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Section IV
Drugs and Drugs of Abuse

6
Raman Spectroscopy of Drugs of Abuse
Steven E.J. Bell1
, Samantha P. Stewart1
and S. James Speers2
1
School of Chemistry and Chemical Engineering, Queen’s University, Belfast BT9 5AG, UK
2
Forensic Science Northern Ireland, 151Belfast Rd, Carrickfergus BT38 8PI, UK
6.1 Introduction
Vibrational spectroscopy, in the form of mid-infrared (IR) absorption spectroscopy is already well established
in the production and analysis of small-molecule pharmaceutical drugs and has similarly become a routine part
of most forensic laboratories’ procedures for characterisation of drugs of abuse [1–4]. Since most of the
instrumentation and analysis methods for simple drug identification/quantification by mid-IR absorption have
now become routine and are based on principles that have been understood for many years, for the purposes of
this chapter we refer interested readers to the standard texts in the area rather than treating them in detail
here [1–4]; see also Chapters 2 and 3. However, new IR-based techniques are starting to emerge and these are
discussed here, along with the area of the vibrational spectroscopy of drugs which is growing and evolving
much more rapidly today, which is Raman spectroscopy.
We have also chosen to divide the discussion in this chapter into two broad strands, bulk materials and trace
detection, rather than carry out a drug by drug survey. This was driven by the observation that both the
underlying principles and the results that might be obtained are much more closely related to the type of
measurement required than to the specific compound of interest. For example, techniques for identification of
cocaine in bulk samples have much more in common with research on bulk amphetamine samples than they
have with techniques for detection of trace cocaine.
6.2 Bulk Drugs
6.2.1 General introduction
A cursory inspection of the structures of typical drugs of abuse (Figure 6.1) makes it obvious that each has
sufficient complexity that they will give unique, information-rich vibrational spectra.
Infrared and Raman Spectroscopy in Forensic Science, First Edition. Edited by John M. Chalmers, Howell G.M. Edwards and Michael D. Hargreaves.
2012 John Wiley Sons, Ltd. Published 2012 by John Wiley Sons, Ltd.

It is a truism that every different compound has a unique vibrational spectrum, based on the fact that any
change to the chemical structure of a compound alters either the number of chemical bonds or their strength.
This, in turn, perturbs the normal modes of vibration, which are the spectroscopic observables. When the
compounds which are being compared are very different in structure they certainly give strikingly different
spectra in which there is little similarity in the number, intensities and positions of numerous bands, justifying
the idea of the data providing a “spectroscopic fingerprint”. In these cases, identification is simply a matter of
matching a complex pattern from the sample to that of a known standard. However, itis useful to remember that
large spectral differences tend to be associated with large structural differences. In the area of drugs of abuse
there are families of synthetic drugs, for example, ecstasy and cathinones, in which the differences between the
members is small and this will be reflected in relatively small differences between the spectra of closely related
members of the same family. For example, Figure 6.2 compares the Raman spectra of three members of the
Wavenumber/cm-1
1000
600 800
MDA
MDMA
MBDB
Amphetamine
700 900 1100
Figure 6.2 The Raman spectra of three members of the “ecstasy” family (see structures in Figure 6.1) compared
with those of amphetamine sulfate. Spectra were recorded using 785 nm excitation and have been offset for clarity.
Adapted from Reference [5] with permission of The Royal Society of Chemistry.
O
N
H
H
O
Br
N
H
H
Amphetamine
MDA
O
O N
H
MDEA
O
O
N
H
MDMA
O
O N
H
MBDB
N
O
O
O
O
Cocaine
DOB
O
O
O O
O
N
Heroin
O
N
H
4-Methylmethcathinone O
O
N
H
H
Figure 6.1 The structures of typical drugs of abuse: MDEA, 3,4-methylenedioxy-N-ethylamphetamine; MBDB, 2-
methylamino-1-(3,4-methylenedioxyphenyl)butane; MDA, 3,4-methylenedioxyamphetamine; DOB, 2,5-di-
methoxy-4-bromoamphetamine; MDMA, 3,4-methylenedioxy-N-methylamphetamine.
318 Infrared and Raman Spectroscopy in Forensic Science

ecstasy family with those of amphetamine sulfate, it is obvious that the most structurally similar compounds do
indeed give closely similar spectra [5].
Close inspection shows that there are some subtle differences that can be used to distinguish between them
(the most useful bands are marked with arrows in Figure 6.2) but it is clear that the general assumption that
every compound gives a very distinct spectrum needs to be treated with some caution. This is particularly true
for seized samples, where the differences that can be used to distinguish between closely related drugs may be
difficult to detect if the spectra also contain bands due to other materials, such as excipients or cutting agents.
However, aside from this general observation, it is clear that provided appropriate care is taken, vibrational
spectroscopy is an excellent method for identification of drugs of abuse. The ability of Raman spectroscopy
and to some extent attenuated total reflection (ATR) IR spectroscopy to provide unambiguous identification of
molecular compounds without the need for sample preparation means that they have obvious potential as rapid
screeningtechniques for identification of drugs of abusein bulk samples. Herewe concentrate on Raman rather
than IR absorption methods for the reasons stated above.
6.2.2 Experimental considerations
Raman scattering methods have always been potentially useful for analysis of drugs of abuse but for many
years the technical difficulties associated with making the measurements, such as low signal levels and the
need for high power laser sources, meant that Raman spectroscopy was carried out in specialist laboratories,
using home-built equipment and was essentially a technique of last resort for structural characterisation.
However, as developments in optoelectronic technology such as lasers, charge-coupled device (CCD)
detectors and notch filters have emerged, the size and cost of the instruments has decreased while their
ease of use has increased. It is worth noting that the reduced cost and increased ease of use would not, in
themselves, have been sufficient to allow widespread adoption of Raman methods for analysis of street quality
drugs, that has also required progress in minimising the effect of background fluorescence. Fluorescence was a
huge problem in early Raman spectroscopic studies of many types of unpurified real-life samples, sincevisible
laser excitation gave excellent spectra for pure samples of target compounds but the signal was completely
masked by fluorescence when unpurified samples were studied.
The reason that so many samples give problematic levels of fluorescence, that is, sufficient to obscure the
Raman bands, is the low absolute level of Raman scattering given by even high concentration or bulk samples.
This means that samples which in normal circumstances would not be regarded as fluorescent can still have
significant fluorescence backgrounds when studied using Raman spectrometers, for which high intensity
excitation, good light collection efficiency and sensitive detectors effectively make them extremely sensitive
fluorescence spectrometers. Moreover, even if the target compound and any excipients do have low
fluorescence yields, even trace levels of fluorescent impurities can still give rise to problems. In principle,
removing fluorescent impurities could eliminate this problem but in practice extensive sample clean-up
procedures are unacceptable and in any case they do not work if the target is itself fluorescent. For these
reasons sample fluorescence needs to be reduced by some other procedure. The two most common methods
are to use surface-enhanced Raman spectroscopy (SERS), in which the fluorescence is quenched by an
enhancing metal substrate (see Section 6.3.2 below, and Chapter 6.3 by Faulds and Smith) or to change the
excitation wavelength. The only other approach which has been explored to any extent is to use pulsed
excitation and gated detection. In this method the detector is turned “on”, either optically or electronically,
during the period when the laser pulse is incident on the sample [6]. Since the Raman scattering occurs
instantaneously the detector is therefore “on” when the scattering occurs. However, if the detector is then
turned “off” immediately after excitation, for example, by an optical Kerr gate [7] or reducing detector
sensitivity electronically, the fluorescence which is emitted following the initial excitation is rejected. The
most efficient rejection is obtained when the laser pulse, and therefore detector “on” time, is short compared to
Raman Spectroscopy of Drugs of Abuse 319

the lifetime of the fluorescence. This means that efficient rejection of fluoresecence on the nanosecond
timescale requires extremely short (picosecond or less) laser pulses and optical gates to give efficient
rejection. This approach has been shown to be extremely effective for rejecting fluorescence from street-
quality samples of cocaine where the fluorescence background was reduced from being overwhelmingly high
to barely detectable, yielding excellent quality spectra as shown in Figure 6.3 [7]. Unfortunately, although this
approach would be expected to be similarly effective for other seized drug samples, the high cost of building
such systems and their complexity means that this approach is not expected to be widely available for the
foreseeable future.
At the moment, the most popular, successful and convenient means to avoid fluorescence is to change the
excitation wavelength. The two options for changing from the visible region are to either move to the UVor to
the deep red/near-IR region of the spectrum. Both have advantages and drawbacks. Using UVexcitation shifts
the Raman signal to the short wavelength end of the spectrum. Since normal photophysical relaxation and
energy transfer processes mean that the fluorescence arises from the lowest lying excited state, it tends to lie at
longer wavelengths, that is, to the red of the Raman scattering. In addition, since the scattering signal increases
as the fourth power of the frequency of the scattered light, UVexcitation gives a useful increase in scattering
probability over visible and near-IR excitation. For example, all else being equal, the absolute scattering at
250 nm is 16 times that at 500 nm and 256 times that at 1000 nm. It was demonstrated using a Raman
microscope with 244 nm excitation that the short wavelength excitation did significantly reduce fluorescence
from impure heroin and cocaine samples. In addition, the fact that the target compounds absorbed in the UV
meant that the signals were also resonance-enhanced, which helped to lift their signals above those of the other
compounds present in the mixtures [8]; see also Chapter 2, and Chapter 6.3 by Faulds and Smith. One
significant disadvantage with UVexcitation is that it is more likely to cause photodamage to the sample than
visible excitation but the main factor preventing its widespread adoption is practical, there are as yet no
portable (or even commercial benchtop) hard UV Raman spectrometer systems available. This is due to the
challenges of manufacturing suitable compact, low-cost UV laser sources. Until these become available UV
Raman spectroscopy will be confined to specialist laboratories.
Figure 6.3 Comparison of the Raman spectra of a sample of street-quality cocaine hydrochloride (75% purity)
using normal continuous excitation, which is completely dominated by fluorescence and a Kerr-gated spectrum of
the same sample. Reproduced from Reference [7] with permission of The Royal Society of Chemistry.

