Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215

Contents lists available at ScienceDirect

Journal of Pharmaceutical and Biomedical Analysis

journal homepage: www.elsevier.com/locate/jpba

Review

Quality assessment of herbal medicines based on chemical

fingerprints combined with chemometrics approach: A review
Yun Li a,b , Yao Shen b,c , Chang-liang Yao b,c , De-an Guo a,b,c,∗
a
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, PR China
b
Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Haike Road 501, Shanghai, 201203, PR China
c
GenChim Testing Technology (Shanghai) Co., Ltd., Meiyue Road 81, Shanghai, 200131, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Herbal medicine (HM) has been playing a pivotal role in maintaining human health since ancient
Received 30 May 2019 times, and its therapeutic theory and clinical experience are the precious traditional medical knowledge
Received in revised form 8 January 2020 reserves. As HM occupies an important position in its own right in global healthcare systems, robust qual-
Accepted 26 February 2020
ity assessment and control over its complex chemical composition was of great significance to assure its
Available online 2 March 2020
efficacy and safety. Over the past decades, the concept of HM chemical fingerprints aiming to obtain a
comprehensive characterization of complex chemical matrices has become one of the most convincing
Keywords:
tools for the quality assessment of HM. This review summarizes the recent analytical techniques used to
Herbal medicine
Chemical fingerprints
generate HM chemical fingerprints, including chromatography, vibrational spectroscopy, nuclear mag-
Analytical techniques netic resonance spectroscopy, and mass spectrometry. The advantages, drawbacks, and the application
Chemometrics scope of each technology have been scrutinized in an attempt to better understand the data analysis.
Quality assessment Furthermore, HM fingerprints together with multivariate and multiway chemometrics methods used for
different application domains, such as similarity, exploratory, classification, and regression analysis, have
also been discussed and illustrated with a few typical studies. The article provides a general picture and
workflow of fingerprinting analyses that have been used for the quality assessment of HM.
© 2020 Elsevier B.V. All rights reserved.

Abbreviations: 2D–COS, two dimensional correlation spectroscopy; AAS, atomic absorption spectrometry; ANN, artificial neural network; APCI, atmospheric pressure
chemical ionization; ATR–IR, attenuated total reflectance infrared spectroscopy; CE, capillary electrophoresis; COSY, chemical shift correlation spectroscopy; DAD, diode array
detection or photodiode array detection; DART–MS, direct analysis in real time-MS; DModX, distance to model in X-space; EEM, excitation-emission matrix fluorescence;
ESI, electrospray ionization; FID, flame ionization detector; FT–MIR, Fourier transform mid-infrared spectroscopy; FT-NIR, fourier transform near-infrared spectroscopy;
FT-Raman, fourier transform Raman spectroscopy; GA, genetic algorithm; GC, gas chromatography; GC–MS, gas chromatography-MS; GLC, gas-liquid chromatography;
GRAM, generalized rank annihilation method; HCA, hierarchical cluster analysis; HM, herbal medicine; HMBC, heteronuclear multiple bonding connectivity; HPLC, high
performance liquid chromatography; HPTLC, high performance thin layer chromatography; HSI, hyperspectral imaging; HSQC, heteronuclear single quantum correlation;
ICP–AES, inductively coupled plasma-atomic emission spectrometry; ICP–MS, inductively coupled plasma-MS; ICP–OES, inductively coupled plasma-optical emission spec-
trometry; ICR, ion cyclotron resonance; IR, infrared spectroscopy; IT, ion trap; k-NN, k-nearest neighbors; LC, liquid chromatography; LC–MS, liquid chromatography-MS;
LDA, linear discriminant analysis; LIBS, laser-induced breakdown spectroscopy; LIT, liner ion trap; MCR-ALS, multivariate curve resolution-alternating least squares; MIR,
mid-infrared; M-PCA, multi-way principal component analysis; MS, mass spectrometry; MSC, multiplicative scatter correction; MSPA, multiscale peak alignment; MSPC,
multivariate statistical process control; N3, N-nearest neighbors; NIR, near-infrared; NMR, nuclear magnetic resonance spectroscopy; N-PLS-DA, multi-way partial least
squares discriminant analysis; OPLS-DA, orthogonal partial least squares-discriminant analysis; PARAFAC, parallel factor analysis; PARS, peak alignment using reduced set;
PCA, principal component analysis; PLS-CM, partial least squares class modeling; PLS-DA, partial least squares discriminant analysis; PLSR, partial least squares regression;
QDA, quadratic discriminant analysis; QqQ, triple quadrupole mass spectrometry; RF, random forest; SFS, spectral fluorescence signature; SIMCA, soft independent modeling
of class analogy; SNV, standard normal variate; SVM, support vector machine; SVR, support vector regression; TLC, thin layer chromatography; UNEQ, unequal dispersed
classes; U-PLS-DA, unfolded-partial least squares discriminant analysis; UV, ultra violet; XRF, X-ray fluorescence spectroscopy.
∗ Corresponding author at: Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization
Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Haike Road 501, Shanghai, 201203, PR China
E-mail address: daguo@simm.ac.cn (D.-a. Guo).

https://doi.org/10.1016/j.jpba.2020.113215
0731-7085/© 2020 Elsevier B.V. All rights reserved.
2 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Scope of this review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Chemical fingerprint techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Spectroscopic techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2.1. Vibrational spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2.2. Atomic spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2.3. NMR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3. MS hyphenated techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4. Chemometrics methods and its applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.1. Data pre-processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.2. Data unfolding and multi-way decomposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.3. Data fusion strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.4. Anomalous samples detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.5. Unsupervised exploratory learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.6. Supervised learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.6.1. Classification analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.6.2. Regression analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

