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or mixed with I. anisatum. I. anisatum contains neacoxic sesquiterpene dilactone anisatin, a strong non-competitive GABA antagonist. Both have morphological similarities. This adulteration case causes many cases of adverse neurological reactions such as nausea, hallucinations, and epileptic seizures, especially in small infants [11].
Another example of adulteration occurs in Saffron (dry red stigmata Crocus sativus L.), one of the expensive raw materials. Saffron is often added with other similar ingredients, reducing therapeutic efficacy. Other raw materials such as ginseng are often diluted with cheap fake ingredients Platycodon grandiflorus (Jacq.) A. DC. or with different ginseng species, such as P. quinquefolius L. (American ginseng), P. ginseng C.A. Meyer (Asian ginseng), or P. notoginseng. There is a problem with this mixing. Different ginseng species have different saponin profiles, thus giving different pharmacological effects. American ginseng and Asian ginseng have been reported to have contradictory effects on the vascular system and blood glucose levels [11].
1.2.2.4 Post-Harvesting Process
Water is a component that determines the physical and chemical properties of plant constituents. Decreasing plants’ moisture content by the drying process, intended to prevent the activity of enzymes and microbes, extends shelf life. Dry raw materials simplify the process of transportation and storage. Many factors affect the drying method. Therefore a drying method must be chosen that does not change or reduce the phytochemical content [11, 37].
Camellia sinensis or C. assamica is the most popular drink in the world whose use can be in the form of green, black, or oolong. Green tea has important and extensive pharmacological activities. But to maintain its quality, the drying method is very limited due to the instability of its chemical content. Chemical ingredients in green tea are vitamins, chlorophyll, flavonoids, dan polyphenols, which have antioxidant activity [38].
The drying process affects the recovery of taxol from Taxus baccata. Yield taxol from the stem is not affected by drying temperature, while the yield of taxol from leaves will increase with increasing drying temperature. Drying at low temperatures will produce a low yield because it requires a longer drying time so that the enzyme activity causes taxol to degrade [37].
1.2.2.5 Storage
After post-harvesting, medicinal plants often have to be stored long enough before being used as raw materials for various products. For this reason, the storage method must be suitable so that it does not cause physical, chemical, and microbiological changes. Storage is intended to ensure that there is no loss of quality. Some methods are used to control humidity and air movement to prevent metabolic activities, which can damage the content of compounds in it. Another way is to prevent attacks by insects, mice, and microorganisms [39, 40].
Echinacea purpurea (Asteraceae) is a medicinal plant with immunostimulatory and anti-inflammatory activities, especially in alleviating cold symptoms. The storage process affects alkamide and cichoric acid content in E. purpurea root, in reverse. Alkamide levels did not change when stored for 60 days in the dark at 50 °C, while cichoric acid levels reduced by 70%. On storage in light at 200 °C, the cichoric acid level did not change, while the alkamide level dropped by 65%. Temperature and light affect the compound content of E. purpurea [39, 41].
The composition of the chemical content of essential oils from aerial parts of Thymus daenensis Celak did not show changes during storage in the freezer (−20 °C). Storage at room temperature (25 °C) also does not reduce its quality because there is an increase in the levels of thymol and carvacrol. The storage temperature affects the composition of the compounds in the essential oil of Hyptis pectinata L. Poit. Compared with storage in the freezer, storage at room temperature showed increased levels of β-elements, α-copaene, germacrene D, and caryophyllene compounds. Oxide and (E, E)-α-farnesene and decreased α-humulene and β-caryophyllene [40].
Changes in chemical composition 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