The rationale for changing from visible to deep red/near-IR (i.e., 750 nm) excitation is that many fewer
compounds absorb strongly at these longer wavelengths, which means that the fluorescence is not excited in
the first place. The two most widely used wavelengths are 1064 and 785 nm. 1064 nm was the first to be used
because it was readily available as the fundamental output of Nd-based lasers. More recently 785 nm, which is
typically produced by diode lasers but can also be provided by Ti/sapphire lasers, has become available. In
principle, there is no fundamental limit to which wavelength diode lasers can produce in the red end of
the spectrum, so that instruments using 780 and 830 nm, for example, are available commercially. However,
the choice of 785 nm is set for good experimental reasons since it gives the best balance between having the
excitation as far as possible to the red, minimising fluorescence interference, while still allowing the Raman
scattering from the C–H region to fall within the sensitivity range of Si-based CCD detectors.
Until recently, all commercially available 1064 nm Raman instruments were based on Fourier transform
(FT) interferometers (see Chapter 2), since multichannel detectors that operated at the long wavelengths where
the Raman signals fell were not available. Indeed, FT systems have been available for many years and they
have been shown to be extremely effective for analysis of a very broad range of drugs of abuse. Hodges et al.
published spectra of heroin, codeine and amphetamine as long ago as 1989 and work using 1064 nm FT
instruments continues to the present day [9, 10]. More recently 785 nm excitation has been used successfully
for examination of a whole range of drugs of abuse, including those from the ecstasy family, cocaine,
amphetamine and so on. Indeed many portable and benchtop instruments operating at 785 nm are supplied
with commercial libraries of the most common drugs of abuse. From a practical view point these systems are
much smaller and less expensive than normal 1064 nm FT Raman instruments, although the fact that they
operate closer to the visible region does mean that there is more probability of encountering problem
fluorescence. In the most useful comparative study, Hargreaves et al. recorded data for street-quality samples
of a range of common drugs using both 785 and 1064 nm excitation [11]. They showed that, although the
spectra of pure samples of all the drugs tested (cocaine, MDMA, amphetamine, cannabis, heroin) gave spectra
with low fluorescence at both the excitation wavelengths used, this changed dramatically when street-quality
seized samples were examined. With 785 nm excitation the presence of the excipients and other adventitious
impurities increased the background levels in the spectra of all the samples. The increases were lower in the
spectra of cocaine, MDMA and amphetamine, so that useful data were obtained at this wavelength (in
agreement with literature reports) but those of heroin and cannabis resin were completely obscured by
background fluorescence. With 1064 nm excitation the background levels were lower for all samples, most
strikingly for heroin and cannabis resin, which gave useful spectra with numerous bands clearly visible, as
shown in Figure 6.4.
Overall, many street quality drug samples can be analysed by both 785 and 1064 nm excitation but visible
wavelength excitation, because of fluorescence emission, is likely to give poorer results for a significant
proportion of seized samples. Some materials, such as heroin and cannabis resin, still show overwhelming
fluorescence at 785 nm but significantly less at 1064 nm, so this wavelength is essential for these samples
unless some sample clean-up procedure, for example, by high-performance liquid chromatography (HPLC;
see Section 6.3.2), is implemented. Similarly, since the range of contaminants, cutting agents and additives,
such as dyes, which are added to street drugs, is huge and unregulated it is inevitable that some samples of drug
types that normally give good spectra, such as cocaine, may have overwhelming backgrounds. This is less
likely to happen with 785 nm than visible excitation but 1064 nm excitation further reduces the proportion of
samples which have this problem.
Of course, as technology improves, fluorescence may become less problematic. For example, recent
advances in long wavelength detector technology have resulted in the first commercial 1064 nm excitation
instruments based on detector arrays rather than interferometers being produced. These clearly have
significant potential for bulk drugs analysis since they combine the advantages of dispersive instruments
(speed and compact size) with long wavelength excitation.

6.2.3 Laboratory-based methods
Despite the fact that a new generation of compact instruments designed for ease of use and field operation are
available, the advantages of laboratory-based instruments, that is, optimised signal-to-noise ratio through
cooled detectors, high resolution from large footprint spectrographs and automated sample handling, mean
that theyare unlikely to be replaced bycompact instruments in the near future. The rapid throughput that can be
achieved because no sample preparation is required before analysis makes Raman spectroscopy a first choice
method for examination of seized samples. Indeed, the widespread availability and use of affordable benchtop
laboratory instruments which can bevalidated to appropriate standards means that benchtop Raman analysis is
becoming a well-established method in much the sameway as FT-IR spectroscopy already has. However, there
are subtleties associated with the measurements which it is useful to discuss here.
6.2.3.1 Screening and Identification
The most obvious use of Raman in forensic drugs casework is as a rapid means of identifying drugs of abuse in
seized samples. The distinct and characteristic Raman spectra of the main targets mean that an experienced
operator can readily identify bands due to particular drugs, even in spectra which have features due to other
materials present in the sample. An additional advantage is that with microheterogeneous samples the focused
probe beam may sample regions that are composed almost entirely of a single component. This is because the
focused spot of even “macro” Raman systems is typically only 10–100 mm and it can be as low as 1 mm in
Raman microscope systems, so that there is considerable potential for the focused spot to be smaller than the
particle size in powdered samples or in tablets prepared by compressing powders. Under such conditions, some
of the spectra obtained from a mixed sample may be significantly enriched in just one of the components [12].
Of course, if the excitation beam falls between domains of different composition then mixed spectra will be
observed but an experienced user can usually obtain spectra characteristic of the different components
Figure 6.4 Raman spectra of a seized heroin sample collected on an FT-Raman Bruker spectrometer 1064 nm
excitation (200 scans, resolution 4 cm1
, laser power 97 mW), Renishaw InVia benchtop Raman spectrometer
785 nm excitation (1 10 s exposure, laser power 110 mW), Renishaw RX210 portable Raman spectrometer
785 nm excitation (1 10 s exposure, laser power 48.9 mW), and Delta Nu Inspector Raman spectrometer 785 nm
excitation (1 10 s exposure, laser power 36.9 mW). Reproduced from Reference [11] by permission of
John Wiley Sons, Ltd.

by randomly sampling numerous points on the surface and identifyingthosewhich have the lowest complexity.
This can be very useful when attempting to identify which spectral features belong to each of the different
components in the spectra of mixedsamples. For example, Figure 6.5 shows spectra recorded at sevendifferent
points on a sample of a white powder containing 4-methylethylcathinone (4-MEC). The spectra recorded at
most of the points are very similar and are dominated by bands due to the drug. However, some of the spectra
have small differences, while spectrum (b) clearly has large additional features at 827, 1049, 1393 and
1420 cm1
. In this case, although the anomalous spectrum is not completely different from the others in the
series, since it still has drug bands present, the peaks of the additional component are so large compared to the
drug that they can readily identified as being due to creatine, the spectrum of which is shown for comparison at
the bottom of Figure 6.5. This cutting agent would have been much more difficult to detect in an averaged
spectrum since the powder is overwhelmingly composed of 4-MEC.
6.2.3.2 Quantitative Analysis
The next step up from identification is quantitative analysis and this is much more challenging. While
quantitative analysis of pharmaceutical dosage forms is now widely accepted and practiced, the same cannot be
said for drugs of abuse, where the vast majority of the published research is concerned with identification [13].
This is a direct result of the huge variability in the composition of seized samples compared to manufactured
pharmaceuticals, for which not only can the proportion of the active drug vary wildly but even the identity the
variousconstituentsisunknown.ForquantitativeRamanmeasurements, itiscommonpracticetousean internal
standard to correct for the changes in signal intensity from a given sample which arise from small variations in
the experimental parameters, such as the laser power and position of the sample in the focal region. With
pharmaceuticals, the amount of active pharmaceutical ingredient (API) in a sample is typically measured by
ratioing the intensity of an appropriate API band to one from the excipient. Although it is possible to generate
similar calibrations for illicit drugs (an example is shown below) this does require significantly more effort,
since a different calibration is required for each drug/excipient combination. In addition, with solid samples it is
alsoimportanttoensurethatthe spectrumthatisrecordedcorrectlyreflectsthecompositionoftheentiresample,
that is, that no sub-sampling takes place.
400
600
800
1000
1200
1400
1600
1800
2000
Wavenumber/cm–1
Raman
Intensity
Creatine
(a)
(b)
(c)
(d)
(e)
(f)
(g)
Figure 6.5 Raman spectra recorded at seven different points on a sample of a white powder containing 4-
methylethylcathinone (4-MEC). The large additional features at 832, 1052, 1397 and 1424 cm1
in spectrum (b) are
due to creatine in the sample. A spectrum of creatine is shown for comparison. Spectra were obtained with 785 nm
excitation and have been offset for clarity.