targeted approach have been proposed, which aimed to profile

1. Introduction
a comprehensive chemical description of HM, so-called ‘chemi-
cal fingerprint’. The World Health Organization (WHO), regulatory
Traditional herbal medicines have been used for the prevention
bodies worldwide such as the China Food and Drug Administra-
and treatment of human diseases for thousands of years. Shen-
tion (CFDA), the Food and Drug Administration (FDA) of the USA,
nong Bencao Jing (Shennong’s Classic of Materia Medica), the oldest
the European Medicines Agency (EMA), and the Ministry of Food
systematic monograph about the medicinal plants, formulations,
and Drug Safety (MFDS) of Korea have accepted the concept of
effect and theory of traditional Chinese medicines, was written
fingerprint to evaluate the quality of HM [2,16–18].
in ancient China from A.D. 25 to 220 [1]. Herbal medicine (HM),
The analyses performed by different analytical techniques pro-
including herbs, herbal materials, herbal preparations, and finished
vided a huge number of variables of fingerprint data, which not
herbal products, has become an increasingly important part of the
only offered a good opportunity for mining useful chemical infor-
global healthcare system [2,3]. Up to date, HM has attracted the
mation from the original dataset, but also mean that it is difficult or
interest of the global public with the trend of ‘return to nature’,
even incapable to exploit the useful chemical information through
and the increasing demand of HM has led to a significant expan-
general univariate analysis [19]. Nowadays, with the development
sion of its product markets [4]. However, at the present stage, HM
of computer science, multivariate statistical analyses of chemi-
has not been fully accepted in some western countries, due to its
cal fingerprint information by chemometrics methods have been
safety and efficacy evaluation data to be insufficient to support the
increasingly applied to the quality research of HM [20]. Chemomet-
criteria set by modern regulatory authorities [5,6].
rics methods are widely used to solve various problems in different
Arrays of phytochemical and pharmacological investigations
fields, such as the similarity analysis, exploratory learning, and
demonstrated that each individual herb could contain hundreds
classification algorithm can be used for qualitative analysis; multi-
or even thousands of chemical components, which exerted the
variate calibration algorithm can be used for quantitative analysis,
pharmacological effects through a network of multiple targets and
and explore the relationship between independent and dependent
pathways [7]. Furthermore, the quality of HM were affected by such
variables. The application of chemometrics to fingerprint data can
factors, as botanical species, medicinal parts (leaf, stem, root, rhi-
extract covered information and knowledge from chemical sys-
zome, flower, seed, etc.), processing methods (wash, dry, steam,
tems by mathematical modeling, which is a potential direction for
etc.), storage conditions (time, temperature, humidity, etc.), culti-
comprehensive quality assessment of HM.
vation years, harvest time, as well as growth conditions (terrain,
soil, climate, and sunlight) [3,8–10]. Those variable factors caused
the variations of chemical composition of HM from batch to batch, 2. Scope of this review
and resulted in a significant difference in pharmacological activities
[5]. Some reviews have summarized the application of chemical
In the existing regulatory systems and pharmacopoeias, qual- fingerprint generated by different analytical techniques combined
itative and quantitative quality assessment of HM was usually with chemometrics methods for the quality assessment of HM.
performed based on the sensory inspections including macroscopic However, most reviews showed a partial point of view, since
and microscopic examination, as well as quantitative determina- they only focused on a specific analytical platform and chemo-
tion of a few intrinsic marker compounds [11]. However, sensory metrics method for a narrowed application range. Nevertheless,
inspections mainly rely on personal experience and lacked ade- the comparison between different analytical techniques, differ-
quate evidence-based validation, which could lead to subjective ent chemometrics methods are needed to determine which one
differences in the qualitative evaluation [12,13]. The determina- is more appropriate to develop an efficient strategy. The choice
tion of single marker compound for the quality assessment of HM of fingerprint techniques and chemometrics methods depended
neglected the importance of the synergistic effect of the multi- on the objective of the current study, and the choice of a suitable
components, and did not represent its holistic efficacy [14,15]. analytical strategy required a clear formulation. Therefore, it is nec-
Techniques for the overall quality evaluation based on the non- essary to put forward a holistic and comprehensive view on the
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
quality assessment of the combination of chemical fingerprint and
chemometrics methods.
This review aims at clarifying the qualitative and quantitative
applications for quality assessment of HM, such as the differ-
entiation of HM from different geographical origins, botanical
species, growth years, harvest time, processing methods, and the
recognition of the confused or adulterated materials. Multivariate
calibration analysis was used to quantify the chemical compo-
nents or adulteration ratio, and regression analysis was used
to screen the quality control markers by modeling fingerprint-
efficiency relationships. The framework of this review focused on
three main topics. Firstly, the review summarized the application of
chemical fingerprint generated by different analytical techniques,
such as chromatography, vibrational spectroscopy, nuclear mag-
netic resonance spectroscopy (NMR), and mass spectrometry. The
advantages, drawbacks, and the scope of application of analytical
techniques were discussed to improve the understanding of data
analysis. Secondly, the workflow of chemometrics analysis, includ-
ing the detail of data pre-processing, data unfolding, data fusion,
anomalous sample detection, and data modeling were concluded.
The general analytical workflow for the second part were shown
in Fig. 1. Finally, the review described the application of differ-
ent chemometrics methods in the practice of quality assessment
of HM, including unsupervised (similarity and exploratory analy-
sis) and supervised learning (classification and regression analysis).
Based on the summary, the recommendations in terms of dif-
ferent requirements were provided for the practice of analytical
approaches and chemometrics methods, and the review could also
provide a reference to enhance the standardization of herbal fin-
gerprint analysis for future applications.
3. Chemical fingerprint techniques
3.1. Chromatography
Chromatography is a physical separation method that can sep-
arate complex chemical matrices in the herbal extract of HM into
plenty of pure substances or relatively simple sub-fractions [21].
Chromatographic techniques, which include liquid chromatogra-
phy (LC) [22–24], gas chromatography (GC) [25,26], thin layer
chromatography (TLC) [27–29], and capillary electrophoresis (CE)
[30], etc., have been used for fingerprint analysis of HM. With
the characteristics of wide suitability, high resolution, selectiv-
ity, sensitivity, and fully automatable operation, LC hyphenated
techniques are the most popular method [11,31,32]. The greatest
advantage of LC is that arrays of detectors could be selected accord-
ing to the chemical or physical attributes of target compounds
[31,33]. Furthermore, in order to get more fingerprint information
of a complex biological sample, the multi-wavelength combination
of high performance liquid chromatography-diode array detection
(HPLC–DAD) [34] and the data fusion of complementary detectors
[35–37] were explored in several studies. GC hyphenated tech-
niques are unanimously acceptable methods for the analysis of
volatile or semi-volatile constituents in HM [38,39]. However, this
technique is not intended for the analysis of polar and non-volatile
compounds. In order to obtain comprehensive chemical profiles
including both volatile and non-volatile compounds, an integrated
chromatographic fingerprint method by LC and GC metabolomics
data fusion was proposed [40]. The advantages of TLC and high per-
formance TLC (HPTLC) include simplicity, versatility, high velocity,
specific sensitivity and simple sample preparation [21]. Neverthe-
less, most of TLC and HPTLC analyses relied on peaks identification
and intensity comparison in a non-chemometric way, while it is
still short of fingerprint analysis based on chemometric methods
[41].
3
In recent years, the application of two-dimensional (2D) chro-
matography showed high peak capacity, resolution ability and
separation efficiency, so that this approach increased the num-
ber of measurable analytes in complex biological matrices [31,42].
Although 2D chromatography provided a promising resolution,
there are still some issues remaining unsolved [43]. In this regard,
chemometric methods have been developed into mathematical
methods for resolving overlapped analyte peaks, such as paral-
lel factor analysis (PARAFAC) [44,45], PARAFAC2 [46], generalized
rank annihilation method (GRAM) [47] and multivariate curve
resolution-alternating least squares (MCR-ALS) [43,48], which
were used to reveal hidden information and correct the distorted
data of those second- or high-order chemical fingerprint [49,50] for
the purpose of providing accurate results for both quantitative and
qualitative analysis [51].
It is apparent that the tremendous advantage of chemical fin-
gerprint generated by chromatography and hyphenated techniques
was due to its multivariate data matrix, containing both qualitative
and quantitative information of most phytochemical constituents
of HM. But the drawbacks of chromatography analysis were time-
consuming and high-cost features and the need of specific prior
experimental or analytical knowledge (methods of extraction and
chromatographic process) for generating the chemical fingerprint.
According to the nature of the chromatographic fingerprint, this
technique is suitable for the similarity and discrimination anal-
ysis of HM among different batches, medicinal parts, species,
origins, processing methods, and the like [5,52–58]. Furthermore,
chromatographic fingerprint could also be applied for fingerprint-
efficacy modeling, thus the related active substances or quality
control markers of HM might be rapidly screened [59].
3.2. Spectroscopic techniques
3.2.1. Vibrational spectroscopy
Due to the growing request for low-cost, real-time analysis
and green analytical chemistry, vibrational spectroscopy includ-
ing infrared (IR) and Raman spectroscopy, seem to offer the most
promising options [60]. IR spectroscopy focused on macroscopic
molecular information, in which the mid-infrared (MIR) region
revealed the molecular fundamental vibrations and associated
structures [61,62], and the near-infrared (NIR) region mainly cor-
responded to overtones, harmonic vibration as the combinations of
fundamental vibrations, and even physical properties [61–64]. Dif-
ferent from the IR spectroscopy that is obtained by the change of
the molecular dipole moment, the Raman spectroscopy is acquired
by a change in the polarizability during molecular vibration [65].
In the biological matrices of HM, fluorescent compounds (intrinsic
ones or impurities) caused a major limitation on the fingerprinting
analysis [66]. Fourier transform Raman (FT–Raman) spectrometer
provided a universal solution for the problem of fluorescent com-
pounds, plays a part on Rayleigh scatter removal, and had good
reproducibility of spectrometric experiments, which attributed to
the large entrance aperture [66,67]. Furthermore, the information
of NIR, MIR and Raman is complementary in nature, which means
data fusion strategies applied to two or more spectroscopic finger-
prints could provide an opportunity to describe complex biological
matrices in more detail [68–70].
Apart from the most commonly used first-order spectroscopy,
the second- or high-order spectral fingerprint generated by two-
dimensional correlation spectroscopy (2D–COS) and hyperspectral
imaging (HSI) have also been applied for HM. With 2D–COS,
the variations of chemical components corresponding to external
perturbation (temperature, pressure or magnetism) and the corre-
lation between these variations were reflected, so that overlapping
peaks can be differentiated in a higher resolution [71–73]. Further-
more, 2D–COS were also carried out between two spectral sources
4 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
Fig. 1. The general analytical workflow of chemometrics methods.
under the same perturbation, and used to exploit complementary
information of each spectroscopic techniques [71,72]. Up to now,
2D–COS fingerprints have been used for quality assessment of HM,
but most studies have only used visual comparisons instead of
chemometric methods for fingerprint analysis [74–76]. HSI typi-
cally performed in Vis-NIR or NIR range, as well as spectral and
spatial information of the sample were obtained by integrating con-
ventional spectroscopy and imaging technology [77]. it was used to
classify the dried fruit of Illicium verum and neurotoxic I. anisatum
[78], as well as distinguish three Echinacea species and identify the
species from commercial products [79], and map the distribution
of Stephania tetrandra and Aristolochia fangchi in a mixed powder
system [80], etc.
The great advantage of vibrational spectroscopy techniques is
that it involved few or no chemical reagents in sample pretreat-
ment and allowed for rapid, non-destructive and on-line analysis
[81–83]. Due to the high complexity of multicomponent systems
of HM, vibrational information is integrated and overlapped, so
quantitative analysis of specific compounds should be supported by
additional chemometric methods [84]. Furthermore, without the
need for prior experimental or analytical knowledge, vibrational
spectroscopy is a kind of irreplaceable method for the identification
of unknown samples. Hitherto, vibrational spectroscopy combined
with chemometrics analysis is widely used for quality assessment
of HM, such as the identification of geographical origin [85–87],
botanic species and adulteration [88–90]; quantitative prediction
of quality markers [84,91], bioactivity components [92] and adul-
terated ingredients [93]; and on-line monitoring [94,95], etc.
3.2.2. Atomic spectroscopy
The inorganic chemical profile of plants and their products is a
reflection of the geochemistry of local soils, climates, and pollution,
as well as the endogenous and exogenous influences of species,
cultivation patterns, and processing methods [96]. Most of the
well-established analytical techniques, such as inductively coupled
plasma-based (ICP-based) techniques, which include ICP-optical
or atomic emission spectrometry (ICP–OES or ICP–AES), ICP-mass
spectrometry (ICP–MS), and the combination of various atomic
absorption spectrometry (AAS) were used to generate an elemen-
tal and isotopic fingerprint of HM [97–100]. Elemental and isotopic
fingerprints are usually applied for the origin recognition [101,102]
and fraud identification [103,104] of HM combined with chemo-
metrics methods. However, sample pretreatment of these common
elemental analyses was time-consuming and relatively expensive,
which needed additional support equipment (microwave digestion
system) and consumes large quantity of chemical reagents. With-
out sample pretreatment, X-ray fluorescence spectroscopy (XRF)
and laser-induced breakdown spectroscopy (LIBS) are allowed in
an easier, quicker and more environmentally friendly way for ele-
mental analysis [105,106]. In terms of applications, two simple
techniques have been used for the quality assessment, i.e., adul-
terate identification [107,108], origin identification [109–111], and
quantification of heavy metal elements [112] of HM.
3.2.3. NMR spectroscopy
NMR spectroscopy is a universal analytical technology for both
qualitative and quantitative analysis, which was developed into
an important tool for profiling the metabolic fingerprint of HM
[113]. Among the major applications of NMR, 1 H NMR is one of
the most frequently used techniques, but metabolite identification
still has problems of low sensitivity and signal overlapping, espe-
cially for complex biological matrices. With the use of multiple
2D NMR techniques including J-resolved, chemical shift correlation
spectroscopy (COSY), heteronuclear multiple bonding connectivity
spectroscopy (HMBC), and heteronuclear single quantum correla-
tion spectroscopy (HSQC), the fingerprint of chemical structure and
composition with greatly improved spectral resolution than that
of 1 H NMR have been provided [114,115]. For data preparation
of 2D NMR fingerprint (second-order), several workflows includ-
ing signal extraction of special regions [116,117], axis projection
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215 5

