Understanding Plant To Extract Ratios in Botanical Extracts

Dietary supplement current good manufacturing practice (cGMP) requires the establishment of quality parameters for each component used in the manufacture of a dietary supplement to ensure that specifications for the identity, purity, strength, composition, and limits on contaminants are met.* Compliance with botanical extract ingredient specifications is assured by using scientifically valid methods of analysis, the results of which are reported on certificates of analysis (CoAs). However, CoAs routinely include additional data that are not amenable to verification through methods of analysis. Such descriptive information may include Plant to Extract ratios, which are ratios of the quantity of botanical article used in the manufacture of the extract to the quantity of extract obtained. Plant to Extract ratios can be misleading when their meaning is not clearly understood.

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Plant to Extract ratios do not completely describe botanical extracts because other important factors influence the makeup of final extracts, such as the quality of the raw starting material (as can defined by pharmacopeial standards), extraction solvent(s) used, duration and temperature of extraction, and percentage and type of excipients present. Other important qualitative descriptions may include constituent “fingerprinting.” Despite these issues, Plant to Extract ratios are often used as a measure of extract strength for dosage calculations. This article defines and clarifies the meaning of Plant to Extract ratios and their proper use in describing and labeling botanical extract ingredients and finished products containing them.

1 Introduction

Botanical extracts are composed of extracted matter obtained from starting materials of botanical origin [United States Pharmacopeia (USP)]. They result from dissolving soluble plant constituents in extraction solvents and separating them from undissolved plant materials. A botanical extract has been defined as “the complex, multicomponent mixture obtained after using a solvent to dissolve components of the botanical material” (Dentali, 2013). Crude botanical extracts (those without added excipients) are called native or genuine extracts. Excipients are often added to extracts to improve their material handling characteristics, to standardize constituent concentrations, and for other functional purposes. The term “botanical extract” here refers to all types of extracts, independent of the relationship between identified constituents and the bioactivity (potency) of the extract.

Although botanical extracts may be subjected to additional processing to enrich the content of a particular chemical class of constituents, once they have been isolated as a fraction or as purified single constituents, these articles and expressed juices are not considered to be botanical extracts. Furthermore, extracts do not include chemically modified plant constituents except where artifacts result from heating or extraction processes. In addition, for the purposes of this article, the term plant or botanical is used in the broad sense to include algae, fungi, and lichens, as well as plant products such as exudates or oleo-gum-resins.

Botanical extracts can be described, in part, by the Plant to Extract ratio of botanical starting crude material (a.k.a. biomass) from which they were made, to the resulting native, or finished, extracts. The European Medicines Agency (EMA) [European Medicines Agency (EMA), 2010] guidelines refer to the ratio of starting material to genuine/native extract ratio as the DER genuine (Drug to Genuine Extract Ratio),† and explain how to disclose the percent of genuine/native extract with the percent excipients for finished extracts. The DER is used as part of the strength characterization of an extract, i.e., the amount of starting material used to make a unit of extract. Community Herbal Monographs from EMA use the DER, together with extraction solvent information, for the determination of crude starting plant material equivalents in comparing extracts, and for estimating extract dosages according to well-established or traditional plant uses.

Plant to Extract ratios may enable the determination of an extract’s raw material equivalents, although the final chemical composition can vary depending on the quality of the starting plant material and the extraction conditions. A close comparability of extracts, also known as their phytoequivalence (Australian Government. Department of Health, 2011), cannot be determined without a detailed comparison of the solvent(s) and manufacturing processes used, sometimes supplemented with comprehensive comparisons of the extracts’ chemical compositions.

This article first provides an overview of botanical extracts, including their different types and forms, standardization, and categorization. Additional sections explain the concept of Plant to Extract ratios and the common misconceptions. Also provided are recommendations on how to apply the Plant to Extract ratio in labeling, and its relevance to the dosage of plant material equivalents.

2 Botanical extracts

Botanical extracts, as defined in the USP General Chapter <565> Botanical Extracts [United States Pharmacopeia (USP)], are often used as ingredients in dietary supplements. Botanical extracts that conform to USP monographs for Botanical Extracts should be obtained from botanical articles that also conform to the corresponding USP monographs. Extracts may be manufactured to concentrate desired constituents, decrease the content of unwanted constituents or impurities, improve shelf life, and produce consistent material for the testing of claimed benefits. Depending on the type of botanical material and extraction technology used, prior to extraction the raw starting material may be subjected to different types of pretreatments, including cutting and grinding to reduce particle size and optimize surface area exposure, defatting, etc.

The composition of botanical extracts from the same plant may vary significantly depending on the extraction solvent(s) used, the temperature and duration of extraction, and the processes used to dry the extracts. Other sources of variation include the steps taken to concentrate or remove targeted constituents or classes of constituents, and the compounds formed during extraction or further processing. Additional variation in the composition of botanical extracts made using the same plant species and plant part as starting materials may occur due to genetic factors, environmental conditions, and agricultural practices. Managing the natural variations in starting material and using standardized extraction procedures can serve to create extracts with consistent composition. Suitable inert substances (excipients) are often added to extracts via granulation or other procedures to act as carriers or diluents which improve physical handling characteristics such as flowability and mixability. Excipients may also facilitate the production of a powder, reduce clumping, and improve homogeneity, bioavailability, stability, and other characteristics. Excipients can also be used to standardize the extract to a defined content of one or more constituents.