As discussed above, the small spot size of a typical Raman probe beam means that the spectrum that is
recorded from a single point on a microheterogeneous sample, which might be a powder or tablet, will
typically not reflect the average composition. While this is an advantage when trying to identify the various
constituents present, it can cause significant problems when it is data that reflect the overall average
composition of the sample that is required. The best way to reduce this sub-sampling effect is to sample
over multiple points on the sample since it has been shown that the standard deviation in the measured signal
decreases as the square root of the number of independent points probed [12]. FT-Raman instruments have an
advantage in this regard since their beam diameters, which can be up to 1 mm, give much more representative
sampling over many microdomains in a single measurement than do tightly focused visible laser systems. For
visible/far-red measurements, commercially available fibre optic probes specifically designed to probe large
areas of samples have been developed [14]. However, it is much more common to use the instrument as
supplied and then either to record data at a grid of points over the surface of a fixed sample or to rotate the
sample during measurement, which again gives a significant increase in the effective number of independent
regions that are probed. The number of points which are included in the average is critical, particularly with
microscope-based systems, which have particularly small spot diameters. For example, Figure 6.6 compares
the reproducibility of macro- and micro- Raman spectra of a seized ecstasy tablet. All spectra in Figure 6.6 are
sums of eight spectra taken from a data set obtained as an 8 8 grid. With the macro-Raman system even
averaging over eight points gives spectra that are reasonably reproducible and reflect the average tablet
composition. In contrast, the data from the microscope-based system show very poor reproducibility in the
relative intensities of the 552 cm1
(caffeine) and 527 cm1
(MDMA) bands since averaging over eight points
was insufficient to eliminate sub-sampling in this case. However, if adequate sampling is carried out
quantitative analysis is straightforward. In the same study [12], MDEA/sorbitol tablets with compositions
0–30% by mass were sampled over a 64-point grid on the surface of the tablets and the resulting single factor
partial least squares (PLS) calibration gave an acceptable model with a prediction error of just 1.1%.
400
(a) (b)
500 600 700 800 900 1000 1100
Wavenumber/cm–1
400 500 600 700 800 900
Wavenumber/cm–1
552
527
808
808
Intensity/
Arbitr.
units
552
527
Micro
Macro
Intensity/
Arbitr.
units
Figure 6.6 Comparison of the reproducibility of macro- and micro- Raman spectra of a seized ecstasy (MDMA)
tablet. All spectra are sums of eight separate spectra taken from an 8 8 grid. (a) macro-Raman system (0.5 mm
spacing, 2 s per point), (b) micro-Raman (50 objective, 0.2 mm spacing, 20 s per point). Note the poor
reproducibility in the relative intensities of the 552 cm1
(caffeine) and 527 cm1
(MDMA) bands in the micro-
spectra due to sampling errors. Spectra have been offset for clarity. Adapted from Reference [12] by permission of
John Wiley Sons, Ltd.

An alternativeapproach to overcoming sub-sampling within inhomogeneous solid samples is to dissolve the
sample before analysis. Katainen et al. [15] dissolved samples of amphetamine sulfate into aqueous acid
solution and then added fixed amounts of sodium dihydrogen phosphate, which was used as the internal
standard. For seized amphetamine powder, 150 mg was dissolved in 600 ml of solution to give a sufficiently
high concentration of the target compound such that it could be detected in the solution. This method allowed
the amphetamine content to be measured, either by directly recording the ratio of the peak heights of bands due
to the drug and internal standard or by building a multivariate PLS calibration based on second derivatives of
the spectra. Both methods gave results that were sufficiently accurate for routine forensic work.
6.2.3.3 Composition Profiling
The objective of composition profiling is to use an analytical technique to provide information on the detailed
composition of the sample, which may therefore allow it to be distinguished from similar, but not identical,
samples. This discrimination is important because it allows exact matches between different samples to be
confidently attributed to them having a common source. Although numerous analytical methods have been
used for this purpose, Raman spectroscopy has been shown to be particularly suitable because, at the least, a
properly sampled single spectrum would be expected to identify the drug, the excipients and the ratio of drug to
excipient. For example, Raman spectroscopy has been used for composition profiling of seized ecstasy
(MDMA) tablets [5, 16].
In an initial study a sample set of 400 tablets, all similar in appearance and carrying the same impressed logo,
was taken from a large seizure of 50 000 tablets that were found in eight large bags [17]. Despite some tablet-
to-tablet variation within each bag, the contents could be classified by Raman spectroscopy on the basis of the
excipients used. The tablets in five of the bags were sorbitol-based, two were cellulose-based and one bag
contained tablets with a glucose excipient.
However, the richness of vibrational spectra may give more than this basic information. So for MDMA it
was shown that the ratios of the peak heights of the prominent drug Raman bands at 810 and 716 cm1
varied
with the hydration state of the drug. This gave an additional parameter, which could be used to discriminate
between samples with similar composition. The high throughput also allowed reasonably large numbers of
tablets from each of the seized bags to be analysed, allowing not only a better estimate of the average
composition but also giving data on the spread of thevalues about the mean. For example, analysis of 50 tablets
from each of a representative series of sample bags gave distribution profiles that showed the contents of each
bag were approximately normally distributed about a mean value, rather than being mixtures of several
discrete types. Two of the sorbitol-containing sample sets were indistinguishable, while a third was similar but
not identical to these, in that it contained the same excipient and MDMA with the same degree of hydration
but had a slightly different MDMA:sorbitol ratio. The cellulose-based samples were badly manufactured and
showed considerable tablet-to-tablet variation in their drug:excipient ratio, while the glucose-based tablets
had a tight distribution in their drug:excipient ratios. The degree of hydration in the MDMA feedstocks used to
manufacture the cellulose-, glucose- and sorbitol-based tablets were all different from each other.
This work was followed by an even larger study of approximately 1500 tablets from numerous different
seizures [16]. The purpose of the study was to determine the extent of variation between batches of tablets
found in different seizures or even between different containers of tablets that were seized at the same location.
In particular, to establish the validity of the approach as a routine drugs intelligence tool it was important to
ensure that there was sufficient variation in composition of ecstasy tablets in circulation to make any matches
between batches taken from different seizures significant, rather than the result of random chance. Thirty
tablets from each sample were analysed. Again the ratios of the peak heights of the prominent drug bands,
which vary with hydration state of the drug, and the strongest drug band at 810 cm1
were measured against
the largest clearly discernible excipient band in the spectrum. The first level of discrimination used was simply
separation of the samples on the basis of the drug and excipient present. For samples with the same drug and

excipient, analysis of variance (ANOVA) and/or t-tests were then used to determine the significance of any
within-batch or between-batch variations in either drug:excipient or drug hydration parameters. A convenient
way to represent the data was to draw scatter plots for each drug:excipient combination with the two most
important Raman band ratios for each batch of tablets plotted as x,y coordinates, as shown in Figure 6.7. In
these plots the degree of variation in both the drug hydration and drug:excipient parameters was represented by
drawing an ellipse around the centre point whose major and minor axes were 1s for the respective ratios.
In general, it was found that therewas sufficient variation in composition in the general sample population to
make any matches between batches of tablets taken from different seizures significant. In this study, despite the
large number of different batches of tablets examined, only two examples of indistinguishable sets of tablets
were found and in only one of these had the two batches of tablets been seized at different times. This implies
that the samples in this study had come from numerous different sources. In later workwhere the techniquewas
embedded as a routine examination method within a forensic laboratory, it was found that during periods
where the law enforcement agencies had been successful in seizing incoming shipments there was much more
commonality in composition of samples which had been seized lower down the distribution chain [18]. This
presumably reflected more widespread distribution of the small number of large batches which were available
for distribution during these periods. This observation demonstrates that the potential benefits of obtaining
highly detailed spectra can indeed translate into information that is not readily available from other methods
but would be useful for tracing of drug distribution networks.
6.2.4 Raman outside the laboratory
The advances in technology which have made hand-held Raman analysis a reality were discussed briefly
above. One of the main applications for such systems is in security/military applications, particularly for the
rapid identification of unknown chemical substances in the field, that is, so-called “white powder incidents”.
However, the main driving force for security applications is the identification of chemical or biological threats
such as explosives, rather than field identification of drugs of abuse. Of course, the existence of the technology
means that it can be applied to this problem and rapid identification of seized materials as drugs of abuse will
certainly increase the efficiency of criminal investigations, for example in interviewing suspects.
2
0
4
6
8
10
12
14
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Hydration ratio
Excipient
ratio
Low drug content, high hydration,
large tablet-to-tablet variation
High quality
Figure 6.7 A scatter plot representing the composition of a series of different seized ecstasy tablets (in this case
MDMA/sorbitol). Band ratios corresponding to the two most important composition parameters (drug:excipient
ratio and degree of hydration) are plotted as x,y coordinates. The degree of variation in both the parameters is
represented by the ellipses for which major and minor axes are 1s for the respective ratios. Adapted from
Reference [15] with permission of The Royal Society of Chemistry.

