Written by Roy Upton
The modern concept of pharmacopeias is defined as containing “pharmaceutical specifications that are intended to secure uniformity in the composition, quality, and therapeutic activity of medicines and that are made obligatory within a political unit by legally effective authority” (Sonnedecker 1993). The term pharmacopoeia is derived from the Greek pharmakon (meaning medicine or charm) and poien (meaning to make). Any of the earlier works of materia medica, which attempted to codify the preparation of medicinal ingredients or formulae, can be considered the antecedents of today’s pharmacopoeias. In this regard, China’s Shennong Bencao, Egyptian papyri (e.g., Eber’s Papyrus), the Caraka Samhita of India, and the early Greek and Roman works of Theophrastus, Dioscorides, and Galen all represent such works. However, over time, pharmacopoeias evolved as consensus documents generated by groups of physicians or pharmacists, versus individual authors, and were given formal authority by authoritative bodies.
Historians differ as to the earliest of formal works of medical authority, but perhaps the first such consensus standard was Nuovo Receptario Composito, a book of medical ingredient standards commissioned by the guild of physicians of Florence and made official in Florence in 1498 (Gaddum 1946). Fifty years later in 1548, the actual word pharmacopoeae appeared in Pharmacopoeae Jacobi Sylvii libri tres of French physician Jacques Dubois, but the term was used only in its generic sense. The first officially sanctioned work with the word pharmacopoeia was the Pharmacopoeia Augustana of 1601 (Sonnedecker 1993) and others soon followed establishing the model for official pharmacopoeias.
Herbal drug standards in early pharmacopoeias
Early pharmacopoeias (e.g., Pharmacopoeia Augustana 1601; Pharmacopoeia Londinensis 1618) were predominantly books of recipes for extracts, syrups, and oils and provided guidance for relative standardization of medicinal preparations, many of which were Galenical, relatively crudely extracted, herbal preparations. Over time, pharmacopoeias (e.g., British Pharmacopoeia 1864) introduced standards of identity and quality for individual herbal medicines. Many of these reflected relative generality, sometimes not specifying plant species (e.g., acacia) but notably included information regarding the identifying morphological characters, origin, collection practices, and drying conditions of the drug material, clearly the primary considerations of early herbalists and plant collectors. Another early pharmacopoeia, the Dispensatorium Lippiacum (Scherf 1792) introduced organoleptic characterizations and the use of magnifiers as part of the assessment criteria for plant medicines. Interestingly, the Dispensatorium Lippiacum was described as “predominantly addressing handcraft savvy pharmacists in small towns” (Friedrich no year), a description that could readily be applied to numerous traditional herbal extract (tincture) manufacturers in the US today.
In addition to being predominantly recipe books of relatively crude herbal preparations, some of the earliest of formal pharmacopoeias (e.g., Augsberg Pharmacopoea 1613), attempted to resist the ever-growing movement to use Paracelsun “chemical” medicines. According to history of pharmacy scholar George Urdang (1882–1960), in a decree of the Augsburg Senate in 1582, the apothecaries (druggists) were “admonished” not to prepare or offer for sale “substances which are known to be detrimental or poisonous, such as Labdanum minerale, the so-called antimony, also Turpethum minerale and other purging mecurials.” Many of the precepts of the Paracelsun use of powerfully acting drugs, were in direct opposition to the empirical lineages of Galenists and Hippocratists. However, soon after, in 1589, the London College of Physicians proposed that the chemicals, salts, extracts, and metals of Paracelsus be included in the London Pharmacopoeia. This was eventually realized in 1618 with the inclusion of calomel (mercury chloride) among the medications for internal use. While the juxtaposition of Paracelsun ideologies and those of the Galenists where in great part an attempt of the Paracelsuns to not blindly follow the empirical philosophies of the ancients, and were very much attempting to apply scientific experimentation in medicine, Galenists were alarmed at what they saw as the introduction of highly poisonous substances that had no basis of safety or efficacy into medical practice. As noted, this trend laid the groundwork for modern drug development that predominates today.