[118–120], data unfolding [115,121], and multi-way decomposi- [158] given a comprehensive overview of what could be achieved
tion [122] have been applied. For the first two approaches, a part of by using DART–MS for quality assessment of HM.
metabolic information has been discarded [123,124]. The greatest
advantage of the last two strategies is that the additional infor-
4. Chemometrics methods and its applications
mation of 2D experiment have not been sacrificed, which makes
these two approaches applicable for 2D NMR data preparation of
4.1. Data pre-processing
fingerprinting analysis [125].
High-field NMR (HF-NMR) offered the benefits of high per-
The original, raw fingerprint data of HM is not suitable for direct
formance, such as greater spectral resolution and sensitivity.
chemometrics analysis due to the following reasons: the irrepro-
Nevertheless, HF-NMR usually required an expensive equipment,
ducibility of experiment parameters from the above-mentioned
and a high running cost with cryogenic fluids, which makes
instruments, such as the retention time of chromatographic tech-
this technology not an optional technique for routine applica-
nology is difficult to precisely reproduce among different samples;
tions [126,127]. In contrast, low-field NMR (LF-NMR, 30–80 MHz)
the multiplicative interferences caused by light scattering and
desktop spectrometers based on permanent magnets are smaller,
particle size of infrared spectroscopy is discrepant between test
cheaper, cryogens-free and highly mobile, but the spectra with
samples. Multiple steps of data pre-processing strategies should
reduced performance in terms of sensitivity and spectral resolution,
be applied to remove the unwanted signal variations before its
meaning that the resonances appear broader and more overlapping
analysis [159]. Generally, global data pre-processing comprised
[126,128]. Nonetheless, the low sensitivity of up-to-date LF-NMR
multiple steps, each step was correct for a particular variation,
can be solved by different hyper-polarization techniques, and the
and the order of pre-processing steps were specific to the data
interference of radiation damping from H2 O is less of an issue in
characteristics and the goal of analysis [160]. In many cases,
low-field than in high-field [128–130]. This offered a low-cost and
the selection of pre-processing steps such as baseline correction,
accessible screening tool for fingerprinting analysis, product con-
smoothing and peak alignment was determined by the nature
trol, and reaction monitoring of HM.
of the analytical signal considered [161] and the order of data
The advantages of NMR over conventional chromatography-
that the instrument produced. For example, the coupling ways of
based techniques are simpler sample preparation and method
standard normal variate (SNV) or multiplicative scatter correction
development, relatively shorter analysis time, higher stability,
(MSC) with Savitzky-Golay derivative/smoothing filters are usually
reproducibility and throughput, but the drawback of lower sensi-
adopted for eliminating the light scattering effect for data acquisi-
tivity still existed [31,113,131]. Similar to chromatography-based
tion of vibrational spectroscopy. As to chromatography and NMR
techniques, NMR spectral fingerprints are suitable for the discrim-
fingerprint, several algorithms were designed for peak alignment,
ination analysis and fingerprint-efficacy modeling of HM. Until
such as genetic algorithm (GA) [162], multiscale peak alignment
now, NMR fingerprinting analysis has been applied to discrimi-
(MSPA) [163], peak alignment using reduced set (PARS) [164], etc.
nate herbal medicines from different origins [100,132,133], species
Modern instruments generated a large variety of fingerprint
[134–136], processed methods [137], growth years and harvest
data matrices, which were classified into first, second, third or
times [138,139], verify the official or adulterated HM [140,141],
higher-order data [165]. Accordingly, spectroscopy (MIR, NIR,
screen bioactive compounds with fingerprint-efficacy modeling
Raman, and NMR) was considered as a vector (first-order), and the
[142,143], etc. Monakhova et al. (2018) has summarized a sys-
data matrix for a set of samples was a two-way array. The LC–MS
tematic review of NMR fingerprint combined with chemometric
or LC–DAD fingerprint was a matrix (second-order), and the data
methods which were applied for the quality control of herbal prod-
structure of a set of samples was a three-way array that consists of
ucts [144].
the dimension of sample, wavelength or m/z and retention time. A
three-order tensor was generated by a 2D chromatography, and
a set of samples yielding a four-way array (1 tR × 2 tR × m/z ×
3.3. MS hyphenated techniques
no.). In Fig. 2, the data structure of the most commonly used tech-
niques for fingerprinting analysis of HM was summarized, and a
MS is mainly hyphenated with chromatographic separation
part of common data pre-processing methods were listed in Table
system for the organic analysis of HM, i.e., LC–MS and GC–MS
S1. In conclusion, data pre-processing is the first important step
were used to measure the abundance of ion fragments after sam-
in chemometrics analysis, an optimal data pre-processing method
ple ionization [mostly ionized by electrospray ionization (ESI)
and sequential workflow are necessary on the basis of informa-
and atmospheric pressure chemical ionization (APCI) sources] for
tion source and data structure. Gerretzen et al. [166] proposed
qualitative and quantitative analysis. Several types of tandem MS
a simple and effective strategy for selecting data pre-processing
systems have been applied according to the optimal application
methods and combinations based on the design of experiments,
ranges for different researches, including triple quadrupole (QqQ),
which offered positive enlightenment and referential meaning for
ion trap (IT), and hybrid MS systems, such as the Q-TOF, Q-Orbitrap,
the data pre-processing.
LIT-Orbitrap, Q-ICR, LIT-ICR, etc. [145,146]. In general, metabolite
profiles obtained by LC–MS and GC–MS have been widely used
for holistic quality assessment and screening of difference com- 4.2. Data unfolding and multi-way decomposition
ponents of HM. Additionally, direct injection and flow infusion
without chromatographic separation were also used for the fin- In most cases, traditional chemometrics methods have been
gerprint analysis of HM [147,148]. Direct analysis in real time-MS directly applied to deal with a two-way array of a set of sam-
(DART–MS) has become an emerging technology for fingerprinting ples. Nowadays, hyphenated analytical techniques and 2D or spatial
analysis of various samples (either solid or liquid) with minimal resolved spectroscopy used in analytical laboratories generated a
or without sample pretreatment [149,150], making it suitable for stream of second or higher-order fingerprint data for HM, which
on-line process monitoring [151]. Up to now, DART–MS fingerprint- bring multiway datasets that could not be calculated by standard
ing analysis were successfully applied to the origins and species two-way chemometrics methods. In order to solve this problem,
discrimination [152–154], quality control marker identification in data unfolding and multi-way decomposition were proposed to
different batches and off-line process monitoring [155,156], and obtain a row vector representation for each sample, and these
the quality assessment of processing degrees [157], etc. Shen et al. extracted features were used for standard multivariate analysis
6 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
Fig. 2. The chemical fingerprint of each data orders and the data array of a set of samples.
[167]. For the first strategy, a three-way array (I × J × K) of a
set of samples was unfolded as multiple two-way arrays (I × J
or I × K), then connected all two-way arrays into a combined
two-way array (I × JK or I × KJ) for next data analysis [115,168].
For the second strategy, various kinds of multi-way decomposi-
tion methods were utilized to calculate the scores of second or
higher-order data, such as Tucker3 and PARAFAC. Then these scores
were connected into a two-way array for traditional chemomet-
rics analysis [169]. For instance, the analysis method, PARAFAC
scores of three-dimensional excitation-emission matrix fluores-
cence (EEM) spectroscopy (second-order data) combined with the
partial least squares-discriminant analysis (PLS-DA), was employed
to classify burdock root according to their geographical origin [170].
In another study, the three-way array of CE–DAD, HPLC–DAD and
spectral fluorescence signature (SFS) spectroscopy of sample set
were decomposed by PARAFAC models, and the scores combined
with hierarchical cluster analysis (HCA) and principal component
analysis (PCA) were applied to authenticate HM in the market [171].
Yilmaz et al. [122] described the use of PARAFAC to decompose a set
of two-dimensional J-resolved 1 H NMR spectra (three-way array).
After the optimization of each PARAFAC model, 239 representa-
tive PARAFAC components were selected for the quality control of
saffron with PCA analysis.
4.3. Data fusion strategy
As mentioned above, chemical fingerprints derived from vari-
ous kinds of independent instrument have been widely used for
the quality assessment of HM. Given the complexity of biolog-
ical matrices and the quality of HM derives from its complex
characteristics, the analytical platform that can achieve complete
chemical profiling will be furthest correlated with quality fulfill-
ment. Generally speaking, due to the ability limitations of each
independent instrument, no single analytical platform could pro-
vide a complete quantitative or qualitative profiling [81,172]. Data
fusion strategies were used to combine fingerprint datasets from
different analytical platforms, which could exploit the synergetic
and complementary information for each technology, and enhance
data authenticity or availability for generating a better inference
[173,174]. Basically, from the viewpoint of chemometrics, data
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215 7