Similar ideas have been implemented using a ﬁeld-portable infrared spectrometer [19]. Transmission
infrared spectra of mixtures containing ephedrine hydrochloride, glucose and caffeine, and ATR infrared
spectra of mixtures composed of methylamphetamine hydrochloride, glucose and caffeine were used to
develop principal component regression (PCR) calibration models. Results for samples containing a single
drug but using a calibration sample set that contained both mixed and pure samples gave a prediction error of
ca. 4% w/w. However, as would be expected, poor predictions of the components in a mixture were found for
samples which contained substances which were not present in the calibration set.
In a recent test of the effectiveness of the current generation of compact Raman instruments, Hargreaves
et al. [20] carried out a study aimed at identifying drugs of abuse in airports. They demonstrated that the
spectrometers are able to collect the spectra of suspect powders, including cocaine and amphetamine sulfate
with unknown constituents, rapidly and with a high degree of discrimination. Other impressive results have
been obtained [21] using spatially offset Raman spectroscopy (SORS, see Figure 6.8; see also Chapter 6.2) to
detect cocaine concealed inside transparent glass bottles containing alcoholic beverages. In this technique, a
narrow, weakly focused laser beam is sent into the sample at an angle (typically 30–60
) to the optical
collection axis but along a direction such that the beam propagates through the sample in the Raman collection
zone. With this system, the spectrum of 300 g cocaine (purity 75%) dissolved in 0.7 l rum in a brown glass
bottle could be obtained with an acquisition time of just 1 s. The detection limit was estimated to be of the order
of 9 g of pure cocaine in 0.7 l (ca. 0.04 mol dm3
). Similar results have also been obtained for powders
concealed within plastic containers in which sugar was used as a surrogate for drugs of abuse [22].
Figure 6.8 The experimental layout used in the non-invasive displaced Raman measurements. Also shown are
spectra obtained with such as system of rum and rum mixed with 300 g of cocaine (purity 75%) in a 0.7 L brown
glass bottle. Reproduced from Reference [21] by permission of Elsevier B.V.

The fact that the Raman spectra of many street quality drugs of abuse show bands which are characteristic
not just of the active compound but also of any excipients/cutting agents can be an advantage for the
composition profiling described above. However, it can also complicate the automated detection of prohibited
substances within spectra which contain numerous other bands, since it makes simple library searching
difficult; see also Chapters 2 and 6.1. In addition, even relativelymodest fluorescence features can compromise
automated detection of drugs of abuse. This latter problem was addressed by Leger et al. [23] who compared
the standard method of derivative pre-processing with a new polynomial method for baseline correction of
Raman spectra with widely varying backgrounds. The methods were tested on spectra of 85 samples of drugs
of abuse diluted with various materials and the performance of both methods was found to be similar. For
example, principal component analysis (PCA) models gave cross-validation errors ca. 8% for cocaine and
heroin 3–4% for MDMA.The novel method did have the advantage that spectra treated with it retained original
peak shapes after the correction.
Ryder et al. [24] carried out the most extensive studies of the use of multivariate data analysis methods to
identify and quantify drugs of abuse in complex mixtures of various types. Initial work in 1999 on cocaine,
heroin and MDMA mixed with foodstuffs, such as flour, sugars and so on, and inorganic materials, such as
talcum powder, showed that it was possible to detect the presence of drugs at levels down to ca. 10% by
mass [24]. Additionally, PLS analysis of data from a series of 20 mixtures of cocaine and glucose (0–100% by
weight cocaine) gave a calibration model with a root mean standard error of prediction (RMSEP) of 2.3%.
When this work was extended to ternary mixtures containing cocaine, caffeine and glucose (9.8–80.6% by
weight cocaine) the concentration of cocaine could be predicted with a RMSEP of 4.1% [25].
Further extension to 85 samples diluted with several different materials showed that when principal
component analysis was restricted to the most intense peaks in the Raman spectrum of the pure drugs
discrimination between cocaine, heroin and MDMA mixtures was possible even though only 2 or 3% of the
original spectral data was used in the analysis [26].
6.3 Trace Detection
6.3.1 Drug microparticles
Identification of microparticles which have transferred onto suspects’ clothing, hands and possessions during
handling of drugs has been a topic of active research. In principle, any particle that is as large as the diameter as
the focused beam gives a signal which is just as intense as that of bulk material, since in both cases the probed
volume is filled with the substance of interest. This means that sub-picogram sensitivity is easily achievable.
In practice, the particles may be somewhat larger than the focused beam so that it has been shown that with
depth-profiling confocalRaman microscopy 5–15 mm diametercocaine andMDMAparticles couldbe detected
in situ trapped between the fibres of both undyed and coloured textile specimens [27]. Interfering spectral bands
due to the fibre or dyes did not prevent identification. Similarly, drug particles could be identified in highly
fluorescent specimens if the beam was focused so as to minimise collection of background fluorescence. This
work has been extended to the use of benchtop and portable Raman instruments for bulk detection of cocaine in
clothing which had been impregnated with the drug for the purposes of concealment [28]. Again it was found
that the drug could be identified by its characteristic Raman bands and that the method provided a simple
and rapid detection procedure.
Confocal Raman microscopy has also been applied to detection of drugs in fingerprints, cyanoacrylate-
fumed fingerprints (see Chapter 4) and on human nail [29–31]. For the fingerprint study, five drugs of abuse
(codeine, cocaine, amphetamine, barbital, nitrazepam) could be clearly distinguished using their Raman
spectra, even when they were held in a cyanoacrylate matrix deposited during the fuming development of
latent fingerprints [29]. Although the cyanoacrylate did give some interfering Raman bands, they did not

prevent identification of the drugs. Similarly, Ali et al. [29] probed drug particles on human nail, where again
the rationale was that particle transfer occurs during use and handling. Raman spectra of pure and street purity
cocaine could be obtained readily. Interestingly, the confocal nature of the instrument used meant that Raman
spectra of drug particles could be acquired even from under a layer of nail varnish.
Of course, in practice, for all microparticle approaches there is an additional challenge of screening what is a
potentially very large number of particles, as inevitably found on a suspects’ person or belongings. Point-by-
point mapping would be possible but unacceptably slow. However, rapid broad area scanning techniques have
now become available and are likely to become more widespread in the future. These have the potential to
dramatically decrease the time to probe an extended area to search for the specific signals associated with
transferred drug particles.
6.3.2 Surface-enhanced Raman spectroscopy
The forensic potential of surface-enhanced Raman (SERS) and resonance Raman (SERRS) as sensitive
detection techniques with high levels of molecular specificity has been recognised for many years. However, it
has taken considerable time for this potential to be realised in practice and it is only recently that there has been
a general acceptance that SER(R)S can, or soon will be, sufficiently reliable and low cost that it will be able to
constitute a viable method of quantitative or semi-quantitative for general chemical analysis, including
forensic applications [32]. Also, although the combination of resonance and surface enhancement found in
SERRS is used in other forensic Raman applications, particularly in studies of inks, pigments and dyes, drugs
of abuse typically do not absorb in thewavelength regions used for normal SERS experiments. This means that
for current purposes the discussion can be limited to SERS.
SERS can be approximately divided into two regimes. In the “low” sensitivity regime (enhancements up
to 106
), the observed signal is necessarily composed of the sum of contributions from numerous scattering
molecules [33]. The averaging effect of these numerous contributions leads to ensemble signals which are
much more stable and reproducible than those obtained when substrates having very high enhancement factors
(up to, or even exceeding, 1010
) are used to detect small numbers of scattering molecules situated at areas of
high enhancement, that is, “hot spots”. These latter signals typically show fluctuations in intensity (blinking)
and/or band positions. Although, in principle, the idea of single molecule detection is attractive for trace
forensic analysis, in practice all the practical forensic applications to date have been associated with averaging
lower enhancement ensemble signals. Indeed, the potential for cross-contamination for single molecule
results would raise huge problems even if the fundamental principles underlying small number/single
molecule phenomena were fully established. In any case, even in the ”low” enhancement regime the
enhancement factors are still huge, so that sample concentrations as low as 106
mol dm3
can routinely
be detected, so SERS can genuinely claim to be a trace technique.
The second main advantage of SERS measurements is that the enhancement of Raman signals is often
accompanied by quenching of sample fluorescence. In general terms, this can be attributed to rapid
deactivation of electronically excited compounds when they are adsorbed onto metal surfaces. This implies
that for the quenching to be effective the fluorescent molecules in the sample need to adsorb to the surface.
With unpurified samples this is as far as the explanation can go because the identity of the compound giving the
fluorescence is typically not known in the first place. However, it is clear from experience that fluorescence
quenching is commonly observed with unpurified street drug samples, so that the most widely occurring
contaminants must fortuitously meet the requirements for quenching in normal SERS experiments.
Since the earliest days of SER(R)S measurements there have been two main classes of enhancing media:
colloidal suspensions of metal nanoparticles (predominantly Au or Ag) and solid substrates with microscopi-
cally rough (randomly textured) surfaces. More recently, a third class of “plasmonic” enhancing materials,
have been made possible through the widespread availability of nanoscale fabrication and characterisation
tools [31]. The structure of these materials can be controlled with much higher accuracy than roughened

