Medicinal Plant Analysis: A Historical and Regional Discussion of Emergent Complex Techniques

Abstract

Introduction

Medicinal plants have been a resource for healing in local communities around the world for thousands of years. Still it remains of contemporary importance as a primary healthcare mode for approximately 85% of the world’s population (Pešić, 2015), and as a resource for drug discovery, with 80% of all synthetic drugs deriving from them (Bauer and Brönstrup, 2014). Concurrently, the last few hundred years has seen a prolific rise in the introduction, development, and advancement of herbal substances analysis. Humans have been identifying and selecting medicinal plants and foods based on organoleptic assessment of suitability and quality for thousands of years, but it is only in the span of the last seven decades since the invention of basic analytical techniques, e.g., paper chromatography, that has seen rapid development from sight, touch, and smell to using sophisticated instrumentation. Though this mechanization of the senses has appeared relatively recently, historically conceptual expansion has been building throughout the scientific revolution, outwards toward the universe and inwards to a scale below recognition capable with a human eye, leading to development of some of the earliest analytical tools assisting the senses, the telescope and microscope. From the initial discovery of new microscopic worlds, through structural, chemical, and atomic levels, the sensitivity and range of human perception has been extended and enhanced.

Rapid progress is especially evident considering that the concept of a laboratory was only formally formed in Europe during the early 1600s. First as an extension of philosophers’, doctors’, and scientists’ workrooms, it becomes a space to study nature and gather empirical evidence (Wilson, 1997), where studies could be conducted at the analyst’s convenience rather than at specific times when daylight or weather permitted. This was a small but important step towards more formalized analytical investigations.

In modern analysis, single techniques such as paper chromatography and much earlier colorimetry appeared. It was followed by a greater range and wider application of these techniques until early hyphenations such as LC-UV emerged, culminating more recently in multiple combinations of multi-hyphenated instrumentation, availing of the analytical advantages inherent in each individual technique. The emergence of hyphenated analytical techniques in many aspects is analogous to the organoleptic synthesis that occurs when selecting a medicinal plant; viewing, smelling and tasting it to use combinations of different senses, increasing the points of reference/statistical degrees of freedom to improve the probability of correctly identifying and assessing its quality. The emergence and application of these hyphenated techniques only became possible and useful as computer systems and data management tools developed, enabling rapid and selective synthesis of information from the large amount of instrumental and analytical data signals generated.

Probably the single greatest influence in recent times in the advancement of the analysis of herbal materials (and arguably analysis generally) is, though, how large amounts of data can be collected, assimilated, and used more meaningfully in human readable forms. Similar to the historical advancements in combinatorial hyphenated instrumentation, now combinatorial data processing techniques like fingerprinting, metabolomic profiling, and pattern recognition algorithms have emerged, further increasing analytical capabilities, while reducing operator time and expertise required. This trend has further accelerated the pace and rate of advancement of analytical techniques and has led to an increase in the pace and capability of the associated research. In this paper, we analyze publication trends and pharmacopoeial developments in order to better understand the role and progression of analytical techniques. Since their initial discovery and development, with a particular focus on China, an Asian country with both deep cultural and long-term historical roots in plant medicine, to more modern day developments and applications.

Publication Trends

Increasing interest in medicinal plant research and analysis is reflected in the number of recent publications, with more than a three-fold increase from 4,686 publications during the year 2008 to 14,884 in 2018. Output published during the 8 years of the present decade alone outnumbered all those combined before 2000, since the included database records began in 1800 ( Figure 1 ).

Open in a separate window

Figure 1

The herbal substance analysis publications trend since search records began in 1800. A keyword search was conducted using the combination “medicinal plant” OR “herbal medicine” AND “analysis” chosen for the maximum retuned records after exploring a list of similar topic and combination of keywords such as “photochemical analysis,” “traditional medicine,” and “herbal.” The Web of Science or collection, KCI- Korean Journal database, MEDLINE^®, Russian Science Citation index, and SciELO Citation index databases were included in the search.

The largest proportion of publications cited in current databases over the last 10 years for medicinal plant analysis reports are in the disciplines of pharmacology and pharmacy ( Figure 2 ). With plant sciences, biochemical molecular biology and agriculture research following closely behind, together comprising almost 70% of the total publications.

Open in a separate window

Figure 2

Herbal substance analysis publications by discipline, 2008–2018 (169,917 records).

Regional Trends—Last 10 Years

The majority (about 58%) of medicinal plant analysis publications in the last 10 years have collectively emerged from mainland China, India, USA, and South Korea ( Figure 3 ). This may be an expression of the strong medicinal plant traditions in Asia in addition to the USA’s dominant presence as an international user of herbal products (Hu et al., 2013). The major East Asian regions, in particular, China, Japan, South Korea, together with Taiwan, contribute more than half of the total citations (55%). This may be indicative of the rapid economic progress and technological capability of these countries. China is the major contributor, with a 15% increase in its dominance of research outputs in the last 10 years. This influence has also been seen in the effect of China’s growing involvement in aiding the development of pharmacopoeias around the world and as a leader in the analysis of Chinese medicinal plants ( Figure 3 ).