Table 1
Application of data fusion strategies in quality assessment of herbal medicines.

Year Herbal medicine Objective Instruments Fusion levels Multivariate Ref.

analysis

2018 Paris polyphylla Six origins discrimination FT–MIR, UV–vis A, B, C SVM-GS, RF [176]
Smith var.
yunnanensis
2014 Cortex moutan Three origins HPLC–DAD, B PCA, LDA, BP-ANN, [177]
discrimination ICP–MS LS-SVM, MLR
2018 Saffron Geographical HPLC, GC–MS, NIR B PCA, OPLS-DA [178]
discrimination and
commercial categorization
2018 Astragali Radix Discrimination from Raman, UV–vis B KPCA, SVM, k-NN [179]
different origins
2018 Notoginseng root Five origins discrimination FT–MIR, NIR A, B, C SVM, RF [189]
2017 Extra-virgin olive Varietal origin HPLC–DAD, A, B PCA, PLS-DA, [36]
oil discrimination HPLC–FLD SIMCA, k-NN
2018 Chrysanthemum Five cultivars HSGC–MS, A PCA, PLS-DA [190]
flower discrimination UHPLC–QTOF/MS
2018 Paris species Botanical and geographical UPLC, FTIR. A, B PCA, t-SNE, PLS-DA, [180]
origins discrimination SVM, RF
2018 Dendrobium Authentication of 11 NIR, UV–vis A, B PCA, HCA, PLS-DA, [182]
species Dendrobium species k-NN, SVM
2018 Wolfiporia cocos Differentiation and FT–MIR, UV B CARS, PLS-DA, HCA [181]
comparison of different
growth patterns, collection
regions and medicinal
parts
2012 Curcuma Rhizome Three species GC–MS, HPLC–DAD B PCA, LDA, BP-ANN, [40]
discrimination LS-SVM
2017 Rhubarb Official/unofficial NIR, MIR B PLS-DA, SIMICA, [184]
discrimination SVM, ANN
2015 Fritillaria Bulbus Species discrimination and E-nose, E-tongue A PCA, DFA [185]
adulteration recognition
2019 Acori Tatarinowii Characterization and UPLC-Orbitrap- A, B PCA, PLS-DA [186]
Rhizoma authentication of Acori MS/MS,
Tatarinowii Rhizoma and ICP–MS
its adulterants
2018 Coptidis Rhizoma Illustrate the metabolic FT–MIR, FT–NIR, A, B PCA, HCA, PLSR [187]
variation and taxonomic HPLC
relationship among four
Coptidis Rhizoma, and
quantitative predict the
content of berberine
2015 Panax notoginseng Real-time quantitative NIR, UV, UPLC A, B UVE-PLSR [188]
monitor of saponins during
Panax notoginseng
adsorption process
2017 Danshen tablet Antioxidant 203, 228, 254, 270 A PCA, PLSR [34]
activity-fingerprint and 345 nm of
relationship HPLC–DAD

A: Low-level data fusion; B: Mid-level data fusion; C: High-level data fusion.