surfaces or colloids, which should lead to greater reproducibility. However, the high cost of plasmonic
substrates means that they have not replaced colloidal particles and random-roughness surfaces, so all three
general types of enhancing material are still widely used. In general, the absolute enhancements provided by
many of the substrates within all three of these three classes is sufficient for most purposes, so the choice
between different enhancing media rests as much in the surface chemistry and ease of use for particular
applications as in the electromagnetic properties of the enhancing substrate.
The main advantages Au and Ag colloids are that they are easy to prepare, arevery low cost and provide high
enhancement factors. Typically, they are synthesised by chemically reducing an aqueous solution of the
appropriate Au or Ag salt to produce colloidal suspensions of particles which are usually in the nm range.
The main factor which distinguishes colloidal particles from roughened or textured enhancing surfaces is
the need to aggregate the particles to obtain optimum enhancement. In early SER(R)S colloid studies the
aggregation was normally induced by addition of simple alkali metal halides, particularly KBr and NaCl, more
recently, a much broader range of aggregating agents has been explored for various reasons [32].
To carry out the SERS experiment the target molecules must be brought to the colloid or the colloid is
brought to the target. A good example of the latter was in a study aimed at detecting a very potent designer
“ecstasy” variant DOB [34]. Normal Raman screening for DOB in tablets is difficult because it is
pharmacologically active at 0.2–3.0 mg, which is ca. 50 times less than MDMA. This makes it more difficult
to detect in seized tablets using either conventional spot tests or Raman measurements, since the normal
Raman spectra of seized DOB tablets are dominated by the bands of the excipient and show no evidence of the
drug component. However, in a study where model DOB/lactose tablets (total mass ca. 400 mg) containing
from 1 mg to 15 mg of DOB were treated by adding a 5 ml drop of silver colloid onto the upper surface, the
spectra which were recorded showed strong enhanced Raman bands of DOB. The amplification was
sufficiently large that in spectra of tablets containing 1 mg DOB per tablet the DOB bands were so intense
that they completely obscured the bands from the remaining 399 mg of lactose in the samples (see Figure 6.9).
Indeed, the most intense DOB band was visible even in tablets containing just 15 mg of the drug, well below the
pharmacologically active dose.
Although the method described above is useful for seized tablets, the most widely used SERS procedure is
the simple generic experiment where a solution of the analyte is mixed with that of the enhancing colloid. In
favourable cases, the target spontaneously adsorbs onto the particles, these are then aggregated by addition of
salt to form clusters which remain suspended in solution for several minutes; during which time they are
Raman probed. This approach was followed by Ruperez et al. [35] who, as long ago as 1991, reported that the
SERS spectra of stimulant drugs, including mefenorex, pentylenetetrazole, amphetamine and pemoline, could
be obtained using borohydride-reduced silver colloid. Spectra were recorded using drug concentrations at the
mg ml1
level. Similarly, Cinta et al. [36] used Ag colloid to detect diazepam and nitrazepam at concentration
of 107
mol dm3
. More recently, Faulds et al. [37] (see also Chapter 6.3) have tested both Ag and Au colloids
for SERS detection of amphetamine sulfate. In this case it was found that Ag colloid gave larger signals than
Au colloid at the higher end of the concentration range tested. However, Au colloid gave a lower detection
limit, which was 105
mol dm3
in analyte solution, corresponding to a final concentration after addition of
colloid of 106
mol dm3
.
The main alternative to colloids is the use of solid substrates, which have the advantage that they allow much
more flexibility in the sampling. Typically, liquid samples are flowed over the enhancing surface while the
monitoringbeam isdirectedontoa singlepointonthesurfaceorthesampleisdepositedas a dropletwhichdries
onto the surface of the medium. The range of substrates is now vast. Randomly roughened surfaces, prepared
carrying out repeated oxidation/reduction cycles on Ag electrodes to build up a very rough metal layer on the
surface, were developed early in the history of SERS and they continue to be used. However, Au or Ag island
films, which also date back to the earliest days of SERS, can be prepared by evaporating Au or Ag onto smooth
substrates and also remain popular. The alternative approach to making roughened metal surfaces is to deposit

uniform metal layers onto rough or textured surfaces so that the morphology of the thin coating follows that of
the underlying substrate. A very successful approach has been to carry out the deposition on ordered arrays
of polymer nanospheres to create AuFONs (gold films over nanospheres) which can be used directly as the
enhancing medium. Commercial Klarite
(Renishaw Diagnostics) substrates also use gold deposited on a
regular textured Si substrate.
A good example of the advantages and problems of solid substrates was in a study by Faulds et al. [36] on the
use of a roughened Ag and Au films for the detection of amphetamine. Figure 6.10 shows the SERS spectra
obtained when 25 ml droplets of amphetamine sulfate solutions at various concentrations were deposited on
vapour-deposited gold films. The sensitivity of the measurements was good but it was found that the intensities
of the spectra from a single sample varied across the film surface. The in-film precision, determined by taking
five spectra at different points on a film and then calculating the relative standard deviation (RSD) of the most
intense peak in the spectra, was found to be 31.6%. However, the precision was improved to RSD of 5.8% by
averaging the scattering from several points on the surface. This suggests that it may be possible to obtain
reproducible data as long as several spectra are obtainedfrom the substrateand averaged, in much thesamewas
as was discussed for tablets above. Interestingly, when the slides werewashed with a drop of methanol and then
re-measured, to determinewhether therewas surface attachment between the drug and the silver and gold film,
the signal obtained was greatly reduced. This demonstrates that the surface attachment between the drug and
the metal surface was very weak.
400 600 800 1000 1200 1400 1600
(a)
(b)
(c)
(d)
Wavenumber/cm–1
(e)
1295
706
1442
796
851
1086
Raman
Intensity
Br
NH2
CH3
OCH3
H3CO
DOB
Figure 6.9 SERS spectra of a series of model tablets prepared from lactose with increasing amounts of DOB. Tablets
are 400 mg lactose plus (a) 0, (b) 15 mg, (c) 60 mg, (d) 250 mg, (e) 1 mg DOB. With 1 mg per 400 mg lactose the
spectra are entirely dominated by the DOB signal in much the same way as is observed for seized samples. Spectra
were obtained with 785 nm excitation and have been offset for clarity. Adapted from Reference [33] with permission
of John Wiley Sons, Ltd.

Trachta et al. [38] recorded the SERS spectra of eight benzodiazepine drugs on AuFONs in 96-well
microtitre plates as SERS-active substrates. These spectra were recorded using a 1064 nm excitation FT-
Raman spectrometer rather than the now more usual 785 nm or visible excitation systems. It was found that
1 mg of analyte per well was sufficient to give spectra of sufficiently high quality to allow identification
and discrimination of the drugs. It was pointed out that the detection limits were at the level that can be
collected at the output of an HPLC instrument employed for separating these drugs from blood serum.
Indeed this work was part of a series of papers in which street quality drugs were first separated from their
matrix and then detected by SERS. In the first such study, Sagmuller et al. [39] used SERS to detect a range
of stimulants and entactogens extracted from seized tablets into cyclohexane solvent. These included
MDEA and MDA as well as the more widely studied MDMA, amphetamine and methamphetamine. In this
case the enhancing medium was a dispersion of silver halide in a gelatine matrix. The active silver surface
was formed photolytically in situ using the same focused 514.5 nm probe beam that was also used to record
the spectra. The sensitivity of the method did not need to be high since the concentration of the 10 ml aliquots
of the extracted drugs which were added to the medium would be expected to be orders of magnitude above
trace levels. The inclusion of the extraction step allowed spectra of the active to be recorded without
interference from other constituents in the seized tablets. This was an advantage in that it removed spectrally
interfering materials such as dyes, but it also meant that any information on the composition that would be
useful for profiling was lost.
This work was followed by a study in which HPLC was combined with SERS detection; this gave even
better separation of the drugs from other compounds within the seized dosage forms. In this case, the fractions
of interest were collected in the wells of a microtiter plate, which contained the same matrix-stabilised silver
halide dispersion. Since microlitrevolumes were used, the limits of detection could be as low as 1 mg of analyte
per well of the microtitre plate. In addition to cocaine and amphetamine, it was possible to record high quality
spectra of several active compounds from street quality heroin, something which fluorescence normally makes
impossible except with long wavelength excitation [40]. Finally, it has been applied to drugs of abuse in blood
and urine [41].
In all the examples above, the success of the SERS analysis using colloids relied on the spontaneous
adsorption of the target onto the surface. Indeed, given a reasonably enhancing substrate, the main factor that
determines whether any given analyte gives a large SERS signal is its ability to locate in the critical region,
Figure 6.10 SERS spectra of amphetamine which was applied as 25 ml droplets onto vapour deposited gold films.
Sample concentrations were: (a) 10–3
mol dm3
, (b) 10–4
mol dm3
, (c) 10–5
mol dm5
. The spectra were obtained
using 785 nm excitation and have been offset for clarity. Reproduced from Reference [36] with permission of The
Royal Society of Chemistry.