Another development marking the distinction between traditional and modern drugs was the introduction of chemical testing methods into pharmacopoeial monographs. Prior to analytical chemistry, the focus of pharmacopoeias and materia medicas was on morphology as the primary identity test and proper harvesting conditions and organoleptic characters as the primary criteria by which herb quality was assessed. The Pharmacopoea Wirttembergica (1741) was the first pharmacopoeia to introduce chemical testing of drugs, a trend that continued as analytical chemistry advanced and chemically characterized drugs became dominant. Whereas the earliest pharmacopoeias and materia medicas reflected a relatively herbal-botanical approach to the assessment of herbal medicines, later Western pharmacopoeias, persisting to the current day, deferred to chemistry.
Identity, purity, quality and testing: The foundation of pharmacopoeial standards
Pharmacopoeias codify the standards of identity, purity, quality, and testing for herbal drugs, traditional and modern. Generally speaking, if a pharmacopoeia does not provide a monograph for a specific drug then the drug cannot be traded commercially. However, in herb-friendly societies, such restrictions do not apply. Most pharmacopoeias worldwide are relatively consistent in the fields of information they provide. The primary principle of pharmacopoeial monographs is to ensure the proper identity of the herbal ingredient to be used in a drug and develop minimal standards of quality and purity, so that when a pharmacopoeial-grade drug ingredient is used it will deliver the intended activity. Some of these pharmacopoeial monograph standards are consistent with herbal assessment practices employed by traditional herbalists. Others are a result of the ever modernization of herbal medicines including the requirement for chemical testing that often overshadows traditional assessment techniques as discussed below. Most pharmacopoeias lack information that is essential to procuring a high quality herbal medicine and rather create a minimum standard of acceptance. This influences many product manufacturers to produce products that meet a minimal quality standard rather than an optimal quality standard. For example, the North American botanical goldenseal root (Hydrastis canadensis) contains from 2.5% to 6% of berberine alkaloids. Most pharmacopoeial standards (e.g. AHP, USP) formally require for the botanical to contain not less than 2.5% berberine alkaloids, the lowest amount the plant contains. In contrast, a traditional herbalist attempts to determine optimal harvest times in order to prepare an optimal medicine. In most all cases, the interface between the medical practitioner, the classical botanical pharmacognosist, and the resultant pharmacopoeial standard has been largely lost creating a significant disassociation between the manufacture and practice of medicine, a connection that traditionally was much more integrated.
Pharmacopoeial standards internationally
Approximately 74% of countries do not have their own pharmacopoeias. Of these countries lacking their own pharmacopoeia, approximately 56% utilize the monographs of the European Pharmacopoeia (EP) or United States Pharmacopeia (USP); approximately 30% utilize no pharmacopoeia; and, perhaps most telling, 78% of countries do not include herbal medicines in their national drug lists (WHO 2005). In both developed and developing nations, unless provisions for access to non-official plant drugs are in place, or at the very least not restricted, availability to traditional herbal drugs can be impeded, a situation currently in place in the US where there is no regulatory allowance of traditional herbal medicines.
The following fields of information are contained in the majority of pharmacopoeial monographs worldwide. Different pharmacopoeias give greater or lesser emphasis to certain fields of information over others. Compliance with all aspects of the monograph in developed countries, most represented by the pharmacopoeias of China, the European Union, Iran, and the United States, is required, a requirement that contains redundancy and, in some cases, unnecessary testing, all of which drives the cost of traditional herbal medicines up.
Most monographs begin by defining the medicinal substance. This definition establishes the identity of the material being used and oftentimes, the minimum quality of the ingredient to be used, usually determined by the presence of a specific quantity of a chemical compound as noted in Table 3.
The pharmacopoeial definition is often the first body of information that establishes that a chemical test is required for acceptance of the herbal drug. Chemical testing is especially relevant when most of the activity of the botanical can be assigned to a specific constituent, when there is a narrow therapeutic to safety window of the drug, or when the medicinal qualities of the plant cannot be discerned through sensory analysis. Generally speaking, and specifically regarding relatively safe herbal drugs, chemical testing has great value as a complement to organoleptic assessment. Chemical assessment is most critical for the more toxic of herbal medicines that possess a narrow therapeutic window. However, analytical chemistry does not take the place of ensuring optimal times of harvest and proper drying, processing, and storage conditions. Chemistry can more fully inform these practices, but in itself is not sufficient to render analytical techniques such as botany, microscopy, and sensory evaluation obsolete or inferior to other techniques (see Macroscopic and Sensory [Organoleptic] Evaluation below).