HPLC–DAD: high performance liquid chromatography-diode array detector; HPLC–FLD: high performance liquid chromatography-fluorescence detector; GC–MS: gas
chromatography-mass spectrometry; FT–MIR: Fourier transform mid-infrared spectroscopy; UV–vis: ultraviolet-visible spectroscopy; ICP–MS: inductively coupled plasma-
mass spectrometry; NIR: near-infrared spectroscopy; MIR: mid-infrared spectroscopy; E-nose: electronic nose; E-tongue: electronic tongue; UPLC-Orbitrap-MS/MS:
ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry; FT–NIR: Fourier transform near-infrared spectroscopy; HSGC–MS: headspace GC–MS;
UHPLC–QTOF/MS: Ultra high performance liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry; PCA: principal component analysis; K-PCA: kernel-
principal component analysis; t-SNE: t-distributed stochastic neighbor embedding analysis; HCA: hierarchical cluster analysis; PLS-DA: partial least squares discriminant
analysis; OPLS-DA: orthogonal partial least squares-discriminant analysis; LDA: linear discriminant analysis; k-NN: k-nearest neighbors; SVM: support vector machine;
LS-SVM: least squares-support vector machine; SVM-GS: support vector machine-grid search; MLR: multivariate linear regression; RF: random forest; BP-ANN: back
propagation-artificial neural network; SIMCA: soft independent modeling of class analogy; PLSR: partial least squares regression; UVE-PLSR: uninformative variable
elimination-PLSR; CARS: competitive adaptive reweighted sampling.

fusion strategies were performed at low, mid, and high-level [174].
In low-level data fusion, the outputs of each individual analytical
blocks were straightly concatenated. Mid-level data fusion was also
called feature-level fusion, the correlated features in this approach
were extracted or selected from each original data and joined into
a new fusion module for data modeling. The high-level strategy
involved to integrate the decision-making of each separate model
(generated by each analytical dataset) into a final response [175].
To data, based on data fusion strategies, multi-source fingerprint
data has been increasingly used for the quality assessment of HM,
such as geographical traceability [176–181], species authentica-
tion [182], consistency assessment [183], authenticity recognition
[184], adulterant identification [185,186], quantitative prediction
[187,188], etc. Table 1 summarized the main applications of data
fusion for the quality assessment of HM.
As a case study, Li et al. [189] applied low, mid and high-level
data fusion strategies to the data obtained from Fourier transform
mid-infrared spectroscopy (FT-MIR) and NIR for the geographical
traceability of notoginseng root, the results showed that the accu-
racy rates ranged from 98% to 100% of high-level was the most
effective strategy. Another example, an integrated metabolomics
strategy based on HSGC-MS and UHPLC-QTOF/MS for analyzing
both volatile and nonvolatile metabolites were applied to distin-
guish five cultivars of Chrysanthemum flowers [190]. The fusion
8 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
dataset of two complementary techniques was then prepared after
variables selection, and two chemometrics methods of PCA and
PLS-DA were used for identifying cultivars and discovering marker
metabolites. Consequently, 21 markers covering 14 volatile and 7
nonvolatile compounds were identified among five cultivars.
4.4. Anomalous samples detection
Anomalous samples were regarded as outliers in chemomet-
rics studies, which may be caused by experimental variation or
malfunction, and the other uncertainty factors of the fingerprint
acquisition. The distribution of outliers was different from the main
group, and the overall trend of the dataset will be completely
changed by outliers and make the model no longer available for
the majority data [191]. The most commonly used chemometrics
techniques were sensitive to outliers. A few outliers are some-
times adequate to distort the group results by altering the mean
performance or increasing variability. In addition, outliers also
could pinpoint changes in production or experimental processes
[192,193]. Therefore, outlier detection was one of the important
steps in constructing a high-quality model, and it was also avail-
able for monitoring the technical process of HM. For example,
Hotelling’s T2 , a kind of outlier detection method combined with
distance to model in X-space (DModX) was used for the batch-
to-batch monitoring of Danshen alkaline precipitation, E-Jiao oral
liquid and the liquid preparation process of Tanreqing injection,
which provided a new perspective for manufacture process moni-
toring of HM [95,156].
4.5. Unsupervised exploratory learning
There were two cases in unsupervised techniques: similarity
analysis and exploratory analysis have been used for fingerprint-
ing analysis of HM [194]. For similarity analysis, the similarity
parameter was statistically calculated to evaluate the simi-
larity/dissimilarity between two fingerprints, i.e., the test and
reference or standard sample. The similarity/dissimilarity was
quantified using distance or similarity parameters to evaluate the
quality consistency, substantial equivalence, and adulteration exis-
tence of HM [5,195–197]. Among the various techniques, majority
of the similarity analysis was used for chromatographic finger-
print, and an overview of its application in HM was summarized
by Goodarzi et al. (2013) [5].
Exploratory learning was available to extract the main fin-
gerprint characteristics and contributed an unbiased view of the
data sets. The cluster tendency information between groups, the
relationship between variables or between samples and variables
could be obtained with the use of exploratory analysis [198,199].
The relationship between variables showed which of them had
a complementary effect and given similar or redundant informa-
tion [198]. The relationship between samples and variables was
applied to evaluate which variables were important for group dif-
ferentiation, so variables with greater variation coefficient between
different groups were available for extracted. Furthermore, the dis-
tribution of outliers was separated from the distribution of the
main group. Therefore, whether the clustering trend or relationship
between samples was consistented with prior knowledge could be
used to detect the possible outliers. In review, as two well-known
algorithms, PCA (multi-way PCA for high-order data) and HCA are
frequently used for the exploratory analysis of chemical fingerprint.
PCA was a multivariate statistical analysis that extracted prim-
itive variables to generate a number of new orthogonal variables
called principal components (PCs). The number of anterior PCs that
retained maximum explained variance and predictive ability were
selected by Q2 value and Kaiser-Harris criterion [200]. The score
plot of PCs provided the feature visualization of the sample distri-
bution into a low dimensional space (two or three dimensions), and
the loadings plot graphically represented the variance contribution
of each variable to the respective PCs. HCA was a method of cluster
analysis, which tried to build a hierarchy of clusters based on the
similarity of fingerprint information, and the results were usually
presented in a dendrogram. Normally, the results of PCA and HCA
were complementary. The representative chemometrics studies by
using the PCA and HCA techniques or combined with supervised
classification and regression learning for quality assessment of HM
were summarized in Table 2.
As a case study, the quality consistency of Melissa officinalis
L. obtained from different manufacturers in Poland was success-
fully evaluated by similarity and PCA analysis of HPLC fingerprint,
and quantitative comparison of six selected phenolic acids [201].
In another study, the holistic quality control of complex medic-
inal preparations Niuhuang Shangqing pill was constructed by
HPLC-QTOF/MS fingerprint profiling and chemometrics analysis
[22]. Using established methods to evaluate the quality of 26 com-
pound formulae from manufacturers, the integrated PCA allowed
visualization of quality differences between batches and further
assisted in determining the components that cause quality differ-
ences. Gad et al. [202] applied ultraviolet (UV) spectroscopy, FT-IR,
1 H NMR and HPLC fingerprints for quality control of Curcumae Lon-
gae Rhizoma in combination with PCA and HCA. The results showed
that, HPLC and UV fingerprint segregate samples into four main
groups depending on their total curcuminoids content, FT-IR finger-
print failed to discriminate the same species with different origins
but succeeded to significantly differentiate between species, there
were more metabolic variabilities in the essential oils/fatty acid
region between samples based on 1 H NMR fingerprint.
4.6. Supervised learning
Supervised statistical analysis was the type of prior knowledge-
based (yes or no, category group variable, continuous property, etc.)
machine learning, which attempted to produce an inferred function
(model) that map an input-output relationship from a set of train-
ing samples. After parameter optimization, the performance of the
resulting function or established model were verified by an exter-
nal unknown dataset as the test set. In fingerprinting analysis, the
purpose of supervised learning could be mainly divided into two
parts: classification and regression.
4.6.1. Classification analysis
For classification, fingerprinting analysis was often performed
to address qualitative issues, the most common of which were the
recognition, differentiation, and traceability of quality assessment
tasks. Classification approaches could be defined into two types:
discriminant, and class-modeling analysis [203]. Discriminant anal-
ysis (also known as ‘hard modeling’) focused on multi-class
problems. For example, the problems mainly included the dif-
ferentiation between each botanical origin, geographical origin,
growth year, and production batch, as well as differentiate among
different methods or levels in the processing produces, etc. The
most often used discriminant techniques were linear discrimi-
nant analysis (LDA), k-nearest neighbors (k-NN), PLS-DA, support
vector machine (SVM), random forest (RF), artificial neural net-
work (ANN) and multi-dimensional strategies including multi-way
PLS-DA (N-PLS-DA), unfolded-PLS-DA (U-PLS-DA) and on the like.
Class-modeling analysis (also referred to as ‘soft modeling’) focused
on the one-class problem and only the target class is concerned. In
the example of authentic and ‘Daodi’ HM recognition, the dataset
which consisted of adulterated or non-‘Daodi’ HM (non-target sam-
ples) cannot be sampled in a comprehensive way, so those samples
failed to constitute a meaningful class. In this situation, authentic or
‘Daodi’ HM was defined as target class in the class-modeling, and
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215 9

Table 2
Application of unsupervised and supervised classification techniques in quality assessment of herbal medicines.