which is on, or near, the surface. Of course, if compounds of interest spontaneously bind strongly to the
enhancing Ag or Au surfaces the only requirement is to bring the molecules in contact with the medium.
However, in cases where spontaneous adsorption to a suspension of particles is ineffective (and these are
surprisingly common) there are still possibilities for SERS analysis, either by drying solution down onto a solid
enhancing surface, which forces the analyte into contact with the substrate (as discussed above for
amphetamine on evaporated Au films), or by modifying the surface so that it has a higher binding affinity
for the target.
A real potential advantage of using surface modification is that it may not only promote adsorption by the
target of interest, it may also be possible to select against adsorption of other compounds in the sample. It is
useful to remember that just as moving from purified samples to real life detection gave considerable problems
with visible excitation, using SERS substrates with no selectivity to analyse real world samples is also likely to
bring problems associated with interference from other compounds in the sample. This makes it important to
consider surface modification strategies for drugs of abuse.
In an interesting early study, Sulk et al. [42] investigated the potential of an approach where the target would
be converted to something more easily detectable by increasing surface binding. In their case amphetamine
and methamphetamine were derivatised by a coupling reaction with 2-mercaptonicotinic acid using a standard
coupling reagent (dicyclohexylcarbodiimide; DCC) to form the corresponding amides which would then be
able to bind to Au or Ag through both their thiol sulfur and the pyridine nitrogen groups. Quantification of the
amides was accomplished using pentachlorothiophenol as the internal standard and measuring the intensity of
Raman bands of the analyte relative to it. Detection limits of 19 and 17 ppm were found for the amphetamine
and methamphetamine derivatives, respectively. However, this method required a complicated coupling
reaction to be carried out before detection, so was a proof-of-concept rather than a practical solution. Although
no examples of the obvious extension of this approach to direct reaction between a drug target and a reactive
coating on the surface have yet been reported, the approach where the surface of a colloid is functionalised in a
way that promotes binding by a target analyte has been extended in using non-covalent interactions rather than
covalent bond formation.
The most obvious method to introduce selective binding onto a surface is to use antibodies or aptamers.
This approach was followed by Chen et al. [43] who used an aptamer sequence engineered for cocaine
which was modified with a reporter molecule, tetramethylrhodamine (TMR), at the 30
end to give the structure
50
-SH-(CH2)6-GAC-AAG-GAA-AAT-CCT-TCAATG-AAG-TGG-GTC-(TMR)-30
. The general principle of
operation of the sensor is illustrated in Figure 6.11; this figure is also featured (as Figure 6.3.4) and discussed
within Chapter 6.3. In essence, when there is no cocaine (or more accurately after the original cocaine template
used to construct the sensor is washed away) the aptamer which is bound to the enhancing surface sits in a
conformation where the reporter molecule is away from the surface. This means that in the “off” state the
reporter signal is low. However, when cocaine binds it triggers a conformational change of the surface-tethered
aptamer and this draws the Raman reporter in close proximity to the SERS substrate. This increases the Raman
scattering signal from the reporter. It is notable that in this case the signal which is measured is not that of
the target, instead the cocaine binding event is signalled by a change in the SERS signal from an entirely
separate reporter molecule. The detection limit for this system (estimated as 3 the standard deviation of the
measurement) was 1 mg, which compares favourably with analogous aptameric sensors based on electro-
chemical and fluorescence techniques. Importantly, since the sensor was based on reversible binding by the
target to an immobilised aptamer on a support, it could be regenerated by being washed with a buffer. This
general methodology clearly has considerable potential, although the fact that the target is not measured
directly means that it will be vulnerable to interference from any factor which causes a change in the aptamer/
reporter conformation. For example, the intensity of the reporter signals are strongly perturbed by changes in
the ionic strength, increasing with additional Naþ
but decreasing with Mg2þ
addition, even at sub-millimolar
concentrations.

An exampleof a similar approach, Sanles-Sobrio et al. [44] measured changesin the spectra of a monoclonal
antibody rather than an aptamer supported on silver-coated carbon nanotubes. In this case the target was not
cocaine itself but was the main cocaine metabolite, benzolecgonine, but the principle is still valid.
The final example of this general approach is a study on MDMA. In contrast to the examples above, the
target does not spontaneously adsorb to normal enhancing media, so that it did not give detectable SERS
signals with conventional citrate- or hydroxylamine-reduced colloids, even at 103
M, which would be
regarded as a high concentration for SERS analysis. To promote MDMA adsorption, Ag colloids were
modified with a range of thiol-terminated modifiers which formed self-assembled monolayers (SAMs) on the
surface [45]. It was found that mixed SAMs of sodium mercaptopropane sulfonate (MPS) and benzyl
mercaptan (BZM) gave the best response (see Figure 6.12).
Strikingly, neither of the colloids modified entirely with BZM or MPS on their own gave any MDMA signal.
However, a surface with approximately 31% MPS and 69% BZM gave the best response, presumably because
this composition gave the optimum combination of attractive interactions. These are believed to be
electrostatic attraction between the secondary amine of MDMA and the sulfonate headgroup in MPS
combined with hydrophobic interactions between the aromatic rings of MDMA and BZM. (see Figure 6.13)
With these monolayers, a PLS calibration was established for MDMA which gave satisfactory performance,
for example the predicted value at the lowest concentration was 10.1 106
mol dm3
, which is 2.4 106
mol dm3
away from the true value. The significance of this result is that it demonstrates a simple and general
method for tuning the surface properties of SERS-active nanoparticles to optimise the binding of a specific
analyte. This has considerable potential, both as a means of allowing detection of non-binding target analytes
and, conversely, for suppressing the signals from interfering species in the sample.
Figure 6.11 Schematic illustration of the principle of operation of a aptamer based sensor for cocaine. In the
absence of cocaine the aptamer sits in a conformation where the reporter molecule (R) is away from the surface, so it
gives a low signal. However, when cocaine binds it triggers a conformational change which draws the Raman
reporter in close proximity to the SERS substrate and increases its Raman scattering signal. Copyright of Wiley-VCH
Verlag GmbH Co. Reproduced from Reference [42] with permission.

6.4 Conclusions
Since Raman spectroscopy comprises a family of related techniques, each with its own particular strengths
and weaknesses, there are numerous possibilities for application of Raman methods to detection and analysis
of drugs of abuse. The technical advances which have allowed the construction of benchtop and now even
1600 1400 1200 1000 800 600 400
(a)
(b)
(c)
(d)
840 800 760 720
Raman Shift /cm–1
Intensity/Arbitrary
Units
812
716
Figure 6.12 SERS spectra of Ag colloids whose surfaces have been modiﬁed with mixed self-assembled monolayers
of alkyl thiols. Spectra are of aggregated thiol plus (a) 7.7 104
M MDMA and (b) H2O. Spectrum (c) shows the
result of subtracting (b) from (a), and spectrum (d) shows solid MDMA.HCl for reference. Spectra are scaled and
shifted for clarity. Inset shows a zoomed in view of spectra (a) and (b) overlaid on the same axes.
S S S S
S S
S
O
O
–
O
S S
S
S
O
O
–
O
N
+
H
H
O
O
Ag Surface
Figure 6.13 Schematic illustration of the possible interactions between MDMA and a surface modiﬁed with sodium
mercaptopropane sulfonate (MPS) and benzyl mercaptan (BZM).

hand-held spectrometers have been important in making the technique more accessible. Some applications,
such as rapid identification of drugs of abuse in seized samples within a laboratory setting, are now well
established. However, there are numerous other possibilities, ranging from compound identification in the field
to composition profiling and trace drug detection using surface-enhanced methods, for which preliminary
studies show tremendous potential. There is still a considerable challenge in moving these from potentially
useful approaches into methods which are widely accepted and utilised for forensic casework.
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6.1
Drugs of Abuse – Application
of Handheld FT-IR and Raman
Spectrometers
Michael D. Hargreaves
Thermo Fisher Scientific Portable Optical Analyzers, 46 Jonspin Road, Wilmington, MA, USA
6.1.1 Introduction
Vibrational spectroscopy, in the form of Raman, mid-infrared [mid-IR; using Fourier transform infrared
(FT-IR) spectrometers] and near-infrared (NIR) is already well established in a multitude of application spaces
and has been described in other chapters in this and many other books. In other sections of this book: in-situ
measurement has been covered in Chapter 4, an overview of drugs of abuse analysis by Raman has been
covered in Chapter 6 and trace analysis of drugs of abuse by surface enhanced Raman spectroscopy (SERS)
and surface enhanced resonance Raman spectroscopy (SERRS) have been covered in chapter 6.3. This chapter
combines several of the themes in those chapters, specifically addressing drugs of abuse identification in the
field by portable devices [1], highlighting the difficulties forensic and hazmat (hazardous materials) personnel
face and the complementary nature of Raman spectroscopy and mid-IR spectroscopy [2].
According to the United Nations world drugs report 2010, cannabis is the most highly used illicit substance,
with world users estimated in the range of 120–190 million people; this is followed by amphetamine, cocaine
and opiates [3].
6.1.2 Advantages of Vibrational Spectroscopy
One must first understand that, whilst there are many molecular scale similarities concerning drugs of abuse,
there are also differences which allow identification (ID) and discrimination of closely related molecules.
Infrared and Raman Spectroscopy in Forensic Science, First Edition. Edited by John M. Chalmers, Howell G.M. Edwards and Michael D. Hargreaves.
2012 John Wiley Sons, Ltd. Published 2012 by John Wiley Sons, Ltd.