Table: Pharmacopoeial definitions of St. John’s wort (Hypericum perforatum)
|European Pharmacopoeia (EP)||Whole or cut, dried flowering tops of Hypericum|
perforatum L., harvested during flowering time.
Content: minimum 0.08 per cent of total hypericins,
expressed as hypericin (C30 H16 O8; Mr 504.4) (dried drug).
|United States Pharmacopoeia (USP)||St. John’s Wort consists of the dried flowering tops or aerial parts of Hypericum perforatum Linne´ (Fam. Hypericaceae), gathered shortly before or during flowering. It contains not less than 0.04 percent of the combined total of hypericin (C30H16O8) and pseudohypericin (C30H16O9) and not less than 0.6 percent of hyperforin (C35H52O4).|
Macroscopic and Sensory (Organoleptic) Evaluation
All pharmacopoeia monographs include a morphological description of the plant drug under various descriptive headings such as: Identification in the European Pharmacopoeia; Botanic characteristics in the USP; and Description in the Ayurvedic Pharmacopoeia of India and Pharmacopoeia of the People’s Republic of China. These sections primarily give the relative form, size, shape, and physical features of the crude plant drug. These were the primary criteria used by traditional herbalists and early pharmacognosists in discerning the authenticity of the plant drug material. Great emphasis was similarly placed on plant morphology in the numerous pharmacognosy works of the 19th and early 20th centuries (e.g., Flückiger and Tschirch in 1887; Mansfield 1926; Sayre 1917; etc.). Detailed instruction was provided in how an appropriate macroscopic/morphological assessment was to be performed on various plant parts. Today there is a plethora of references (e.g; Applequist 2006; Leon and Lin 2018; Pfaender 1991; Wichtl 2004; Zhao 2009; 2014) on the morphological assessment of crude plant drugs that provide a scientifically valid means for identifying a large number of medicinal plants to determine conformity with pharmacopoeial identification specifications.
Organoleptic assessment was, historically, and among herbalists today, the most important suite of characters for determining the relative quality of a crude plant drug. Organoleptic evaluation of plant material includes an assessment of the flavor, aroma, texture, and sensation experienced by the assessor and requires a specialized skill set akin to those required by food scientists and sommeliers, but to a much lesser degree. From a botanical medicine sense, flavor is broadened to include the sensation of texture and mouth feel. Flavor arises when chemicals in foods (and herbs) react chemically with receptors on taste buds (gustatory calyculi) on the tongue, mouth, and throat. The tongue is covered with 2000–5000 taste buds, each one containing 50–100 taste receptor cells. In modern food sensory evaluation, five basic flavors are recognized: sweet, sour, salty, bitter, and umami. This latter umami flavor was defined by the Japanese to describe the “savory” flavor of the commonly used food flavoring monosodium glutamate (MSG). There are relatively few herbs that possess this flavor and so its relevance to organoleptic assessment of botanicals is limited. More relevant are the flavors recognized in traditional herbal medicine systems, namely, sweet, sour, bitter, salty, pungent, and in Ayurveda, astringent, which is more accurately a mouth feel, but never-the-less, regarded as a flavor for purposes of describing herbal actions.
From an evolutionarily perspective, flavors are either aversive or desirable and inform human decisions about what and what not to eat. At a very basic level, the sweet flavor typically identifies high-energy foods; strongly bitter and or strongly acrid flavors are undesirous and may indicate a poison.
