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This regulation is obviously made for the preparation of active substance concentrates or
the recovery of pure active substances, and should also apply to all potent medicinal
preparations. This means that standardization is carried out on drugs containing active
substances which can be determined chemically or biologically and even then only on
commercial products.
Regulation is preceded by standardization, which is primarily used for verifying the identity
of the investigated sample (drug material or preparation). In every case where the active
substances are not known and hence cannot be determined chemically or biologically,
standardization is at the same time the method used for quality assurance. The strict
separation of the terms ‘standardization’ and ‘regulation' has still not been fully brought
about. The statement of the composition of a purgative given in the Rote Liste '1 dragee
contains: 85.75-100 mg of dried extract of deresinified Alexandria senna fruits adjusted
to 20 mg hydroxyanthracene derivatives,
calculated as sennoside B', is complete and correct. It contains both a statement of the
quantity of extract contained in the preparation and its origin and also a statement on the
regulation and the basis of its calculation. It must be emphasized that the formulation
'adjusted to 20 mg hydroxyanthracene derivatives... represents regulation, even though
no quantity range as defined in the 'Pulveres normati’ of the pharmacopoeias is given. It
can, however, be considered as a . mean value of a quantity range within the rules
applying to solid medicinal dosage forms for total content and content uniformity. In
1 dragee contains: Extr. Fol. Sennae sicc. 155.6-200 mg (standardized to 14 mg
sennosides A + B)', is incorrect, although it has the same stated content, as far as clear
terminology is concerned, as here the term ‘standardization' is used instead of the term
Statements such as ‘l tablet contains: sennosides A + B from follic. Sennae S mg’ are
incomplete, as they do not indicate any relationship between the quantity of extract used,
and hence the quantity of accompanying substances, and the active substance content.
The many different statements on ready-to-use medicines are certainly attributable to the
existing lack of a uniform terminology. Every effort should however be made to
standardize the terminology for new registrations and licensing of medicines and for
renewal of these.
6.2. Standardization
Drugs are generally standardized according to the ten points listed under Section 2.2.1
and with consideration of the remarks made under Section 6.1.
343 If these are drugs for which monographs are given in the current pharmacopoeias,
their individual examinations should be carried out in accordance with the directions
given. If no such monographs exist, it can be helpful to consult older editions of the
pharmacopoeias or other literature, especially publications which are up to date with the
present state of knowledge.
Generally speaking, no difficulties occur with medicines containing potent constituents
and those with biologically or chemically determinable components. Standardization is
more difficult with drugs which have no pharmacological action (measurable
pharmacological action is not to be equated with efficacy or activity) and the active
principles of which are not known. The tests listed under Section 2.2.1, with the exception
of point 8, must be referred to here for quality assurance. Thin layer chromatographic
investigations (point 2), with which a so-called fingerprint of the drug can be obtained, are
particularly suitable for identification of these drugs.
The need to search for one or more principal indicative substances is debatable,
especially when the activity of the drug is to be ascertaincd by their quantitative
determination. It must not be expected that the indicative substance content of the drug
will be proportional to the content of active substances. The custom of selecting indicative
substances of a drug from the class of substances to which the active principle is
assumed to belong has often led to disappointments. Worldwide endeavours to isolate
and discover the chemical nature of the active substances in such drugs have
necessitated the replacement of the previously chosen indicative substances by other
substances. Striking examples of this are camomile flowers, valerian roots and hawthorn
Whereas the present opinion is that the cardioactivity of Crataegus preparations is
principally attributable to procyanidines, DAB8 permits the identity of the drug to be
checked using thin-layer chromatography via chlorogenic acid and flavonoids
(comparative substances: chlorogenic acid and rutin); the flavonoids are determined with
the prescribed content determination and calculated as hyperoside.
Figure 6.1 shows a chromatogram of the flavonoid fractions of various species of
Crataegus. The chromatogram was developed with a running solvent which differs from
that given in DAB 8. The illustration was taken from the thesis by Adelheid E. Hecker-
Niediek, Marburg, 1983.
SUBSTANCES Indicative substances for identification
Thin layer chromatography is a simple and reliable aid for supporting the
macro- and microscopic identification of a plant drug/drug plant and also for identification
of an extract and of any medicinal dosage forms which may be prepared from it. If no
tested, authentic drug plant or extract material is
available, indicative substances are also chromatographed. They can be selected from
among the constituent substances of the drug plant, irrespective of whether these are
active or accompanying substances. They should however be characteristic of the drug
plant under investigation and easily demonstrable. Analytical data other than those
obtained by thin layer chromatography can also be used for identification and quality
assurance. The total nitrogen content or a qualitative amino acid analysis can, for
exarnple, be used for Urticae herba or other drug plants.
However, it is not sufficient to demand that identically coloured zones or spots from the
investigated solution appear in the chromatogram at the level of the indicative
substances. Rather, the colour and R, value of the zones appearing in addition to the
indicative substance spots must be described.
It is interesting that DAB 8 permits the use of so-called external indicative substances
which are not contained in the drug plant itself. "Arnica flowers, DAB 8' may be quoted as
an example. A comparative solution of rutin in methanol is also applied to the thin layer
plate in addition to the solution under investigation which is prepared by extraction of the
drug powder with methanol. This flavonoid (rutin), which does not occur in Arnica flowers,
is used to recognize any possible adulteration by marigold (Calendula) flowers, as it is