Year Herbal medicine Object Instruments Multivariate analysis Ref.

2015 Gastrodiae Rhizoma Research chemical difference between four origins TLC PCA, HCA [29]
2017 Notoginseng root Five origins identification FT–MIR DWT, PLS-DA, SVM [85]
2018 Epimedii Folium Determination of geographical origin NIR DA, BP-ANN, k-NN, [86]
SVM
2016 Lonicerae Japonicae Identification of four geographical origins in China ICP–MS LDA [101]
Flos
2018 Pseudostellariae Radix Rapidly authentication of different regions Raman PCA, PLS-DA, OPLS-DA [87]
2015 Blumea balsamifera DC. Discriminate samples from two geographical LIBS PCA, PLS-DA [109]
regions
2018 Angelica pubescens, Discriminate samples from different origins LIBS PCA, BP-ANN [110]
Codonopsis pilosula, and
Ligusticum wallichii
2012 Cumin Determination of the country of origin XRF DA [111]
2015 Angelica gigas Identification of the geographical origin DART–TOF–MS PCA, OPLS-DA [152]
2018 Burdock root Discrimination of the geographical origin 3D EEM spectroscopy PARAFAC, PLS-DA [170]
2014 Ginger Five producing countries identification HPLC–DAD HCA, PCA, LDA [208]
2017 Chinese quince Classify samples from six category origins NIR LDA, QDA, SVM [209]
1
2016 genus Passiflora leaves Classification based on genetic and geographical H–NMR, UPLC–MS PCA, HCA, OPLS-DA [134]
origins
2013 Melissa officinalis L. Assessment the quality consistency of 19 batches HPLC–UV SA, PCA [201]
2019 Niuhuang Jiedu pill Assessment the quality consistency of 22 batches HPLC–DAD SA, PCA, HCA [197]
2014 Niuhuang Shangqing Determining which component was contributing HPLC–QTOF/MS PCA [22]
pill to batch-to-batch quality differentiation
2018 Saffron Investigate the effects of soil salinity on saffron TLC PCA, k-means [27]
chemical profile
2017 Ginseng Folium Differentiate the cultivation ages of mountain UHPLC–QTOF/MS PCA, PLS-DA [57]
cultivated ginseng leaves
1
2016 Propolis Classification of Brazilian propolis from different H NMR PLS-DA, RF [132]
harvest seasons, and production regions
2017 Paris polyphylla var. Discriminate different harvesting times UPLC–UV–MS, FT–MIR PLS-DA [56]
yunnanensis
2018 Ginseng Radix et Discriminate the ginseng samples of different UPLC–QTOF/MS OPLS-DA [211]
Rhizoma cultivation years and discover the marker
compounds
1
2010 Ginseng Radix Evaluation of the cultivation age of dried Ginseng H–NMR PCA, CA [138]
Radix and its commercial products
1
2015 Isatis tinctoria Comparison of different accessions, harvesting H–NMR PCA, CA, k-NN [139]
dates, and the effect of repeated harvesting
2017 Rehmanniae Radix Mining the differential marker compounds UPLC–PDA–QTOF–MS/MS PCA, OPLS-DA [212]
between raw and processed Rehmanniae Radix
2018 Leonuri Fructus Reveal the difference between crude and HPLC–ELSD, GC–FID PCA, HCA [26]
processed Leonuri Fructus
2018 Moutan Cortex Rapid characterization of chemical markers for ESI–QTOF/MS PCA, PLS-DA [147]
discrimination of Moutan Cortex and its processed
products
2017 Paris species Chemotaxonomy studies of nine Paris species LC–MS/MS, FT–MIR PCA [55]
1
2017 genus Paeonia L. To determine the distribution of metabolites in the H–NMR PCA [136]
root barks of seven tree peony cultivars
2014 Echinacea species Distinguish three Echinacea species and identify HSI, UPLC–MS PCA, PLS-DA [79]
whether it present in commercial products or not
2018 Ephedra species Discrimination of three Ephedra species and their ICP–MS HCA, PCA, DA [102]
geographical origins
2017 Flower buds of Lonicera Discriminate five kinds of Lonicera plants Hand-held FTIR PCA, LDA [90]
plants
2015 Clematidis Radix et Distinguish three official plant sources UPLC–QTOF/MS PLS-DA, GA-SVM [210]
Rhizoma
2015 Rauwolfia species Distinguish six Rauwolfia species DART–MS PCA [154]
2012 Umbelliferae Classification of morphologically similar DART–TOF/MS OPLS-DA [153]
Umbelliferae medicinal herbs
2019 Myristicae Semen Distinction of quality nutmeg from low-grade PTR–MS, FI–ESI–MS PCA/Q, k-NN [148]
nutmeg products
2016 Panax ginseng Discriminate four herbal parts and root adulterant UPLC–QTOF/MS PCA, OPLS-DA, PLS-DA, [58]
with leaf of Panax ginseng ANN
2014 Chinese Propolis Distinguish from its adulterant TLC SA, HCA, k-means, [28]
ANN, SVM
2013 Anisi Stellati Fructus Recognition of its neurotoxic adulterant (Illicium HSI PCA, PLS-DA [78]
anisatum)
2016 Stephania tetrandra Recognition of its neurotoxic adulterant HSI, UPLC–MS PCA, PLS-DA [80]
(Aristolochia fangchi), and mapping the adulterant
distribution in a mixed powder
1
2018 Serenoa repens Authentication of saw palmetto H NMR, IRMS, GLC PCA [104]
2017 Saffron Distinguish saffron from its six characteristic FT–MIR PLS-DA, PLSR [205]
adulterants, and quantify the adulterant
concentration
10 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215

Table 2 (Continued)

Year Herbal medicine Object Instruments Multivariate analysis Ref.

1
2018 Polygoni Multiflori Identify Polygoni Multiflori Radix, adulterant H NMR PLS-DA, N3 [140]
Radix (Cynanchi Auriculati Radix) and their mixtures
2015 Kudzu starch Distinguish kudzu starch from its adulteration NIR PLSCM [207]
1
2018 Two cinnamon species Chemometrics authentication of cinnamon drugs H–NMR PCA, OPLS-DA [135]

LC–MS/MS: liquid chromatography-tandem mass spectrometry; TLC: thin layer chromatography; UPLC–QTOF/MS: ultra-performance liquid chromatography-quadrupole
time-of-flight mass spectrometry; UPLC–MS: ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry; NIR: near-infrared spectroscopy;
ICP–MS: inductively coupled plasma-mass spectrometry; 1 H–NMR: hydrogen-nuclear magnetic resonance spectroscopy; IRMS: isotope ratio mass spectrometry;
GLC: gas-liquid chromatography; GC–FID: gas chromatography-flame ionization detector; UPLC–UV–MS: ultra-performance liquid chromatography-triple quadrupole
mass spectroscopy with ultraviolet detection; DART–TOF–MS: direct analysis in real time-time of flight-mass spectrometry; ESI–QTOF/MS: electrospray ionization-
quadrupole time of flight-mass spectrometry; PTR–MS: proton transfer reaction mass spectrometry; FI–ESI–MS: flow infusion electrospray ionization mass spectrometry;
UPLC–PDA–QTOF–MS/MS: ultra-high performance liquid chromatography coupled with photo-diode array detector and quadrupole time-of-flight mass spectrometry;
HPLC–DAD: high performance liquid chromatography-diode array detector; HPLC–ELSD: high performance liquid chromatography-evaporative light scattering detector;
FT–MIR: Fourier transform mid-infrared; HSI: hyperspectral imaging; XRF: X-ray fluorescence spectroscopy; LIBS: laser-induced breakdown spectroscopy; EEM: excitation-
emission matrix fluorescence; PCA: principal component analysis; HCA: hierarchical cluster analysis; SA: similarity analysis; CA: canonical analysis; DWT: discrete wavelet
transform; PLS-DA: partial least squares discriminant analysis; PLSR: partial least squares regression; OPLS-DA: orthogonal partial least squares-discriminant analysis; N3:
N-nearest neighbors ; DA: discriminant analysis; LDA: linear discriminant analysis; QDA: quadratic discriminant analysis; k-NN: k-nearest neighbors; SVM: support vector
machine; GA-SVM: genetic algorithm-support vector machine; RF: random forest; PARAFAC: parallel factor analysis; PLSCM: partial least squares class model; BP-ANN: back
propagation-artificial neural network.

