that occur in the storage process will cause biological activity changes. Nine medicinal plants from Africa showed a loss of anti-inflammatory activity (inhibition of COX-1), while the antibacterial activity did not change [42].
The type of packaging used in the storage process will also affect the chemical content of the stored medicinal plants’ raw materials. Various studies show that the packaging used dramatically influences compounds’ content and composition in essential oils, polyphenol group stability, and color stability [40].
1.2.2.6 Complex Mixture of the Pharmacologically Active Constituent
The plant synthesizes primary metabolites for normal growth, development, and reproduction for its original life. Primary metabolites such as sugar, protein, vitamins, lipids, and starches are needed for growth and development, whereas chlorophyll, amino acids, nucleotides, and carbohydrates needed for metabolic processes such as photosynthesis, respiration, and nutrient assimilation. However, to protect themselves from potential dangers from environmental conditions or other species, plants will synthesize secondary metabolites. This secondary metabolite is synthesized from the substrate used for the primary metabolite or modification of the synthetic pathway from the primary metabolite. Secondary metabolites are not directly needed for growth and will accumulate during growth. This compound has biological activity, so it has the potential for humans to be used as a medicine [43, 44].
The complexity of the chemical content makes it challenging to control herbs’ quality. Therefore, the development of new drugs is preferable to use isolates of active compounds obtained from the separation and purification process guided by bioassays. In 1897 aspirin, which is synthesized from salicylic acid extracted from willow bark, causes an era of concept dominance mono-drug therapy and the development of synthetic drugs and causes a decrease in natural products drug discovery [45].
Various studies have shown that the separation and purification process reduced or even reduced its pharmacological activities. The antimalarial activity of artemisinin is lower than the whole extract of Artemisia annua L. This decrease in effect is strongly related to the loss of pharmacokinetic synergy between constituents after herbal extracts have been purified. The decreased activity also occurred in the process of isolating aconiti (Aconitum carmichaelii Debx), gentiopicroside (Gentiana manshurica Kitag), liquiritigenin and isoliquiritigenin (Glycyrrhiza uralensis Fisch), ginsenoside Re (P. ginseng C. A. Mey), cryptotanshinone and tanshinone (Salvia miltiorrhiza Bge), schizandrin (Schisandra chinensis (Turcz.)). The pharmacokinetic synergy effect between constituents in herbal extracts can occur during absorption, distribution, metabolism, and excretion [45, 46].
The content of 5′-methoxyhydnocarpin, a strong P-gp inhibitor, increases cellular absorption with substrates p-glycoprotein (P-gp). Both of these compounds are found in Berberis plants.Arteannuin B, one of the compounds in Artemisia annua extract, can increase the AUC0–t (2.1-fold) and peak concentration (Cmax, 1.9-fold) of oral artemisinin in mice [46]. Radix Polygoni multiflorum Tunb. contains 2 main components, stilbene glucoside, and emodin. Stilbene glucoside can increase the absorption and duration of action of emodin by inhibiting UDP-glucuronosyl-transferases 1A8. Thus it was inhibiting emodin glucuronidation [47].
The flower of Abelmoschus manihot (Linn.) contains flavonoids such as rutine, hyperoside, isoquercitrin, hibifolin, myricetin, quercetin-3′-Oglucose, quercetin. This flowers’ decoction is traditionally used to treat chronic renal disease, oral ulcers, and burn in China. This decoction also contains nonflavonoids of small molecule ingredients such as organic acids, amino acids, nucleosides, oligosaccharides, and non-flavonoid macro-molecule fractions such as pigments, resins, polysaccharides. Various study showed that the bioavailability and elimination of flavonoid compounds were influenced by non-flavonoid compounds [48].
The compound contents’ complexity and the synergistic pharmacokinetics that occur naturally in herbs is a high-efficiency natural drug delivery system in herbal extracts. This pharmacokinetic synergy can through various mechanisms including by increasing solubility, preventing enzymes from metabolizing drugs, eliminating first-pass 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