Open in a separate window

Figure 3

Herbal analysis publications by region, 2008–2018.

Regulation and a Changing Analytical Landscape

From a regulatory perspective, the pharmacopoeial requirements are the central reference point for the analysis of medicinal plants. Though internationally many pharmacopoeias exist, the most comprehensive of these relating to herbal medicinal materials is the Chinese Pharmacopoeia (ChP). The current ChP introduced in 2015 is the 10th iteration presented in three volumes and includes 5,608 drugs, a 10-fold increase from its first edition in 1953. More than half of the current monographs (Hamid-Reza et al., 2013, 598) relate to CHM specifically including raw plants, slices, herbal mixtures, and oils. A noticeable inclusion in the current version compared with the previous version is the addition of 400 herbal mixtures (Qian et al., 2010).

Pharmacopoeia Monographs—Their Influences and Challenges

Though more recently the ChP is playing an increasing role in influencing medicinal plant analysis, the development of the ChP has been heavily influenced by Western pharmacopoeias. Historically the identification, preparation, and analysis of medicinal plants were based on classic texts such as the Shengnong Bencao Jing (Shengnong Materia Medica, 25–220 CE), where the category and quality of 365 plants and 113 prescriptions were assessed by taste. Organoleptic sensing of bitterness, sweetness, saltiness, and even neutral tastes were thought to indicate the function and application of the medicine. Arguably, the most influential Chinese pharmacy monograph is the Bencao Gangmu (Compendium of Materia Medica, 1368–1644 CE) containing 1,892 plant descriptions and 11,096 prescriptions sorted in 16 divisions and 60 orders, emphasizing appearance, taste, and odor as a key to authentication and quality.

However, the main precursor to the modern format of the current Chinese Pharmacopoeia was printed in the 1930s with 670 drugs. Even at this early stage, the then dominant Western powers such as Britain, Germany, America, and Japan found challenges in understanding and forming consensus for recognizing, categorizing, and assuring the quality of Chinese medical materials. At this time a difficulty emerged in securing materials for the more Western styled “scientifically run” hospitals. Initially it was though that as Japan had adopted a translation of the German pharmacopoeia in 1886, the Chinese could follow suit using the British Pharmacopoeia, which in 1927 had been translated into Chinese as a joint effort by the London and British Chambers of Commerce. However, some differences in opinion between the four occupiers had to be first resolved.

Many of the technological demands necessary to produce and maintain the pharmacopoeial standards required by the Americans was beyond the ability and technological capability of the Chinese at that time. America had recently just printed a Chinese translation of its United States Pharmacopeia (10^th edition) published in 1926. The strict American standards for aconite, digitalis, adrenalin, and insulin were purported to be managed by new or foreign trained pharmacists (Read, 1930). Preparations such as liniments found in the British and U.S. Pharmacopoeias were included in the Chinese version. Syrups such as those of codeine and glucose and tinctures of cannabis were from the British influence. Foreign residents in China found it difficult to ingest local food and stated an “extensive need for bowel remedies.” Therefore, drugs of the time, albuminis, aspidium, and emetin, were included. Vaccines for diphtheria, tetanus, and smallpox were maintained through the instruction of the USP.

German chemists had already gained a reputation for the isolation of chemical compounds, many of which were used medicinally and were already included in the Japanese Pharmacopoeia such as oxalic acid, pyrogallic acid, and bromine. Therefore, the existing German-Japanese analytical methods were generally utilized for these areas, which comprised about 25% of the new Chinese Pharmacopoeia. Whereas more British and American derived analytical methods and preparations were included for vegetable- and animal-based materials.

Agreement over the correct translation and naming of chemical compounds also proved problematic, e.g. when attempting to resolve disagreement between German-Latin and Anglo-American descriptions such as “natrium chloratum” and “sodii chloridum.” The shared Latin common language elements aided European and American common understanding; however, translation into Chinese was troublesome. A potentially easier route would have been to adopt the Japanese Pharmacopoeia names and descriptions, often possessing the same Asian (Hanzi) character as that in China, however, this was resisted due to the strong nationalistic sentiment at the time in mainland China (Read, 1930).

Though the Japanese favored direct foreign phonetic transliterated terms for drugs, about 60 original Chinese materia medica entries had persisted in the Japanese Pharmacopoeia including entries for camphor, ginger, aloes, cardamom, and star anise.

Difficulty in plant identification and common naming was not confined to Asia. During the early 1900s period of European and American political expansion, attempts were being made in Europe to catalogue multilingual terms for similar plants such as the publication of “the illustrated polyglot dictionary of plants names” in Latin, Arabic, Armenian, English, French, German, Italian, and Turkish languages (Bedevian, 1936), cataloguing 3,657 plants in eight languages.