Subtle differences, especially in complex mixtures can be challenging to solve by vibrational spectroscopy
techniques, given the complexity of having several spectral components superimposed and possible chemical
interactions, which may give rise to band shifts and band shape changes [4, 5]. What makes vibrational
spectroscopy so powerful and useful are the following attributes:
. The ability to quickly collect spectra and perform an identification non-destructively;
. The selectivity and specificity of mid-IR and Raman spectroscopy;
. The complementary nature of mid-IR and Raman spectroscopy;
. The handheld/portable nature of several units, allowing them to be taken to the point of need;
. The ability to add new library spectra rapidly, and pass them to other team’s spectrometers;
. The cost saving of screening samples before they get sent to the laboratory for verification.
The main types of drugs of abuse can be largely covered by four classes: opium/heroin, coca/cocaine, cannabis
and amphetamine-type; this is a vastly over simplified list, but covers the majority of those drugs of abuse
trafficked around theworld for illegal gain. Emerging new threats are the so-called “synthetic narcotics”; these
include such chemicals as mephedrone, recently classified as a controlled substance in several countries,
which are becoming more of an issue in several regions of the world. This highlights one very important issue;
as quickly as chemicals are outlawed, the supplier changes to another similar molecule, and so the threats can
change very rapidly. The ability to identify/screen is therefore very important, as the drug investigation
laboratories are almost always dealing with long backlogs; the ability to rapidly identify an unknown sample,
would allow better use of laboratory resources.
6.1.3 General Drugs of Abuse – Introduction
The structures of drugs of abuse have been introduced in Chapter 6 (see Figure 6.1), in which it was highlighted
that these types of molecules are complex molecules that yield characteristic molecular fingerprints, which in
some cases, given the very similar molecular structures, can yield very similar vibrational spectra, but
distinguishable by chemometric methods [6–10], see Figure 6.1.1. The addition of cutting agents and the
concentration of the “active” component can lead to complex spectral interpretation. As a general rule,
vibrational spectroscopy has a limit of detection (LOD) of approximately 5%, this can be higher or lower
depending on the application and analytes in question, but practically the lowest LOD achievable is around 1%.
The following sections of this chapter highlight both mid-IR FT-IR and Raman spectroscopy for the analysis
of bulk samples; trace analysis using SERS and SERRS is described and covered in Chapter 6.3. The
portability of modern Raman and FT-IR instrumentation makes them desirable techniques for use in the
identification of drugs in forensic applications such as detection of bulk seizures of samples. In the drugs
overview chapter (Chapter 6) several benefits of benchtop instrumentation were highlighted. Specifically the
coupling to microscopes, which allows macro sampling and imaging or mapping (as discussed in Chapter 3).
Further intelligence may be gathered if the mixture of components is the same for several samples, indicating a
common source.
6.1.4 Vibrational Spectroscopy
Interest invibrational spectroscopy,principally Raman and mid-IR (FT-IR) spectroscopy continuesto increase
as these analytical techniques may be applied to a widevariety offields, including the narcotics sector [11–15].
Raman and FT-IR spectroscopy have seen rapid deployment for use in homeland security applications, largely
due to their high chemical specificity, which allows robust identification. Raman, FT-IR and NIR spectroscopy

are very powerful techniques that can be brought to bear on the identification of unknowns, including drugs of
abuse; the aspects of the techniques and the advantages of these techniques are covered in several sections of
this book: Chapter 2 and specifically in Chapter 6.
In the context of narcotics identification with mid-IR, Raman and NIR spectroscopy, there are several
practical aspects that govern applicability. Some materials that cannot be identified by Raman spectroscopy,
because of fluorescence (Figure 6.1.2) are amenable to identification by mid-IR spectroscopy and vice
versa [5]. For example, some materials can be very difficult to identify with Raman systems due to
overwhelming fluorescence (discussed in Chapters 2, 4 and 6). Some street sample materials are particularly
problematic in this regard when using a laser excitation below 1000 nm/1 mm excitation [readers are directed
Figure 6.1.1 Handheld Raman (785 nm) and mid-IR (ATR/FT-IR) spectra of common narcotics.
Drugs of Abuse – Application of Handheld FT-IR and Raman Spectrometers 341

to Chapter 4.5 (Figure 4.5.5) and Chapter 6 (Figure 6.4)], due either to the molecular structure, matrix
materials or degradation of the components. An example of a cocaine street sample is shown in Figure 6.1.2,
and the sloping baseline is indicative of fluorescence. Even though the spectrum shows a reasonable degree of
fluorescence an identification is still achievable, using chemometric identification methods.
Fluorescence is not a limitation in mid-IR spectroscopy, nor is there an ignition risk for dark materials from
laser heating, but aqueous samples are difficult to measurewith mid-IR spectroscopy due towater interference.
Water is rarely an interferent in Raman analysis, but if an analyte is present in very low concentration, below
the LOD, neither Raman nor mid-IR spectroscopy will identify it, unless, in the case of Raman spectroscopy,
SERS or SERRS can be applied.
Tactically, Raman spectroscopy has the advantage of being non-contact and capable of performing analysis
of materials contained in transparent containers (e.g., glass bottles, plastic bags), which is very advantageous
to hazmat and law enforcement personnel as it limits exposure to unknowns; while FT-IR spectroscopy with an
attenuated total reflection (ATR) head requires intimate sample contact with the ATR element, presenting
some risk when handling unknowns and pressure-sensitive energetic materials. Although some thick
containers and fluorescent containers (e.g., coloured glass bottles) can be challenging for Raman spectroscopy,
today’s Raman devices coupled with the appropriate signal processing often have little difficulty providing
unequivocal identification in conditions that were historically challenging.
In the real world, unfortunately, it is rare to find street narcotic samples that are pure, that is, one component.
It is also important to consider that the drugs may degrade over time depending on the storage conditions. This
is most likely in border and custom points were the drugs are being smuggled in or out of a country. Standard
backscattered Raman spectroscopy is “line of sight”, which requires a suspicious package or container to be
identified by other technologies or personnel. Advances are being made in the form of SORS (which allows
detailed analysis through opaque containers; see Chapter 6.2), although substances contained within metallic
containers remain beyond the capability of detection by optically based technologies.
FT-IR/ATR spectroscopy is now routinely used in benchtop, portable and handheld FT-IR units, as this
method requires minimal sample preparation and is non-destructive, unlike the use of KBr discs, for
example. As mentioned above, a limitation of FT-IR/ATR spectroscopy is the required intimate contact of
Figure 6.1.2 Representative 785 nm excitation Raman spectrum of a cocaine HCl street sample; reference spectra
of cocaine HCl and phenacetin are also shown.

the sample with the ATR element, usually diamond, in order to conduct an analysis; handheld/portable
devices use an anvil or crusher arrangement to ensure good contact and hence record a good FT-IR spectrum.
As narcotics samples and other types of samples are frequently mixtures, it requires either sophisticated
mixture analysis, which can be found on handheld and portable units and/or time consuming offline spectral
analysis. On some units this is an automatic routine, requiring no user intervention or it requires user invention
to decide on mixture components. More details of spectral identification methods can be found in Chapter 2
and in the chapter on handheld Raman and FT-IR spectrometers, Chapter 5.3.
6.1.5 Analysis of Street Samples
As eluded to earlier, seized street narcotics are very rarely only the “active” component, usually they are mixed
with so called cutting or bulking agents, which typically are whatever the criminals can get a hold of; examples
of common cutting agents are: caffeine, lactose, acetaminophen, calcium sulfate, acetylsalicylic acid and
cellulose, to name but a few [16]. The homogeneity of samples is an important consideration, whether
sampling by Raman spectroscopy (through a container) or by FT-IR/ATR spectroscopy.
6.1.5.1 Considerations when analysing in situ
Measurements in the field, certainly in the case of narcotics can be undertaken at clandestine laboratory
locations, where identification of the narcotics and the precursors is required; this is because, unhelpfully,
criminals seldom label their containers with their contents! Alternatively, handheld units are being deployed
with police officers and customs officials, who can scan unknown powders rapidly and non-destructively and
effect a rapid identification, and give cause for arrest. Measurement of samples in the field is very different to
analysis in the laboratory, for the following reasons. Users in the field have to deal with the environment around
them, which may or may not be conducive to making measurements. For instance very bright overhead
sunlight can make Raman spectroscopic measurements take longer or blind the system, or it may be raining,
windy, dusty and so on.Some handheld units are designed for such exploits,others not, a recent study of several
Raman spectrometer systems looked at the robustness of those systems [17].
The packaging that contain narcotics, may not be amenable to backscattered Raman spectroscopy;
advances are being made in the field of SORS, but it is unclear at this point if that technology could be
made into a handheld instrument [18, 19]. In most cases of dealing with an unknown it may be preferable,
where the situation allows, to sample a small amount and scan separately, ensuring the safety of the personnel
undertaking the measurement. The protocols around the world are very different, with some standard
operating procedures (SOPs) stating to measure with a Raman system first, as this can scan through
transparent containers, others use an FT-IR system first, meaning that contact is required, as all portable/
handheld FT-IR units applied to this field currently use ATR. The distinct advantage of handheld/portable
units is the capability to take the units directly to the point of need, thereby allowing users to make safe the
local environment by rapidly identifying the chemicals in the vicinity and selecting samples for further
analysis if required.
6.1.5.2 Considerations when analysing in the laboratory
Typically when a sample is sent to the laboratory for analysis, there is a reasonable likelihood that there is a
narcotic or banned substance present. Some parts of the world use a presumptive colorimetric test kit, in which
a colour change is induced depending on the narcotic present; this affords some degree of pre-screening of
samples. There have been investigations by police forces using Raman spectroscopy to undertake this
screening step, as Raman spectroscopy is more selective and less prone to false-positives and negatives.

