of crude drugs

Chapter 11 Production of crude drugs



SOURCE MATERIALS 87

ENVIRONMENTAL CONDITIONS 87

CULTIVATED AND WILD PLANTS 88

COLLECTION 90

DRYING 91

STORAGE 92

EUROPEAN REGULATIONS 92

The crude drug that reaches the pharmaceutical manufacturing line will have passed through various stages, all of which influence the nature and amount of active constituents present. These aspects will be considered under the headings ‘Source Materials’, ‘Environmental Conditions’, ‘Cultivated and Wild Plants’, ‘Collection’, ‘Drying’, ‘Storage’ and ‘European Regulations’.



SOURCE MATERIALS


It is imperative that correct identification of the source material is made. Adulteration may be accidental, particularly if collection is made from wild plants, or it may be deliberate. Failure in this area can result in poisoning (e.g. hemlock fruits mistaken for other umbelliferous fruits) or inactive products (e.g. substitution of St John’s wort with other vegetable material when demand exceeds supply). For pharmacopoeial drugs, precise macroscopic and microscopic characters are available.


For the isolation of specific constituents, the source can vary, e.g. particular steroids may be obtained from various diverse plants (q.v. Chapter 25) or hyoscine from a number of solanaceous species. Recently a potential problem concerning the production of the oral antiviral against avian flu—Tamiflu® (oseltamivir)—arose from a shortage of Chinese staranise (q.v.), the source of the starting material (shikimic acid, see Fig. 18.8) for the synthesis. However, the toxic Japanese star anise, regarded as an adulterant of the Chinese drug, also contains shikimic acid and could provide an alternative source (D. V. C. Awang and M. Blumenthal, HerbalGram, 2006, 70, 58).


In the article ‘Plant part substitution—a way to conserve endangered medicinal plants’ S. Zschocke et al. (J. Ethnopharm., 2000, 71, 281) explore the possibility of using the leaves of plants that are traditionally used for their barks, bulbs and roots, thus conserving the plant.



ENVIRONMENTAL CONDITIONS


Plant growth and development, and often the nature and quantity of secondary metabolites, are affected by temperature, rainfall, aspect, length of day (including the quality of light) and altitude. Such effects have been studied by growing particular plants in different climatic areas and observing variations. The findings of such research are illustrated by work on cannabis by El-Kheir et al. in 1986 in which seeds of cannabis, grown in England and rich in CBD and devoid of THC, when cultivated in Sudan started to produce THC in the first generation and in the second generation contained up to 3.3% THC with a further decrease (down to 0% in some plants) of CBD (see ‘Cannabis’ for explanation of chemistry). However, it is impossible to control all the variables in such experiments, and special laboratories (phytotrons) have been constructed in which all the factors are independently controllable. Even so, a meaningful expression of the results can often present some difficulty. For example, a particular factor may lead to the development of a small plant which, when analysed on a percentage dry weight basis, indicates a high proportion of metabolite, even though the overall yield per plant could be quite low. Conversely, certain nutrients may result in the production of large plants with a somewhat low analytical figure for constituents on a percentage dry weight basis, but yield per plant may exceed that of the control.



Temperature


Temperature is a major factor controlling the development and metabolism of plants. Although each species has become adapted to its own natural environment, plants are frequently able to exist in a considerable range of temperature. Many tropical and subtropical plants will grow in temperate regions during summer months, but lack frost resistance to withstand the winter. In general, the highest temperatures are experienced near the Equator, but as the temperature falls about 1 °C for every 200 m of elevation, it is possible in, say, Jamaica to have a tropical climate on the coast and a temperate one in the mountains. The annual variations in temperature are just as important as the temperature of the hottest month. At Singapore the annual range of temperature is as little as 1.5 °C, whereas Moscow, with its hot summers and cold winters, has a range of 29.3 °C. In general, the formation of volatile oils appears to be enhanced at higher temperatures, although very hot days may lead to an excess physical loss of oil. The mean optimum temperature for nicotine production in Nicotiana rustica is 20 °C (lower at 11–12 °C and at 30 °C). Several authors have indicated that fixed oils produced at low temperatures contain fatty acids with a higher content of double bonds than those formed at higher temperatures.



Rainfall


The important effects of rainfall on vegetation must be considered in relation to the annual rainfall, its distribution throughout the year, its effect on humidity and its effect coupled with the water-holding properties of the soil. Variable results have been reported for the production of volatile oils under different conditions of rainfall and may in some instances be coupled with the development of glandular hairs. Continuous rain can lead to a loss of water-soluble substances from leaves and roots by leaching; this is known to apply to some plants producing alkaloids, glycosides and even volatile oils. This could account for low yields of some active constituents in wet seasons from plants whose general condition appears to be good.


With Cassia angustifolia (Tinnevelly senna) it has been shown that short-term drought increases the concentration of sennosides A+B but in the longer term causes loss of leaf biomass (H. Ratnayaka et al., Planta Medica, 1998, 64, 438).