Chronology of Pharmacopoeial Developments in China

Metabolomics

Pharmacopoeial methods focus on authentication and quality of herbal materials; however, metabolomics allow us to go a step beyond authentication and look in more detail at a broad range of secondary metabolites. By coupling analytical data to multivariate software, this allows us to develop statistical models to firstly differentiate between species but also to get a better idea of a typical metabolite composition for a particular species. The advantage of this is that it can help to inform any laboratory test or clinical intervention. There has been great emphasis on making sure that any experiment or intervention uses plant material that is authenticated, with a herbarium specimen deposited. However, the requirements do not stipulate that a good representative of the species should be used. This is where metabolomics can provide essential information—by collecting a wide range of samples from different geographical locations, altitudes, growing conditions, it allows us to map their metabolite differences and highlight how diverse or how similar metabolite composition is. When an experiment is performed, we have the choice to use a specimen that may be typical, i.e., contains an average composition or we can look at compositions that are atypical, containing greater amounts of specific metabolites or even different metabolites. Moreover, if a particular experiment produces positive results and we want to reproduce the data, a metabolomic model allows us to choose species that have a similar composition.

This approach has important economic implications as a detailed understanding of metabolomic analysis allows us to inform industry as to how to grow plants that will be of the best composition and so help to support local livelihoods of farmers and primary processors in developing economies, e.g., Chachacoma (Senecio nutans Sch. Bip.) cultivation in the high altitude regions of Chile where metabolomics has helped to establish the best altitude for growing plants with the highest content of the anti-inflammatory acetophenone (Lopez et al., 2015).

This strategy also has applications in product development, where metabolomics can help to determine the quality of products based on their metabolite content, e.g., Curcuma longa L. (Turmeric products) (Booker et al., 2014), and also help to provide evidence that can lead to value addition of a product and greater confidence in its quality and safety.

Nanoparticles

Nanoparticles 1–100 nm sized ions or organic/inorganic molecules have proven to be important in the development of new analytical testing (Tao et al., 2018), occupying the analytical regions of space between the ionic dimensions and small molecules.

Recent developments in nanoparticle research has led to an increased focus on chemo-bio sensing, as DNA has become the most used biological molecule to functionalize nanoparticles. Nanoparticles have provided many advantages to more consistent and specific testing including providing a more reproducible stable matrix for research and development, more controllable and reliable basis for designing and conjugating to functional molecules, and a wide rebate of flexibility for purification, selection, and modification of analytes. Nanoparticles have been used in creating a biological bar code for trace analysis of mycotoxins in Chinese herbs e.g. conjugated nanoparticles with DNA fragments to bind and target Chinese medicinal plants, e.g., Jue Ming Zi [Cassia seeds—Senna obtusifolia (L.) H.S.Irwin & Barneby], Yuan Zhi (Polygala tenuifolia Willd.), and Bai Zi Ren [Platycladus orientalis (L.) Franco] (Yu et al., 2018).

The Future

The next steps in analytical advancement in combination with technological improvements will most likely occur in the realm of artificial intelligence. Neural networks have already shown promise in consumer electronics and online search engine optimization. Self-learning algorithms have been in development for decades, with great potential for the application of self-synthesizing, auto-creating, and auto-adapting algorithms, which can optimally recognize and synthesize analytical data into meaningful and useful patterns. This goes beyond what a single human mind could hope to achieve in lifetimes, now possible in seconds with current and more so with future technology. This extends not only the human potential of thinking and observation but also prediction and design. This could potentially play a role in self-design of analytical instrumentation and its modules, self-optimizing of methods in real-time, saving time that would perhaps take an analyst weeks or months of human work-hours to complete.

The greatest challenge with AI is its opacity and computational complexity. With self-learning systems already self-generating codes and pathways that would take decades for a single human to decode and understand, if ever possible. This presents a great challenge for use in reproducible, validated quality-driven, audit-trailed regulated orientated environments. This is where natural compounds such as herbal substances can play a significant role i.e. data from the same plants species with variable composition can help verify the input and outputs of complex analysis and recognition software. In AI-driven systems, natural substances are ideal candidates for testing the analytical attributes such as accuracy, precision, and robustness of whole AI-instrumentation systems.

Conclusions

As pharmacopoeial requirements continue to develop and instrumental technology advances, it is clear that we will be able to delve further and further into the chemical composition of medicinal plants and develop more advanced techniques for the detection and quantification of adulterants and contaminants. However, it should be considered that although these technological advances give us this opportunity, more traditional organoleptic analysis also provides us with essential sensory information regarding medicinal plant quality.

We have shown the emergence and historical importance of complex analytical techniques used in medicinal plant analysis. However, any analytical approach, can only provide a partial perspective on complex multicomponent preparations. So future improvements in this area may not entirely rely on developing ever more complex analytical techniques, but in implementing best practice throughout all stages of the production and supply of herbal medicines.

Author Contributions

AB wrote the sections on applications of metabolomics, NIR, parts of the introduction, and conclusions. MF wrote most of the instrumentation, trends in publications and history, part of the introduction and conclusions. MH contributed towards the methodological design of the study and assisted with the data analysis.

Funding

MF scholarship is funded by Brion Research Group (Sun Ten Pharmaceutical Co) and Herbprime, UK.

Conflict of Interest

MF scholarship is funded by Brion Research Group (Sun Ten Pharmaceutical Co) and Herbprime, UK.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References