Fig. 3. Application differences between discriminant analysis and class-modeling analysis.

adulterated or non-‘Daodi’ HM was constituted a heterogeneous
group that separated from the target class. The main class-modeling
techniques were unequal dispersed classes (UNEQ), multivariate
statistical process control (MSPC), soft independent modeling of
class analogy (SIMCA) and its modification version, etc. [204]. The
application differences between discriminant analysis and class-
modeling analysis were shown in Fig. 3. Table 2 summarized a
series of studies related to the classification algorithm combined
with fingerprint techniques for quality assessment of HM.
There are two situations of HM authenticity recognition: dis-
tinguish authentic HM from its adulterants (confused materials)
and adulterated materials. Based on the above definition, discrimi-
nant analysis was more suitable for identifying adulterants of HM,
due to the varieties of confused materials had already been known
through the investigation or experience. Six characteristic adulter-
ants of Saffron: Calendula, Safflower, Turmeric, Buddleja, Gardenia
and Saffron Stamens were discriminated by diffuse reflectance FTIR
combined with PLS-DA, and the adulterant concentrations of saf-
fron were quantitated by partial least squares regression (PLSR)
[205]. Sun et al. [140] using novel characteristic profiling of 1 H NMR
fingerprints combined with PLS-DA and N-nearest neighbors (N3)
model, successfully identified Polygoni Multiflori Radix, adulter-
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
ant (Cynanchi Auriculati Radix) and their adulterate mixtures. By
comparison, class-modeling analysis was more suitable for non-
targeted authentication [206]. In this case, only authentic samples
participated in the modeling, while adulteration, confused or other
authentic samples were used to verify the model performance. For
instance, a one-class classifier: partial least squares class modeling
(PLS-CM) is used to estimate the sample distribution of authen-
tic kudzu starch based on NIR fingerprint [207]. To validate the
developed model, approximately 1/3 authentic samples and all
adulterated samples [the doping levels are 2%, 4%, 6%, 10% and 20%
(w/w) for four cheaper plant starches; 0.5%, 1%, 2%, 5% and 10%
(w/w) for talcum powder] were included in the test set. The result
showed that the dopping levels exceeded 0.5% of talcum powder
and 4% of plant starch could be detected by this strategy.
For geographical origin discrimination or ‘Daodi’ HM recogni-
tion, a majority of studies focused on classifying the HM from
different origins and screening the differential metabolic markers.
As examples, the relationship of gingers from five different produc-
ing countries (China, India, Malaysia, Thailand, and Vietnam), has
been described by using HCA and PCA combined with HPLC–DAD
fingerprint, and LDA classification model provided a high recog-
nition of 97% and 91% predictive ability to distinguish five origins
[208]. Furthermore, markers discovery performed by T-statistics
suggested that gingerol acts as a marker for Indian ginger, methyl
gingerol for Thai ginger, and diacetoxy gingerdiol, gingerol, methyl
diacetoxy gingerdiol for Chinese ginger. Other example introduced
the use of NIR spectroscopy in combination with LDA, quadratic
discriminant analysis (QDA), and SVM to classify Chinese quince
produced from six different origins [209]. Comparing the classifi-
cation performance of three models, QDA and SVM showed better
results than LDA, and QDA achieved the best performance with
100% accuracy both in calibration and validation dataset.
For botanical origin discrimination, the metabolite fingerprint
containing 4623 variables of three official Clematis herbs (Clema-
tidis Radix et Rhizoma) was generated by UPLC–QTOF/MS. After
PLS-DA modeling, 28 variables with VIP value above 4.8 were fil-
tered out for the next step SVM analysis [210]. The result showed
that this strategy could successfully distinguish herbs with a vari-
ety of botanical origins, and provided a promising method of the
formulation processes tracking of HM. In order to discriminate
ginseng of different cultivation years, the metabolic profiling pro-
duced by UPLC–QTOF/MS in combination with orthogonal-PLS-DA
(OPLS-DA) were used to classify ginseng samples of 2–6 years,
and more than 50 compounds contributing to the age discrimi-
nation were identified [211]. In terms of exploring the scientific
basis in traditional processing of HM, fingerprint combined with
PCA and OPLS-DA was used to mining difference marker com-
pounds between raw and processed Rehmanniae Radix, and the
main mechanism for components transformation during process-
ing were elucidated [212]. Table 2 summarized the recent typical
applications of classification algorithms which were applied for
quality assessment of HM.
4.6.2. Regression analysis
In regression analysis of HM fingerprint, the multivariate
calibration algorithm aimed to model a relationship between fin-
gerprint data and a corresponding continuous property, i.e., the
content of chemical compounds or water, pharmacological or tox-
icological activity, adulteration ratio, etc. The commonly used
regression techniques were PLSR, support vector regression (SVR),
and ANN, etc. Generally, regression analysis was carried out for
different applications depending on the properties of fingerprint
information. For example, as described in Section 3.2.1, vibrational
spectroscopy had obvious advantages in real-time analysis, while
11
the limitation could not be directly used for quantitative analysis.
In this case, the application of multivariate calibration techniques
to vibrational spectroscopy available for indirectly quantify some
specific substances. Therefore, this strategy was used for rapid
screening for superior provenance in medicinal breeding [213] and
quantitative assessment [214]. As a case study, the use of atten-
uated total reflectance-IR (ATR–IR) spectroscopy combined with
PLSR provided a reliable calibration model for determining the
content of camphor, ˛-thujone, ˇ-thujone, ˛-pinene, ˇ-pinene,
and 1,8-cineole in Salvia officinalis L. The results were consistent
with the reference of GC-flame ionization detector (GC–FID) and
GC–MS analyses [215]. Furthermore, numerous studies regarding
the aforementioned methods were conducted. The total content
of phenolic compounds in two Pueraria species was quantified by
using FT–Raman combined with PLSR [216]. The content of total
saponins, flavonoids, and polysaccharides [85,217,218] of notogin-
seng root was quantified by using FTIR fingerprinting analysis.
For chromatographic and hyphenated techniques and NMR,
both qualitative and quantitative information of phytochemical
constituents of HM were included. In an attempt to explore the
effective or toxic material basis from a chemical complex matrix
of HM and explain the action mechanisms, multivariate calibration
techniques were used to model relationships between chromato-
graphic or NMR fingerprint and pharmacological or toxicological
activities (fingerprint-efficacy), and then compounds that made
a great contribution to the regression model will be considered
as potential efficacy- or toxicity-related constituents. For exam-
ple, the relationship between multi-wavelength (225, 254, 313 and
370 nm) HPLC fingerprints and antioxidant capacity of Turpiniae
Folium were investigated by PLSR model, and then seven com-
pounds which respond to the antioxidant activity were investigated
[219]. Fingerprint-toxicity modeling showed that two diterpenoid
lactones, 8-epidiosbulbin E acetate and diosbulbin B, were the most
hepatotoxicity-related markers for Dioscorea bulbifera tuber [220].
Additionally, two flavonoids displaying adenosine A1 binding activ-
ity were screened from a large number of chemical compounds in
Orthosiphon stamineus with the aid of 1 H NMR fingerprint-efficacy
modeling [143]. A review of fingerprint-efficacy modeling with
the use of chromatography techniques was summarized in Ref
[59]. Except for the mentioned above, vibrational spectroscopy
was also applied for investigating the fingerprint-efficacy relation-
ship of HM [92,221]. Different from chromatography and NMR,
fingerprint-efficacy modeling with vibrational spectroscopy was
mainly focused on rapidly and non-destructively assessing the
pharmacological activities. For instance, the anti-inflammatory
index of eight species of the Genus Lonicera (Caprifoliaceae) has
been successfully quantified by using ATR–FTIR spectroscopy com-
bined with PLSR model [221].
For adulteration recognition, classification algorithm for the fin-
gerprinting analysis could not quantify the dopping levels, which
only recognized whether the test materials were adulterated or not,
unless the different dopping level samples have been labeled. In
this situation, multivariate calibration techniques combined with
a chemical fingerprint were used to quantify the adulteration ratio
of herbal materials. As a case study, Wang et al. [222] proposed an
effectivity strategy with the use of three MS profiles (wooden-tip
ESI/MS, UPLC–QTOF/MS and UPLC–TQ/MS) combined with PLSR to
identify and quantify the adulteration ratio of Fritillariae Ussurien-
sis Bulbus in famous herbal called Fritillariae Cirrhosae Bulbus.
Another example is that the adulteration ratio of Gleditsiae Spina
powder was successfully quantified by using Fourier transform-
NIR (FT–NIR) combined with PLSR [223]. Table 3 summarized the
recent typical applications of regression techniques utilized in the
chemometrics studies of HM.
12 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215

Table 3
Applications of regression techniques in quality assessment of herbal medicines.