Day-length and radiation characteristics


Plants vary much in both the amount and intensity of the light which they require. In the wild state the plant will be found where its shade requirements are met, and under cultivation similar shade must be provided. In certain cases research has shown that light is a factor which helps to determine the amount of glycosides or alkaloids produced. With belladonna, stramonium and Cinchona ledgeriana full sunshine gives a higher content of alkaloids than does shade. At Gif-sur-Yvette experiments indicated that with Datura stramonium var. tatula long exposure to intense light brought about a sharp increase in hyoscine content at the time of flowering. An important in vivo reaction in the formation of the antitumour alkaloids of Catharanthus roseus is exemplified by the dimerization of the indole alkaloids catharanthine and vindoline leading to vinblastine; Hirata et al. (Planta Med., 1993, 59, 46) demonstrated that irradiation of intact plants with near ultraviolet light in the range 290–380 nm (peak 370 nm) stimulates the synthesis of dimeric alkaloids, probably by inducing catharanthine oxidation as a trigger reaction. This observation has support from in vitro studies.


It has been shown that under long-day conditions peppermint leaves contain menthone, menthol and traces of menthofuran; plants grown under short-day conditions contain menthofuran as a major component of the volatile oil. Furthermore a long photoperiod for young leaves activates the reduction pathway with conversion of menthone to methol. In studies on the day–night changes in the relative concentrations of volatiles from flowers of Nicotiana sylvestris and other species a marked increase (about tenfold) in aromatic compounds including benzyl alcohol was detected at night, whereas no increase in the volatiles (e.g. linalool, caryophyllene) originating from the mevalonic acid pathway (q.v.) was noted (J. H. Loughrin et al., Phytochem., 1990, 29, 2473).


The daily variation in the proportion of secondary metabolites is probably light-controlled and is discussed more fully under ‘Collection Times’. Many plants initiate flowers only in certain day-lengths, and where flowering is essential this factor must be carefully considered before planting in a new region. Presence or absence of light, together with wavelength range, have a marked effect on the secondary metabolite production of some plants in tissue culture.


The type of radiation which plants receive is also important. With Ocimum basilicum, C. B. Johnson et al. (Phytochemistry, 1999, 51, 507), have found, in relation to herbs raised under glass and receiving no UV-B radiation, that supplementary UV-B radiation increases levels of both the phenyl-propanoids and terpenoids of the leaves. Flavonoids and anthocyanins are also known to be influenced by UV-B radiation. Depletion of the ozone layer and the consequent effect of increased radiation at the earth’s surface has been a topic of much recent speculation. Concerning medicinal plants, R. Karouson et al. (Phytochemistry, 1998, 49, 2273) raised two chemotypes of Mentha spicata which were subjected to increased UV-B radiation equivalent to a 15% ozone depletion over Patras, Greece. In one chemotype essential oil production was stimulated by the treatment while a similar non-significant trend was noted with the other.



Altitude


The coconut palm needs a maritime climate and the sugar cane is a lowland plant. Conversely, tea, cocoa, coffee, medicinal rhubarb, tragacanth and cinchona require elevation. In the case of Cinchona succirubra the plants grow well at low levels but produce practically no alkaloids. The bitter constituents of Gentiana lutea increase with altitude, whereas the alkaloids of Aconitum napellus and Lobelia inflata and the oil content of thyme and peppermint decrease. Other oil-producing plants may reach a maximum at certain altitudes. Pyrethrum gives the best yields of flower-heads and pyrethrins at high altitudes on, or near, the Equator. It is therefore produced in East Africa and north-west South America. However, vegetative growth is more lush under irrigated conditions at lower altitude, so the propagation farms (for the vegetative multiplication of plants) are, in Ecuador, situated at lower levels than the final commercial farms.


G. A. Statti et al. (Fitoterapia, 2004, 75, 212–216) studied bergamot (Citrus bergamia) grown at different altitudes and solar exposures in Calabria, Italy; they found both chemical (linalool, linalyl acetate composition) and biological (antioxidant and antifungal activities) diversities.


The flowering heads of Arnica montana, grown in Austria in experimental plots at altitudes between 590 and 2250 m showed no altitude effect on the total contents of sesquiterpene lactones and flavonoids but the latter with vicinal-free hydroxy groups in ring B increased with altitude relative to the other flavonoids. Caffeic acid derivatives were 85% higher at the summit compared with the valley (R. Spitaler et al., Phytochemistry, 2006, 67, 407). For a study of the effect of altitude on the podophyllotoxin content of the aerial parts and underground organs of Podophyllum hexandrum populations from the Kumaun region of the Indian Central Himalayas, see M. Nadeem et al., Planta Med., 2007, 73, 388.



CULTIVATED AND WILD PLANTS


Certain drugs are now obtained almost exclusively from cultivated plants. These include cardamoms, Indian hemp, ginger, and peppermint and spearmint for oil production. Others include Ceylon cinnamon, linseed, fennel, cinchona and opium. In other cases both wild and cultivated plants are used. Some plants have been cultivated from time immemorial (e.g. flax, opium poppy and coca). Others are now grown because supplies of the wild plants are insufficient to meet the demand or because, owing to sparse distribution or inaccessibility, collection is difficult. Cultivation is essential in the case of drugs such as Indian hemp and opium, which are subject to government control, and recently for those wild plants in danger of over-exploitation and which have now been given CITES (q.v.) listing. In many cases cultivation is advisable because of the improved quality of the drug which it is possible to produce. The improvement may be due to the following.


1 The power to confine collections to species, varieties or hybrids which have the desired phytochemical characters (e.g. aconite, cinnamon, fennel, Duboisia, cinchona, Labiate drugs and valerian).

2 The better development of the plants owing to improved conditions of the soil, pruning, and the control of insect pests, fungi, etc.
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Jul 18, 2016 | Posted by in PHARMACY | Comments Off on of crude drugs

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