pharmaceuticals and improved design allow the quantitative analysis of complex samples with high sensitivity. In addition, in most recent studies ESI is generally coupled to a triple quadrupole or hybrid triple quadrupole for quantitation purposes.

All authors approve the final version to be published.

Competing interests. We declare we have no competing interests. Funding. G.L. greatly acknowledges the Ysebaert-Devos Fund of KU Leuven for financial support.

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Authors’ contributions. G.L. drafted the article, A.V.S. and D.C. contributed to the concept and revised it critically.

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spiking can be used to assess and correct for these MEs. This can be done using structural analogues or isotopically labelled standards. The use of SIL-IS is more accurate, but also much more expensive. Therefore, a new approach using a limited number of standards that are postcolumn infused to correct for all MEs in multi-residue analysis is very promising. Alternatively, the development of IMS-MS will be a very promising tool to preclude MEs because isobaric ions will be separated based on their mass or structure. Furthermore, hyphenation with state-of-the-art separation techniques will prevent or minimize the simultaneous introduction of multiple compounds into the ionization source and will therefore have a positive influence on the matrix effect. Although CE, HPTLC, SFC and GC can be used, LC is generally used to analyse pharmaceuticals. Therefore, many advances in LC stationary phases have been made to enhance the column selectivities. By decreasing the column dimensions, the sensitivity will increase owing to minimized void volumes and higher efficiencies. An alternative to reduce co-elution is the use of sample preparation techniques. Moreover, such sample preparation techniques will generally increase the sensitivity. Although different types of sample preparation procedures exist, they all rely on the partitioning between two phases. In contrast with environmental studies where the use of SPE is preferred, the sample preparation technique of choice in bioanalysis mainly depends on the extraction efficiency for the analyte of interest. Therefore, protein precipitation is still frequently used, often in combination with other techniques such as LLE and SPE or their derivatives. Recent applications also show the pursuit of performing highly sensitive measurements and a progress to automation. For this reason, online SPE is used more and more because it allows obtaining high sensitivities with a limited sample amount.

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