The formulation and manufacture of plant medicines
G. Brian Lockwood
Chapter contents
Plant-based products in medicinal use
Quality control of crude plant drugs
Production methods used to obtain plant-derived active constituents
Extraction of active constituents
Concentration, purification and drying of extracts
Formulation and manufacture of plant-based medicines
Active-constituent considerations
Finished-product considerations
Key points
• Quality control of crude plant drugs is more complex than for single chemical entities.
• A wide range of formulations of plant medicines are increasingly available.
Introduction
Drugs obtained directly from plant sources are notably alkaloids, glycosides and phenolic compounds. Plant material is also a favoured source for volatile (essential) oils. They are used in a number of different dosage forms; conventional plant derived pharmaceuticals, OTC preparations for minor ailments, herbal remedies, homoeopathic mother tinctures and medicines, volatile (essential) oils used medicinally and in aromatherapy, nutraceuticals (single and complex entities), antioxidants plus a vast array of traditional usages worldwide.
The European Pharmacopoeia alone contains more than 166 monographs for herbal drugs and 77 for herbal drug preparations, with an increasing number under study for future inclusion (Vlietinck et al, 2009).
Plant-based products in medicinal use
There is a wide range of plant derivatives in use for the manufacture of medicinal products. These include fresh and dried plant material, acellular products, a wide range of types of extracts including standardized extracts, and pure and in-vitro biotechnology-derived individual compounds. A range of conventional single-component pharmaceuticals derived from plants is listed in Table 44.1.
Table 44.1
Single chemical entities available after extraction from plant sources
| Chemical entity | Current prescription medicine application | Plant source |
| Atropine | Antispasmodic, ophthalmic | Atropa belladonna |
| Codeine, morphine | Analgesic | Papaver somniferum |
| Colchicine | Gout treatment | Colchicum autumnale |
| Digoxin | Cardiac glycoside | Digitalis lanata |
| Ephedrine | Bronchospasm, nasal congestion treatment | Ephedra spp. |
| Galanthamine | Alleviation of Alzheimer’s disease | Narcissus spp |
| Pilocarpine | Treatment of xerostomia, myotic | Pilocarpus jaborandi |
| Quinidine | Treatment of ventricular fibrillation | Cinchona succiruba |
| Sennosides | Laxative | Cassia senna |
| Vinblastine, vincristine | Anti-cancer agents | Catharanthus roseus |
The problems involved with the use of collected wild plant material include dramatic variability in quality as a result of the genetic variability of the wild stock, poor knowledge of the plants’ life cycle and the effects of differing habitats on levels of active constituents. Uncontrolled collection from the wild has led to devastation of certain supplies.
In order to control the influences of agro-ecological factors on levels of active constituents with the plant, cultivation is employed for production of the best quality raw materials. Medicinal plants should ideally be grown from homogeneous, genetically selected strains chosen for high yield of the relevant constituent(s) or other useful traits such as insect/fungal resistance.
Transport delays between collection and processing is a particular problem with the use of fresh plant material, which further compromises quality, leading to the possibility of degradation of the active constituent(s) as a result of microbial infestation, oxidation, reduction, hydrolysis and numerous other reactions. In spite of these disadvantages herbalists are still convinced of their benefits.
Quality control of crude plant drugs
Quality control (QC) techniques are described in a range of monographs in national and international pharmacopoeias, as well as in herbal and homoeopathic pharmacopoeias. QC procedures should be applied to the herbal starting materials, their extracts and the finished products. Quality control techniques used for plants and their extracts are outlined in Table 44.2. Modern chromatographic techniques are also used for separation and quantification of specific individual constituents. This chapter will not detail the specific analytical techniques described and the reader is referred to other texts for this information.