According to USP General Chapter <565> Botanical Extracts [United States Pharmacopeia (USP)], botanical extracts can be classified according to their physical state as either liquid (e.g., fluidextracts and tinctures), semisolid (soft), or solid (dry) forms. These physical forms are defined in Table 1.

3 Standardization of botanical extracts

Various organizations define botanical extract standardization differently

The American Herbal Products Association (AHPA) (American Herbal Products Association, 2003), the leading herbal trade organization in the United States, defines standardization as “the complete body of information and controls that serves to optimize the batch-to-batch consistency of a botanical product. Standardization is achieved by reducing the inherent variation of natural product composition through quality assurance practices applied to agricultural and manufacturing processes.” AHPA (American Herbal Products Association, 2021) points out that, “[i]n fact, standardization—when properly performed—entails a lot more than merely controlling the content of a particular marker compound … It comprises a wide variety of raw material and process controls, as well as use of a consistent recipe.”

Marker compounds are constituents that may or may not be associated with therapeutic activity and often are used as in-process controls. They also can help demonstrate identity when specific to the botanical raw material under consideration. On the other hand, marker compound levels may not vary proportionally with other compounds of greater importance relative to therapeutic activity, due to differences in genetics, growing conditions, or stability during processing and storage.

The EMA categorizes “standardised extracts” as those where the identified constituents are understood to fully account for an extract’s proven therapeutic activity [European Medicines Agency (EMA), 2010]. The relationship of identified constituents to an extract’s biological activity may not always be clear. Awang (2004) noted that the identity of constituents responsible for biological activities of a plant extract are rarely clearly established, even with bioassays and clinical studies, and numerous constituents may be active to different degrees and in various respects. A few examples of bioactive constituents in “standardised extracts” include the laxative sennosides of senna leaf, the hepatoprotective silymarin flavonolignans of milk thistle fruit, and the anti-nauseant gingerols of ginger rhizome.

Elimination of unwanted constituents, so-called negative markers, from extracts is also considered a form of standardization. Examples of negative markers include the neurotoxic thujones found in tansy, and hepatotoxic pyrrolizidine alkaloids found in comfrey and other herbs. Marker compounds include constituents that are characteristic of a particular species or variety of a plant, and thus are useful for standardization but may not be entirely responsible for the intended therapeutic activity. Examples include parthenolide in feverfew and echinacoside in Echinacea angustifolia and E. pallida.

Bioassays of extracts may provide some measure of therapeutic activity, although they are rarely used for standardization. A classic example is the use of in vivo bioassays with frogs, cats, and pigeons to standardize extracts of digitalis (Dieuaide et al., 1935; Lehman, 1936). In another example, bioassay is recommended as a way to ensure reproducible pharmacological activity (potency) of the dragon’s blood (Croton lechleri) latex botanical drug (U.S. Department of Health and Human Services, 2012). Although they may be useful for standardizing extracts to a potency measurement, challenges with bioassay-based standardization include cost, complexity, and demonstrating the relationship to clinically relevant effects in humans.

Standardization to either active or marker constituents and bioassays that reflect the underlying mechanisms of action were described by van Breemen et al. (2007). Hubbard et al. (2019) reported that recent developments in bioinformatics and bioassay technology have made it possible to address large numbers of phytochemical constituents in a plant extract and the potential diversity of their biological effects. This allows a much greater level of detail for characterizing the features that could be used for plant extract standardization.

4 Categorization of botanical extracts

In addition to the classification of extracts as to whether they are liquid, soft, or dry, the aforementioned EMA category of “standardised extracts” is joined by two other categories of extracts, namely “quantified extracts,” and “other extracts,” depending on the relationship between known constituents and the extract’s biological activity [European Medicines Agency (EMA), 2010]. Unlike the EMA-designated standardised extracts, in quantified extracts the identified constituents partly, but not fully, account for an extract’s bioactivity. In this case, and for “other extracts” that have no relationship between identified constituents and extract bioactivity, the whole of the extract is considered to be the active material.

Crude extracts may be processed further, or a selective extraction may be performed at the outset to concentrate particular classes of phytochemicals or to decrease the content of unwanted constituents, or both. Gymnema leaf extract containing NLT than 5.0% of gymnemic acids as USP Purified Gymnema Extract, and USP Powdered Ginkgo Extract that contains NLT 22.0% and NMT 27.0% flavonol glycosides, and NLT 5.4% and NMT 12.0% of terpene lactones, are examples of extracts in which specific constituents are enhanced. Licorice root deglycyrrhizinated extract and green tea leaf decaffeinated extract with a concentrated content of catechins as USP Powdered Decaffeinated Green Tea Extract represent extracts in which specific constituents have been removed.

These specialized extracts fall along a chemical complexity continuum from selective and semi-purified botanical extracts or extract fractions that concentrate a phytochemical class, to an isolated class of phytochemical constituents, to a single compound (Figure 1). Depending on the degree of chemical purification, these latter two examples may no longer be appropriately considered extracts. Examples of concentrated constituent classes of compounds include sennosides extracted from senna leaflets or senna pods (USP Sennosides) and curcuminoids extracted from turmeric rhizome (USP Curcuminoids).

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