Phytopharmaceuticals. Группа авторов

a poor therapeutic effect and even cause unwanted effects [14].

      1.2.2 Variability of Chemical Content in Raw Material

Side effects of herbal product usage have been widely reported. These incidents are caused by mistaken authentication, adulteration, contamination by microorganisms or toxic chemicals, overdose, improper use, and interaction with drugs. There are still many raw materials of medicinal plants obtained from wild populations. Whether intentional or unintentional, mistakes often occur in the harvesting process, causing raw material to be contaminated by other species or unneeded plant parts. The poor quality of finished products is caused by the use of raw materials of phytopharmaceuticals that do not have high enough quality standards. The quality of raw materials of medicinal plants is greatly influenced by various factors such as intrinsic (genetic) and extrinsic (environmental) factors during their growth, cultivation, harvesting, post-harvest process, transportation, and storage [8].

       1.2.2.1 Intrinsic Factor

      Plants synthesize secondary metabolites such as phytoprotein and phytoalexin to defend themselves from environmental conditions involving insects, plant microorganisms, and other plants. The secondary metabolites in plants can be manipulated using genetic engineering, to increase desirable production and reduce the undesirable compounds. The synthesis of flavonoids and anthocyanins is the first genetic engineering that has been successfully carried out because the biosynthetic pathway is well known. The results can be detected from changes in flower color. The indole terpenoid alkaloids pathway is an attractive target for genetic engineering because about 15 terpenoids, alkaloids, and indole terpenoid alkaloids have an essential role in anti-tumor alkaloids, vinblastin, vincristine, and camptothecin. The success of genetic engineering in the future achievement of the pharmaceutical industry is used for the expansion of new compounds with new activities. But in some cases, excessive gene expression occurs so that it does not reach the desired target compound [29].

       1.2.2.2 Extrinsic Factor

      The environment and habitat are external factors that affect the types, proportions, and levels of active substances of the widespread species. Biosynthesis of the active substances in a plant results from interactions between plants and the environment in a long evolutionary process. The research on Eucommia ulmoides Oliv. reported that the height of the location and the average annual temperature were highly significant with chlorogenic acid and flavonoids levels. The duration of yearly sunlight positively correlated with geniposidic acid but negatively correlated with geniposidic acid levels. Potentilla fruticosa L. in traditional Chinese medicine is used for detoxification and for treating diarrhea, hepatitis, rheuma, and scabies. The P. fruticosa grows in cool and high regions in the northern subarctic mountains. Liu et al. proved that altitude has negatively correlated with tannin content, whereas the length of annual sunlight and altitude has positively correlated with flavonoid levels and antioxidant activity. The average yearly temperature has negatively correlated with total phenolic levels, while altitude has positively correlated with total phenolic levels [30].

Ecological factors such as climate, geography, land, and topography can affect plants’ growth, development, reproduction, behavior, and distribution. To overcome these effects, plants can regulate the synthesis of secondary metabolites. Different ecological factors cause differences in plant quality when compared to the original area. Dendrobium officinale, one of the traditional Chinese medicinal plants, is used as a tonic, nourish the stomach, relieve throat inflammation, improve eyesight, and promote body fluid. The main ingredients of D. officinale are polysaccharides, alkaloids, and flavonoids. To meet market demand and keep the original plant, the study results indicate that this plant’s cultivation must fulfill the factors such as humidity, temperature, duration of sunlight, soil pH, nitrogen, and phosphorus content in the soil needed by the plant [31].

      Plant interaction with their environment causes variations certain secondary metabolites’ classes’ composition and production. The composition of constituents can be used for characterization as chemical markers for plants that grow from certain geographical areas, which are harvested at certain seasons or certain ages, based on qualitative and quantitative analysis of its chemical constituents. Tithonia diversifolia (Hemsl.) A. Gray, belonging to the Asteraceae family, commonly known as Mexican sunflower, produces essential oils that spread worldwide. This species is native to Mexico and Central America and is a weed that spreads in various ecosystems, especially in Africa and China. The results of Sampaio and Da Costa’s research showed that there are different chemotypes for T. diversifolia species according to the samples’ geographical origin. Differences in the accumulation of ß-pinene in essential oils and variations in the production of certain classes of secondary metabolites, such as terpenes, seem to respond to different abiotic environmental conditions directly. This study also shows that tissue-specific changes that produce secondary metabolism are adaptive strategies for different environments [32].

       1.2.2.3 Harvesting

      Determination of harvest time is critical to get quality raw materials. Post-harvest processes such as processing into dry raw materials, transportation, and storage must also be carried out at optimal conditions to produce the reproducible quality of raw materials. The primary source of medicinal plants comes from the wild, so that exploitation can cause natural damage and extinction of some species. Plant collected from the wild have problems regarding the homogeneity of the quality. The agroclimatic conditions will affect the chemical composition and therapeutic properties. One medicinal plant widely used in India, Terminalia chebula, originates from India’s various parts, known to have different therapeutic properties [33].

      Harvest time will affect the composition of the chemical content in plants. Therefore the harvest must be done at the right time. It is known that the chemical content of plants is directly correlated to the stage of plant development. In Ayurveda, Andrographis paniculata (Kalmegh) is used as a hepatoprotective. A study conducted by Pandey and Mandal revealed that the maximum andrographolide levels (2.85%) were found at the initiation of flowering or harvested after 130–150 planting days. The highest level of Rauwolfia serpentine root alkaloid is at the age of 18 months. The plant maturation stage at the root of Wihania somnifera (Ashwagandha) is 130–180 days after planting, while the peak maturity of Tinospora cordifolia (Giloe) stems is 15 months. In Ayurvedha, Adhatoda vasica (Adusa or Vasaca), used as a bronchodilator, contains vasicine on its leaves. This plant blooms in March (fully bloomed) and September (partially blooms). At the flowering stage, these compounds’ levels were 3.0 and 1.4% in March and September, respectively. Whereas at the vegetative stage, the vasicine levels are very low [33].

Lemongrass oil, obtained from (Cymbopogon citratus), is one of the essential oils widely used in the perfume, cosmetic, beverage, and pharmaceutical industries as aromatic and antiseptic. Citral content is a characteristic of lemongrass oil quality. There are 65 compounds in lemongrass oil, but only 13 compounds are always present in the lemongrass oil harvested at different ages. Citral levels are also different when lemongrass is harvested at different maturity stages. Optimal citral content in lemongrass oil is obtained when harvested at the age of 6.5 and 7.0 months [34, 35].

      Artemisia annua L. (Asteraceae) which has antimalarial activity, is a commercial antimalarial compound source. Essential oils of A. annua are used in the perfume and cosmetics industries. In the essential oil is found main compounds such as camphor, artemisia ketone, germacrene D, and 1,8-cineole. The variability of the chemical composition of essential oils of A. annus depends on the geographical origin and stage of plant development. Before the flowering stage, the essential oil content was 0.8%, then increased rapidly to 1.38% after the flowering stage. The main compounds (artemisia ketone, camphor, and 1,8-cineole) and the highest antioxidant activity in essential oils are taken at the full flowering stage [36].

      Adulteration that occurs is often done for profit. Adulteration is done by adding foreign material, which is usually cheaper and dangerous. Illicium verum Hook. F., which is used as a drug for