Table 44.2
Classical techniques for quality control
| Standard | Technique | Purpose |
| Sampling | Selecting representative samples for analysis. Pharmacopoeias may suggest the number of samples from large consignments. | To ensure all analytical data obtained truly represent the characteristics of the batch |
| Preliminary investigation | Organoleptic testing; observation of colour, odour, taste | Observation for evidence of poor quality or adulteration, to ensure high quality of final product |
| Foreign matter | Observation for excreta, mould, etc. | To ensure high quality of final product |
| Moisture content | Loss on drying at 100–105 °C, Dean & Stark measurement, GC, Karl Fischer method, IR, UV, NMR spectroscopy | Inhibit or minimize enzymic or microbial degradation |
| Extractive values | Water soluble extractive, ethanol (45–90%) extractives, range of non-polar solvent extractives | To determine whether low levels of compounds of specific polarity are present or even absent |
| Ash values | Incineration at 450 °C for total ash | Indication of level of inorganic matter or silica |
| Insoluble ash values | Water- and acid-insoluble ash contents | Indication of level of contamination with earth or silica |
| Crude fibre | Defatting followed by boiling | Confirmation of normal level or detection of excess material, stalk for example |
| Macroscopical analysis | Comparison with botanical description | Initial identity of material |
| Microscopical analysis | Description of cells, inclusions and structures | Identification of material |
| Tannin content, bitterness value, swelling index | Quantitative measurements | Used for specific plants, containing either tannins, bitter substances or those used for swelling ability, e.g. laxatives |
| Microbiological contamination | Limits for levels of specific organisms | Check for levels of organisms above 103–104 microorganisms per gram |
(Courtesy of Evans 2009, with permission.)
Plant preparations are often considered to be active due to their combination of constituents, and these often complex mixtures can be identified by a semi-quantitative proof of content, such as a chromatographic fingerprint in combination with an appropriate assay of major constituents (Vlietinck et al, 2009). A combination of data from three types of chromatography are able to provide much qualitative and quantitative information.
Thin layer chromatography (TLC) is a semi-qualitative technique using specified standards. By determination of Rf (retardation factor) values, this technique allows comparison between extracts of different origins and composition with known standards. This will give evidence for the presence of the component(s) of the standards, plus indicative quantitative data as to their levels in the materials being tested.
To obtain true quantitative data either high-performance liquid chromatography (HPLC) or gas chromatography (GC) should be used. These techniques are predominantly used for assays of either polar or volatile constituents, respectively. GC is increasingly widely available coupled with mass spectroscopy (MS). This GC-MS combination allows identification and quantification of a wide range of components without the need for standards.
In addition to these chromatographic techniques, a number of spectroscopic techniques are widely used such as visible, infra-red (IR) and ultraviolet (UV) spectroscopy for determining semi-quantitative levels of constituents. In addition to these latter techniques, assays for specific constituents have been devised using NMR spectroscopy, immunoassay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA) and fluorescence analysis. Near infra-red spectroscopy (NIR) has recently been used for routine analysis of dry plant material and formulated products (both liquid and solid) and has the added advantage that it is non-invasive and can therefore be used for quality control in production and in packaging lines.
Herbal remedies often contain numerous herbal extracts, in many examples numbering more than 10. This creates analytical difficulties and this challenge, associated with the increasing usage of all herbal remedies particularly traditional and complementary medicines (TCM), has inspired analysts to produce more inclusive techniques, such as chemical pattern recognition, spectral correlation, etc. (Liang et al, 2004). DNA fingerprinting has recently been used to establish the identity of highly expensive raw materials, particularly prone to substitution.
Production methods used to obtain plant-derived active constituents
The wide variety of medicinal plants, types of plant parts and varying textures of material, makes it impossible to standardize mechanical procedures, from harvesting through to drying, size reduction, or even essential oil extraction. The fibrous texture of in vivo or field-grown plant material and also unorganized crude drugs often requires severe mechanical disruption prior to extraction. Table 44.3 outlines the basic processes involved in production of plant extracts. These are applied to both conventional plant-based pharmaceuticals and complementary herbal medicines.
Table 44.3
The major stages in the conversion of plant material into a concentrated extract
| Production process | Purpose | Constraints |
| Harvesting | Stop metabolism at optimum time | Weather |
| Drying | Inactivate enzymes, inhibit microbial infestation | Plant part and temperature determine speed. Essential in tropical conditions |
| Size reduction (comminution) | Increase surface area for effective solvent extraction | Solvent flow impeded if particles too small, possible release of excessive mucilage which hinders later filtration |
| Extraction of active constituents | Production of most active base for formulation | Financial constraints to complete (100%) extraction |
| Extract concentration | Minimize volume/weight of extract, for ease of transport, storage, and ease of distribution in the final formulation | As above, but extra investment |
Harvesting
The first stage, harvesting, is strictly an agricultural and not a pharmaceutical process, but it can have a great influence on the quality of the final product. Each procedure requires specialized equipment, often using modified versions of commercial agricultural machinery.
Further mechanical processing techniques are often required, which may include cleaning or washing. Procedures are needed to eliminate unwanted foreign matter, such as other plant material, minerals, any other organisms and agrochemical residues. In some instances, manual techniques are still superior to mechanization.
