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mediated efflux-drug-transporters, increasing membrane permeability, opening tightly crossing paracellular cells, and changing the shape and absorption of bioactive compounds (for example, by forming efflux-drug-transporter-mediated naturally occurring nanoscale particles) [46].

Unlike synthetic drugs, phytopharmaceutical contains many pharmacologically active components. The complex constituent composition of phytopharmaceutical is an advantage because various compounds can produce additive or even synergistic effects or can also work multifactorial, which involves many pathways from target therapy. Interactions between chemical substances can also increase solubility and bioavailability simultaneously. However, its complex chemical composition is also an obstacle that must be faced to make it reproducible. The concentration of chemical composition can vary from batch to batch. This variation in the chemical composition will affect its effectiveness [11, 49, 50].

1.3 Strategy to Guarantee the Quality of Phytopharmaceutical

      In the past, the use of herbal products was done by individual healers. In this case, the healer will be the only one determining the quality of raw materials and their production. The success or failure of therapy are also primarily determined by the patient’s trust in the healer. The absence of reproducibility of therapy is unacceptable in phytopharmaceutical products. Reproducibility of product quality and the guarantee of effectiveness and safety are very important. The most important thing to ensure the quality, from raw materials to finished products, is to develop the suitable quality control method to be able to guarantee its quality [51].

      Quality assurance begins with standardization. Standardization is not only analytical operations that only determine the identity and level of active compounds in phytopharmaceuticals. Standardization is an activity that establishes the complete information and control needed to ensure the consistency of the composition of the constituent of phytopharmaceuticals. The use of analytical methods must pay attention to the fact that plant material has a constituents’ complex composition. It also must understand the variability and inconsistency of the composition influenced by many factors that cannot be eliminated.These conditions complicate the standardization of phytopharmaceuticals, so the application of analytical methods for quality control requires the latest innovations and techniques [52, 53].

Quality control is a process involved in maintaining the quality and validity of manufacture. In general, quality control is based on three aspects, Identity, Purity, and Content. Identity mainly concerns species authentication and all characteristics under the specifications of phytopharmaceuticals raw materials. Its characteristics include macroscopic and microscopic tests, organoleptic tests such as color, smell, and taste. The purity of phytopharmaceuticals raw materials is related to the uses’ safety. Purity is related to ash value, contaminants (microorganisms, heavy metals, pesticides), and foreign matter. The application of the latest analytical methods can measure aflatoxin, radioactivity, and extracting solvent residues. Content or assay is the most challenging aspect to do, considering the variability and complexity of phytopharmaceuticals’ chemical content. This aspect also includes the determination of loss on drying, moisture content, and essential oil content. The chemical constituents’ determination in phytopharmaceuticals is quite tricky because in most herbal medicines the active constituents are unknown. The pharmacological activity of phytopharmaceutical comes from all the compounds in it. The concept of marker can be used to determine quality but cannot describe the reproducibility of the whole component. For this reason, the concept of a metabolite profile or metabolite fingerprinting must be used [1, 51, 54].

      It is well understood that, like all herbal products, phytopharmaceuticals contain multicomponent. The multicomponent composition is not yet known and is not clearly understood. The complexity of phytopharmaceuticals’ chemical content requires different concepts in quality assurance. The approach that can be used today is compound-oriented or pattern-oriented. The compound-oriented approach uses certain components with some chemical properties known as targets, while pattern-oriented uses all components that can be detected as targets. The compound-oriented approach is based on a marker compound concept with the target is certain chemical compounds with known molecular structures. A pattern-oriented approach based on a metabolite profile or fingerprinting or phytoequivalent concept with a target is all chemical compounds with structures known or unknown or that have partial chemical information eg. retention time, mass spectrum, and ultraviolet spectrum [55–57].

      1.3.1 Marker Compound Concept

      In phytopharmaceuticals, the resulting pharmacological activity comes from all the compounds in it. The active compound cannot be ascertained. Besides, the ingredients are very complex and varied, so that it becomes more challenging to characterize. Under these conditions, a marker is needed to represent phytopharmaceuticals’ characterization. These marker compounds are used to control quality but do not always represent the constituents associated with drug activity [1, 54, 58].

      In pharmacopeia, phytopharmaceuticals are considered drugs so that the quality is based on a chemical marker, which is expected to ensure consistency. According to the European Medicines Agency (EMEA), chemical marker are constituents or constituent groups used for quality control purposes, have or do not have therapeutic activity. To be a marker of quality, ideally, a chemical marker has unique and specific characteristics and must contribute to the therapeutic effect of phytopharmaceuticals. Differences in the number of chemical markers can indicate differences in the phytopharmaceuticals pharmacological activity. Thus, the number of chemical markers can indicate the quality of phytopharmaceuticals [59, 60].

In the concept of marker compounds, the key first step in determining phytopharmaceuticals quality is the selection of marker compounds. There are three ways to choose or select a marker compound that will be discussed below as illustrated in Figure 1.2.

      – Major or easy-to-get compound

      The selection of marker compounds isn’t too easy because the therapeutic or bioactive components of phytopharmaceuticals are unknown and not yet clearly understood. Under such conditions, the marker compound can be selected from several components that are not specific but easily obtained. But, this has a weakness. The marker compound cannot ensure the effectiveness of phytopharmaceuticals [60]. This easy-to-get compound is usually a major compound. At least, because the levels of these compounds are large, they also have a major contribution to phytopharmaceuticals’ pharmacological activity.

Figure 1.2 Tree ways to select a marker compound.

      An example of this case is ethyl-p-methoxycinnamate as a marker compound in the ethanolic extract of Kaempferia galanga rhizome [61]. The compound content is 14.54%. In the ethanolic extract of Andrographis paniculata, the Andrographolide level is 10.82%. This compound is used as a marker compound for products containing A. paniculate extract [62]. However, various research showed that the pharmacological activity of the extract is greater than its marker compound. This indicates that the selected marker compound is not therapeutically active. But the level of these compounds can be a marker of the quality of their pharmacological effects. These compounds can be called active marker compounds.

      – In silico Virtual Screening

      Marker compounds must have clear pharmacological activity so that their levels in the product are an indication of product quality. Bioassay screening is indispensable to obtain such compounds. The next process is to carry out bioassay-guided isolation. Then proceed with bioactivity confirmation using animal models, organ and tissue models, cellular models, or receptors and enzymatic. However, this method is time consuming, difficult, and has not revealed the effects of interactions with other compounds. Therefore requires an integrated new approach for predicting potential active constituents in herbs [60].

Recent developments in efforts to explain the pharmacological

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