Year Herbal medicine Object Instrument Multivariate analysis Ref.

2017 Notoginseng root Quantification of saponins content FT–MIR, HPLC OSC-PLSR [85]
2017 Notoginseng root Quantification of total flavonoids content FT–MIR, UV–vis OSC-PLSR [217]
2018 Epimedii Folium Quantitative analysis of icariin content NIR, HPLC CARS, PLSR [86]
2018 genus Ganoderma Assessment of polysaccharides from mycelia of NIR, UV–vis mwPLS, iPLS [214]
genus Ganoderma
2015 Salvia officinalis L. Quantification of essential oil components ATR–IR, GC–FID, PLSR [215]
GC–MS
2015 Pueraria species Quantification of total phenolic content FT–Raman, PLSR [216]
2018 Notoginseng root Quantification of total polysaccharides content FT–MIR, UV–vis SVR [218]
2018 Potentilla tormentilla Quantification of 7 active ingredients Raman, ATR–IR, DRIFTS PCA, PLSR [84]
(NIR and MIR), HPLC
2017 Rhei Radix et Rhizoma Quantification of total content of five major NIR, HPLC PLSR [91]
anthraquinones
2018 Ganoderma lingzhi Rapid screening of mutated strains by plasma NIR, UV–vis mwPLS, iPLS [213]
mycelia mutagenesis
2018 Tobacco roots Quantitative analysis of Cadmium LIBS, ICP–OES iPLS, BiPLS, SPA, [112]
iPLS-SPA, BiPLS-SPA,
PLSR, SVR
2016 Fu-fang Shuanghua On-line monitoring the concentrations of NIR, HPLC PLSR, iPLS, siPLS [94]
oral solution chlorogenic acid, total phenolic acids, total
flavonoids and soluble solid contents
2017 Saffron Quantification of saffron adulteration ATR–IR, Raman, LIBS PLSR [107]
2017 Fritillariae Cirrhosae Identify and quantify the presence of Fritillariae wooden-tip ESI/MS, PLSR [222]
Bulbus Ussuriensis Bulbus in the adulteration of UPLC–QTOF/MS,
Fritillariae Cirrhosae Bulbus UPLC–TQ/MS
2018 Gleditsiae Spina Classification of adulterated and authentic samples FT–NIR LDA, SVM, BP-ANN, [223]
and quantify the adulterant levels PLSR
2015 Commercialized herbal Quantification of herbal medicines adulterated NIR PLSR, MLR [93]
medicines with sibutramine
2019 Zhenju Jiangya Tablets Evaluation of the quality consistency of Zhenju HPLC–DAD SA, PCA, PLSR [195]
Jiangya Tablets and investigate the relationship
between fingerprint and antioxidant activity
2019 Glycyrrhiza extract Evaluation of the quality consistency of glycyrrhiza HPLC–DAD SA, HCA, PLSR [196]
extract and discovery of potential markers
2017 Acori Tatarinowii Describe the relationship between radical GC–MS PLSR [25]
Rhizoma scavenging activity and volatile components
2016 Neptunia oleracea Screening of antioxidant and ␣-glucosidase 1
H NMR PLSR [142]
inhibitory metabolites
2016 Turpiniae Folium Research the relationship between HPLC HPLC PLSR [219]
fingerprints with antioxidant capacity and search
effective components
2018 Dioscorea bulbifera Model the fingerprint-hepatotoxicity relationship UPLC–QTOF/MS PLSR, BP-ANN, CA [220]
tuber and screen the toxicity markers
2017 genus Lonicera Anti-inflammatory properties prediction ATR–IR PLSR [221]
1
2011 Orthosiphon stamineus Bioactivity screening of adenosine A1 receptor H NMR PLSR, OPLSR [143]
binding compounds
2016 Chrysanthemi Flos Quantification of six crucial Q-markers and NIR, HPLC–QTOF/MS siPLS, PLSR, SVR, [92]
anti-inflammation activity evaluation BP-ANN, RF

HPLC: high performance liquid chromatography; HPLC–DAD: high performance liquid chromatography-diode array detector; UPLC–QTOF/MS: ultra-performance liquid
chromatography-quadrupole time-of-flight mass spectrometry; HPLC–QTOF/MS: high performance liquid chromatography-quadrupole time-of-flight mass spectrometry;
wooden-tip ESI/MS: wooden-tip electrospray ionization mass spectrometry; UPLC–TQ/MS: ultra-performance liquid chromatography -triple quadrupole tandem mass
spectrometry; UV–vis: ultraviolet-visible spectroscopy; GC–FID: gas chromatography-flame ionization detector; NIR: near-infrared spectroscopy; FT–MIR: Fourier transform
mid-infrared spectroscopy; FT–Raman: Fourier transform Raman spectroscopy; FT–NIR: Fourier transform near-infrared spectroscopy; ATR–IR: attenuated total reflectance
infrared spectroscopy; DRIFTS: diffuse reflectance infrared Fourier transform spectroscopy; LIBS: laser-induced breakdown spectroscopy; ICP–OES: inductively coupled
plasma-optical emission spectrometry; GC–MS: gas chromatography-mass spectrometry; 1 H–NMR: hydrogen-nuclear magnetic resonance spectroscopy; PLSR: partial least
squares regression; OSC-PLSR: orthogonal signal correction-partial least squares regression; CARS: competitive adaptive reweighted sampling; iPLS: interval partial least
squares; BiPLS: backward interval partial least squares; siPLS: synergy interval partial least squares; SA: similarity analysis; SPA: successive projections algorithm; mwPLS:
moving window partial least-squares; BP-ANN: back propagation-artificial neural network; CA: cluster analysis; MLR: multivariate linear regression; OPLSR: orthogonal
partial least squares regression; LDA: linear discriminant analysis; SVM: support vector machine; RF: random forest; (BP-)ANN: (back propagation-) artificial neural network;
SVR: support vector regression.

5. Conclusions chemical fingerprint combined with chemometrics methods was

With the increasing attention of the public on the safety and
quality of HM, the corresponding standards that efficiently assess
the HM made from the raw materials to the medicinal products
are becoming increasingly paramount to human health, also to
the sustainability of its supply and industry. Owing to the advan-
tages of overall quality evaluation, the chemical fingerprint used
to get a comprehensive characterization of complex matrices was
of promising and expected to become a powerful tool for quality
assessment of HM. In this review, the framework practiced with
described and clarified in depth. Well-established chemical finger-
print techniques used for the quality assessment of HM and the use
of chemometrics methods for data analysis were discussed.
In conclusion, as observed from various studies, depending
on different application scopes and purposes, a proper finger-
print analysis should include adequate analytical techniques, data
pre-processing workflow, and suitable chemometrics methods.
More works will still be required in the future to apply chemi-
cal fingerprint-based chemometrics analysis for the conventional
quality assessment of HM. Hopefully, based on the standardiza-
 Y. Li, Y. Shen, C.-l. Yao et al. / Journal of Pharmaceutical and Biomedical Analysis 185 (2020) 113215
tion and validation of the whole framework, the development of
chemical fingerprint combined with chemometrics methods will
be further broadened in terms of applicable filed for the quality
surveillance of HM in the future.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
The authors would like to acknowledge the financial support of
National Natural Science Foundation (No. 81530095) and National
Key R&D Program of China (2018YFC1707900) for the financial sup-
port.
Appendix A. Supplementary data
Supplementary material related to this article can be found,
in the online version, at doi:https://doi.org/10.1016/j.jpba.2020.
113215.
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