"No zones with a yellowish to green colour should appear in the chromatogram of
the investigated solution at the same level or below the zone in the chromatogram
of the comparative solution.' Indicative substances for content determination
Only those substances which actually occur in the material being evaluated can be
considered in the selection of indicative substances for quantitat
aluation of a drug plant material or of a product prepared from this. An "external'
indicative substance cannot be used.
The choice of the indicative substance is also governed by the probicin question.
The quantitative determination of any substance regularly occurring in the drug
plant for ensuring the constant action of the drug or 01 2 preparations is
meaningless if this substance cannot be demonstrated to be the active principle. It
can, however, be meaningful if it is carried out Campie, on an extract which occurs
up to a certain percentage in a tablet preparation, as the extract content in the
ready-to-use preparation can be ascertained via determination of the indicative
substance. In such cases the choice of the indicative substances is made on an
analytical basis, 1.e. they must be easy to isolate and to determine exactly in small
quantities without great effort and expense. Indicative substances for stability testing
The shelf life or the stability limits of plant drugs and their products containing active
substances which cannot or cannot yet be detected and determined chemically or
biologically also cannot be determined. The use of indicative substances as a substitute
for the unknown active substance can be regarded as justified insofar as, by definition,
no one substance or group of substances but the whole range of extractable constituent
substances is considered to be responsible for the action of phytopharmaceuticals.
Difficulties occur in the selection of the indicative substance. The multiplicity of
constituents, their qualitative and quantitative differences through the growing period and
the numerous influences, e.g. time of harvesting, further processing of the drug plant
material, etc., make the demand that the most labile compound must always be chosen
as the indicative substance for testing of stability hardly logical. Furthermore, each type
of preparation requires its own choice of indicative substance, as its lability differs greatly
under various environmental conditions. A compound susceptible to hydrolysis would not
be a suitable indicative substance in dry preparations. The same applies to substances
sensitive to oxidation or to light. In this situation it seems more logical to check
phytopharmaceutical preparations and their precursors both organoleptically for taste,
smell and appearance and chemically and physically for any alterations at regular
intervals during storage.

