April 1, 2001
The Benefits and Pitfalls of Standardizing Botanical Extracts
by Mark Roman, Ph.D. One major problem in assuring the consistent quality of herbal supplements is caused by the natural variation of endogenous phytochemicals that occurs in plants. The chemical "fingerprint" of a particular species of plant can vary widely depending on the age of the plant, time of harvest, soil conditions, weather conditions, and other factors. It is reasonable to think that plants that have very different phytochemical profiles will have different therapeutic effects, even if the plants are from the same species.The Europeans, and in particular, the Germans, first seized upon the concept of standardization as a means of assuring product quality and batch-to batch consistency to reduce or eliminate this variation. In a standardized extract, a bulk extract is either diluted or concentrated until a particular phytochemical, or group of phytochemicals, is achieved at a predetermined concentration in the extract. This predetermined concentration is usually expressed as a percent of the total extract.Standardization is a fairly simple concept. The biologically active compound in a plant is identified. The plant is extracted with a suitable solvent that targets the active compound, and the solvent is then removed from the extract. The concentrated extract is analyzed to determine the concentration of the active compound, and then diluted with an appropriate filler or carrier. Standardization of herbal extracts has several advantages compared to non-standardized extracts. The most obvious advantage is in the batch-to-batch reproducibility of the final product. A standardized extract has a concentration of marker compound that is known to a high degree of accuracy, and because both the amount of plant material that is extracted and the amount of carrier that is added can be varied, it is possible to compensate for natural variability in the plant material.In addition, standardized extracts can theoretically have higher therapeutic efficacies than the whole herb or non-standardized extracts, as the active principal has been concentrated to a level much higher than exists in the plant itself. When the plant active is known to be a single compound, and the standardization concept is taken to the extreme, the result is a single-entity pharmaceutical. A good example is paclitaxel, better known by the trade name Taxol. Paclitaxel is an antineoplastic drug first found in the bark of the Pacific yew tree, Taxus brevifolia. Before synthetic and semi-synthetic means were developed to produce paclitaxel, the only source of the drug was from the repeated extraction and purification of the Pacific yew tree bark. This "herbal" remedy was a standardized extract containing 100% paclitaxel.Unfortunately, the standardization concept also has some major drawbacks. While some plants, such as ephedra and gotu kola, have well- known active components (ephedrine alkaloids and caffeine, respectively), the active components in many herbal products are not known or not well understood. Instead, the extracts from these plants are standardized to arbitrary "marker" compounds. These marker compounds are usually unique to that particular plant, and may or may not possess biological activity. Different manufacturers often standardize extracts from the same plants to different marker compounds. Thus, it is possible to go into a store and find echinacea products standardized to either phenolic compounds or alkylamides, dong quai standardized to either ligustilide or ferulic acid, or St. John's wort standardized to either hypericin to hyperforin. Sometimes the differences in labeling are subtle--"free" fatty acids vs. "total" fatty acids in saw palmetto, "hypericin" vs. "total dianthrones calculated as hypericin" in St. John's wort, "silymarin" vs. "silybin" in milk thistle. In each case, however, the difference in standardization can be significant.The danger in standardizing extracts to marker compounds that do not have a proven biological activity is that the phytochemicals that do possess the biological activity can be left behind during the extraction process. St. John's wort, an herb used to treat depression, is usually available as an extract standardized to 0.3% hypericin (actually, 0.3% total dianthrones). The herb is believed to work by inhibiting serotonin and dopamine re-uptake within the synapse. A paper published in Pharmacopeial Forum, however, showed that there was no correlation between the level of hypericin in various products, and the serotonin and dopamine re-uptake inhibition (Rininger JA, et al, "The Value of Bioassays in Assessing the Quality of Botanical Products," Pharm Forum; 26:857-864, 2000). In fact, several products that had among the highest levels of hypericin showed almost no activity.Furthermore, when herbal extracts are standardized to a class of compounds, such as ginsenosides in ginseng, kava lactones in kava, or oxindole alkaloids in cat's claw, to name a few, the ratios of the individual compounds are often not preserved from the original plant material. Since the desirable biological activity in the plant may be due to the synergistic effect of all the individual components in the class of compounds, significantly altering the ratios can result in biological activity that is markedly different from the plant. Because there are often no specifications for the ratios of the individual compounds in the standardized extracts, adulteration and spiking can become a problem.Complicating matters even more is the disparity in analytical test methods used to quantify these marker compounds. There can be several different test methods for a particular product, all with significant differences. A raw material that meets product specifications using one test method can fail using another test method.What are the solutions to these problems? Correctly identifying active components in the plant would be the best solution. Since this is often not possible, perhaps the next best solution would be to standardize extracts to several different classes of marker compounds in the plant. As an example, some ginkgo biloba extracts are standardized not only to 24% flavonglycosides, but to 6% terpene lactones as well. Manufacturers should strive to use validated analytical test methods and avoid using proprietary test methods that they are unwilling to make public. A test result is meaningless if it cannot be duplicated by anyone else.The main attractiveness of nutraceuticals to the consumer has been the cost-effectiveness compared with pharmaceuticals; however, consumers will abandon nutraceuticals if efficacy cannot be ensured. The concept of standardization of botanical extracts has some definite advantages, and is appealing not only from a quality perspective, but from a marketing one as well. The standardization of each product, however, must be carefully chosen, and the methods used to ensure that standardization must be rigorously validated. Mark Roman, Ph.D., is director of research and development with ChromaDex Inc., a supplier of analytical reference standards based in Laguna Hills, Calif. He worked previously at RP Scherer developing and validating analytical test methods. He can be contacted at [email protected].
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