Flavors contribute part of the sensation of foods, and are complemented by aroma detected by olfactory epithelium receptors, texture detected mechanically such as through nerves in muscles, temperature through thermoreceptors, and sensations of coolness (peppermint leaves or oil), heat (cayenne, black pepper), and pungency (cloves, ginger root) through chemical sensations detected by skin and mucous membranes (chemesthesis), all of which are referred to by some as the “nature” of the herb. In some cases, the flavors directly correspond to medicinally active constituents as established in western science, such as menthol from peppermint; capsaicin and piperine from cayenne and black pepper, respectively; and eugenol and gingerol from cloves and ginger root, respectively. Medicinally, menthol is an active constituent in topical analgesics. Menthol triggers cold-sensitive TRPM8 receptors in the skin. It is through this mechanism that the familiar cooling sensation when inhaled, ingested, or applied topically is experienced (Eccles 1964), while menthol’s analgesic properties are mediated through a selective activation of κ-opioid receptors (Galeottia et al. 2002). The yellow color and bitter taste of the Chinese herb huang lian (Coptis spp.) (Zhao and Chen 2014) and the North American goldenseal root (Hydrastis canadensis) is correlated with berberine content, the herbs’ putative primary active constituent; the mucilaginous content of herbs such as slippery elm (Ulmus fulva), flax seed (Linum usitatissimum), and psyllium seed (Plantago ovata), as determined by the swelling index included in most pharmacopoeias, is correlated with the soothing and moistening nature of the herbs; the bitter flavor of Ganoderma species is correlated with immuno-modulating triterpenes (Kubota et al. 1982; Nishitoba et al. 1989); the numbing effect of Echinacea angustifolia root experienced when chewed is correlated with isobutylamides, which are among the most biologically and pharmacokinetically relevant of echinacea constituents (Woelkart et al. 2005). These are only a few examples where there is a clear association between herbal flavors, known active constituents, and pharmacological effects.
Prior to the advent of chemistry, traditional herbal systems developed a very sophisticated system of sensory assessment that formed the didactic basis for understanding the pharmacology of the herbs. These systems also linked sensory qualities found in nature with sensory qualities of pathology and health (hot, cold, moist, dry, etc.), and then correlated those with the sensory quality of plant drugs. On a philosophical level, Chinese medicine assigns the five specific flavors identified in that system to five organ complexes, respectively; bitter to the heart; sweet-spleen/pancreas; pungent-lungs; salty-kidneys; sour-liver. Each taste is considered to have specific attributes such as bitter substances are draining and drying; salty substances soften and attract moistness; sweet substances nourish; pungent substances disperse; and sour substances astringe. Chemically, bitter substances often correspond to alkaloids and certain triterpenes; sweet substances to carbohydrates and complex sugars (e.g. polysaccharides); pungency to volatile oils; salty substances to mineral salts; and sour to flavonoids and plant acids. While these basic flavor-chemistry correspondences are simplistic and not specific to disease complexes from a Western medical approach, they form the basis of pharmacology that is completely unified in the diagnostic system of Ayurvedic and Chinese medicine.While herbalists historically did not specifically know what compounds were correlated with what activity, they recognized that it was the whole herb and the predominant nature of the herb that was considered active and that the quality of the herbal drug was discerned, and often directly correlated, to its sensory characteristics. These relationships were then either proven or disproven through experience and refined over centuries. In Ayurveda and TCM, this system of sensory relationship between nature, humans, and medicines, is still actively applied by almost all herbal practitioners and has been integrated somewhat by some western herbalists. It is this very system that uniquely correlates qualities of nature, with qualities possessed in plants, with qualities reflected in anatomy, physiology, and pathology, creating a unified system based on natural principles of human health that is, itself, a microcosm of nature and is the traditional antecedent to individualized medicine. This is yet another stark differentiator between traditional and modern systems whose diagnostic systems seldom look at the nature of the person but rather defer the understanding of human health and pathology to machines that generate often arbitrary values that reflect symptomatic changes in a statistical norm but says little about the individualistic needs of the human being. This is one of the very reasons why there is a rapid and increased recognition of traditional herbal systems worldwide. It is not a fad, but a universal need to restore humanistic values to human health. The relationship with the plant itself is reflected in numerous herbal traditions as follows:
“The crude drug is the foundation of the pharmaceutical preparation… the [pharmacognosist] must be able to judge of the intrinsic qualities of drugs. This last is the most important part of the art of pharmacognosy, for while it is easy to learn to identify different drugs it is difficult to obtain the experience necessary to judge of quality shades….The study of crude drugs is most important.” (John Uri Lloyd 1849-1936).
“Visual inspection provides the simplest and quickest means by which to establish identity, purity and, possibly, quality. If a sample is found to be significantly different, in terms of color, consistency, odor or taste, from the specifications, it is considered as not fulfilling in the requirements.”(WHO 1998)
“The way of using herbs, there is one way, there is no other. That is to master the herb’s nature and flavor, and to understand its yin and yang. Only with this understanding, even if the herbs are many, can you achieve desired results.” Zhang Jingyue (1563–1640) Jingyue Quanshu (Complete Works of Jingyue)