Laboratory based Raman and FT-IR spectroscopy instruments, afford extra sampling flexibility; the
coupling of microscopes to both techniques allows samples to analysed on the macro scale, single particles
can be scanned and maps or images can be collected to highlight the sample homo- or heterogeneity.
Understanding the full sample matrix can help the authorities understand the origins of batches of narcotics,
providing intelligence on the source(s).
Coupling of other techniques, for instance scanning electron microscopy (SEM) and atomic force
microscopy (AFM), known as tip enhanced Raman spectroscopy (TERS), with Raman spectroscopy can
allow other analytical data to be collected on the same particle [20]. The same advantages and disadvantages
are at play, as with the handhelds; Raman spectroscopic systems can, if desired, penetrate plastic bags or
bottles, meaning a sample does not need to be removed, whereas FT-IR systems require a sample to be
removed. Several papers have highlighted the analysis of narcotics under nail polish or in fingerprints, which
may afford extra intelligence [21–23].
Lastly, the major benefit of laboratory analysis is the ability to screen with several other complementary, but
destructive technologies, requiring consumables, including liquid chromatography or gas chromatography
coupled with mass spectrometry, LC-MS and GC-MS, respectively, both affording the ability to screen and
identify at trace levels, which can act as a confirmatory tool to field analysis results [24, 25].
6.1.6 New Narcotic Threats
There are several new classes of narcotics that have made a dramatic appearance, certainly within Europe; one
of these is the cathinone group of chemicals. Cathinones is the name given to a group of drugs that are related to
amphetamine-like compounds. Some cathinone derivatives were previously sold online and in shops as so-
called “legal highs”. Cathinone derivatives include a variety of chemical compounds including: cathinone,
methcathinone, mephedrone, flephedrone, methylone and several others.
The structure of cathinones is shown below in Figure 6.1.3; essentially, different functional groups are
placed around the molecule in the R1–R4 positions. The most challenging aspect of this class of compounds
from an identification perspective is that they are being modified and shipped from their source(s) all the time.
Mephedrone was recently banned in the United Kingdom and in most of the rest of Europe and further afield. It
is still available in the European Union on the black market, like all narcotics, so an important element of field
identification is the ability to keep up to date with the most recent threats and ensure the database library of
fielded units is as current as possible. Users can rapidly add new user spectra to the libraries of portable and
handheld units and pass them to all other units in the fleet to ensure the same performance. The spectra of
mephedrone HCl is shown below in Figure 6.1.4.
6.1.7 Identification of Drug Precursors
Not only are the narcotics themselves of interest to the authorities, the precursors and chemicals used in the
manufacturing and processing of the narcotics are of importance too. The identification of chemicals in
Figure 6.1.3 Cathinone building block.

clandestine narcotics laboratories or at borders can provide important information on the threats and
intelligence on who the authorities should be tracking.
The list of precursors from around the world remains largely the same, as the same chemical building blocks
and solvents are used to manufacture and process the narcotics. It is getting more and more difficult for the
criminals to obtain these chemicals as the governments and in turn the suppliers operate with ever more
stringent rules and regulations.
The ability for end-users to be able to identify a whole range of chemicals, not just narcotics, is an obvious
advantage, with several handheld/portable units utilising reasonably large libraries, including the United
States Environment Protection Agency (EPA) high volume production (HVP) chemicals [26].
Figure 6.1.5 shows the spectra for several chemicals listed in several controlled narcotics lists. The ability to
be able to identify these (and others) in the field is very advantageous, as it allows the users to operate in a safe
manner (retreating if they find chemicals of immediate concern) as often the response teams are met with a
room with lots of mislabeled or unlabelled containers.
Figure 6.1.4 Raman (785 nm) and mid-IR (FT-IR/ATR) spectra of mephedrone HCl.
Figure 6.1.5 Raman (785 nm) and FT-IR/ATR spectra of several internationally listed narcotics precursors or
chemicals used in the illicit manufacture of narcotics.

6.1.8 Case Studies
An analyst can never have too much information, regardless of what they are trying to analyse; the same is
true for drugs of abuse. The more pieces of analytical information at their disposal the better the chance of
understanding the complex spectra associated with drugs of abuse. Given the very real issue of sample
fluorescence with Raman spectroscopy, and the lack of it in mid-IR spectroscopy, it is highly preferable to
have both vibrational spectra available, either to backup and complement each other or to facilitate
an identification (ID), where one has failed to give an answer, whether it be because of fluorescence for
Raman spectroscopy or water interference for mid-IR spectroscopy. Both examples given in the following
sections measured the same sample by both Raman and FT-IR spectroscopy. (Please note these are not real
case examples).
6.1.8.1 Case study I
The sample was an off-white/yellow solid sample. The inexperienced user scanned the sample using a Raman
spectroscopic unit initially; the sample is consistent with a mixture of three components: a narcotic, heroin
hydrochloride, and two common cutting agents, caffeine and sucrose. The Raman spectrum for the unknown is
shown in the top left of Figure 6.1.6; the Raman signal is very weak above the fluorescence, but there is still a
signal. Heroin is known to be difficult for Raman spectroscopic units operating below 1064 nm to identify,
Hargreaves et al. [5] investigated the effects of laser excitation on street drugs of abuse samples, concluding
that, in some cases, for instance heroin and cannabis, the longer excitation wavelength yields less fluorescent
Raman spectra and hence a greater chance of identification.
In order to verify the result from the Raman unit, the user repeated the measurement, with the same sample
on an FT-IR unit. The unit returned a mixture identification for the same components identified by the Raman
unit. In this case, it highlights the complementary nature of Raman and mid-IR spectroscopy; Raman
spectroscopy, as mentioned above, can suffer, depending on the laser excitation wavelength from sample
fluorescence. This can prevent an identification in the field. Mid-IR spectroscopy does not suffer from the issue
of fluorescence and performs very well for solids, gels and pastes; interference from water absorption bands,
however, can sometimes be a hindrance for single-bounce ATR spectral interpretation.
Figure 6.1.6 Raman (785 nm) and mid-IR (FT-IR/ATR) spectrum of an “unknown” sample.

6.1.8.2 Case study II
The sample was an “unknown” off-white solid in a glass container. The user scanned the sample with a Raman
spectroscopic system initially, because no sampling was required. The Raman and FT-IR spectra of the
unknown are shown as the top spectra in Figure 6.1.7. The Raman spectrum also shows contributions from the
glass container. Spectral analysis shows the data is consistent with a mixture of two components, cocaine
hydrochloride, a white solid in pure form, and D-mannitol, a sugar, and a common cutting agent. The sample
was also removed from the glass container and run on an FT-IR unit. Again the spectrum is consistent with a
mixture of two components, cocaine hydrochloride and D-mannitol, again highlighting the complementary
nature of Raman and mid-IR spectroscopy.
It is rare for field operatives to find drug samples in a high purity state, most samples have been cut with some
form of cutting agent, examples of which are highlighted here. Typically, samples are cut with the same types
of cutting agents, usually easily sourced powders, such as sugars, acetaminophen, caffeine and so on.
The cutting agents used can in some cases infer a particular batch or origin.
6.1.9 Conclusion
Raman and FT-IR spectroscopy, particularly with handheld spectroscopic units, may be utilised by police and
customs personnel for the routine identification of a whole range of solids and liquids, including drugs of
abuse. Tactically, Raman spectroscopy has the advantage of being non-contact and capable of performing
analysis of materials contained in many clear and coloured transparent and translucent containers.
In the case of drugs of abuse, Raman spectroscopy can be restricted in its application due to fluorescence. In
some cases spectral processing can assist, but in some the fluorescence completely masks the Raman signal.
Where this does occur, shifting to a longer excitation wavelength can help, with handheld/benchtop dispersive
1064 nm laser excitation units beginning to appear on the market [27–29]. Mid-IR spectroscopy is a highly
complementary technique, which can be used as a confirmatory tool or as an identification tool where no result,
due to fluorescence, has been achieved by Raman spectroscopy.
Both Raman and FT-IR spectroscopic systems may also be used in a number of other related applications;
theyare used by agencies to identify energetics, suspiciouspowders and liquids. In thewider application space,
Figure 6.1.7 Raman (785 nm) and mid-IR (FT-IR/ATR) spectrum of an “unknown” sample.

portable Raman and FT-IR spectroscopic units may also be used in the pharmaceutical arena for raw material
ID and counterfeit detection, providing those in the field with valuable, timely information.
Disclaimer
The views expressed in this chapter are those of the author and not necessarily those of Thermo Fisher
Scientific.
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