Determination of the density, refract preparations and especially the comme fresh
material with those prepared upon con
cal ra
It can be stated in conclusion th more indicative substances permits no a the
activity when the active principle taken not to interpret every in
Hon of the density, refractive index and alcohol content of liquid and especially the
comparison of thin layer chromatograms of with those prepared upon completion
of manufacture of the
provide definite indications of the stability limits. e stated in conclusion that
quantitative determination of one or Icative substances permits no definitive
statement on the stability of ty when the active principle is not known. Care should
therefore be O to interpret every little alteration as a serious instability.
6.3. Regulation
MC adjustment of phytopharmaceutical preparations to a certain active Substance
content, known as regulation, can easily be carried out in liquid preparations such
as fluid extracts, tinctures, etc., by further cautious Poduct conserving
concentration or by dilution with the menstruum. Dried extracts should be adjusted
as described under Section
Un certain cases the active constituents are enriched by removal of so-called
ballast substances. The active substances can also be concentrated by extraction
methods other than the usual ones, such as, for example, extraction with
supercritical gases (see Section 4.2.4). However, it must not be forgotten that we
are constantly concerned here with the manufacture of phytopharmaceutical
preparations, the demands for the quality of -which are not based solely on the
exactly determinable active substance content (see Section 1.1. Hefendehl and
Lander (6.12) emphasized that the extract or the tincture is regarded as the active
component of a medicine designated as a pharmaceutical preparation, not an
individual substarice contained in it. One
must therefore proceed in such a way in any regulatory adjustment, irrespective of
whether it is concentration or dilution, that the original ratio of active substances
to accompanying substances of the same drug plant material is preserved within
acceptable limits.
Although the regulatory adjustment of dried extracts ultimately depends on the selection
of drug materials of higher content (in the following called strong or stronger) and lower
content (in the following called weak or weaker) drugs, possibilities are discussed here
for the adjustment to the required content at various stages of preparation. (1) Drug
materials of various content are mixed as already described in Section 6.1 in a ratio which,
depending on their contents, results in an endproduct with the required content when they
are extracted together. This
method is difficult and is rarely used in practice. (2) Each part of a drug plant is extracted
by a fixed method. This produces extracts of differing contents. The mixture ratio for two
or more components can be determined by the rules of mixture calculation (S. Meyer,
Grosser Rechenduden (Handbook of Calculation), Bibliographisches Institut, Mannheim,

Extract A has an alkaloid content of 1.55%. Extract B has an alkaloid content of
The adjusted extract shall have a total alkaloid content of 1.30-1970 calculated as
hyoscyamine. Extract A is therefore too strong. The mixture ratio calculation is
shown in Table 6.1.
It should be noted that mixing of the two extracts must result homogeneous
product, which can only be satisfactorily achieved when the starting-extracts have
approximately the same particle-size ranges: (P) inhomogeneities can be
prevented by mixing extracts of different Content when the extracts are still in
liquid form. The outlay of analytical apparatus and materials is very much greater
here, as not only the active substance contents of both of the liquid extracts, but
also their total quantities which are to be processed and their dry residues with
respect to residual moisture, have to be determined. The calculation is then made
as described in Section, where x signifies not the quantity of inert adjuvant
substance which is to be added but the quantity of weaker extract

en is to be used. This method would be too cumbersome in practical

industrial preparation.
6.4. Physical quality assurance
Quality assurance of phytopharmaceutical products has so far been disSUSSed
solely from the chemical and physiological points of view. The Physical quality
however plays an equally important role for the manufacturer and processor of
plant extracts. Without the addition of suitable adjuvant substances many plant
extracts occur in a form which makes further processing considerably more
difficult, often even impossible. Hence extracts of Crataegus fruits, Curcuma
extracts and many others cannot be processed to more manageable dry products
either by roller, belt or spray drying. One particular example is the male fern extract
already mentioned in Section, which is produced as a solvent-free thin
extract. In all such cases the manufacturer cannot handle this without considerable
additions of inert adjuvant substances. Before drying, therefore, a proportion of
Aerosil, lactose, maltodextrin, glucose syrup or starch constituting up to 50% of
the end-product is added to such plant extracts. As the ratio of active substances
to accompanying plant substances remains unaltered here, the manufacturer has
only to declare the measures he has taken, for example as follows:
*100 g of the preparation contains 45-55 g of Extractum ..., corresponding to 5g of
active substance group XY (e.g. total alkaloids. glycosides and others), calculated
as Y. Maize starch was used as excipient.'
6.5. Quality assurance by cultivation and breeding Although medicinal plant
cultivation and breeding are not in the province of pharmaceutical technology, we
mention here a development which may well have a great influence on the use of
phytopharmaceuticals as useful medicines.
The two alternatives of gathering wild medicinal plants and cultivating them have already
been mentioned in Section 2.1.2. For various reasons the cultivation of medicinal plants
will become increasingly dominant in the future. C. Franz (6.8] cites a number of these
reasons: (1) The fact that many medicinal substances of natural origin cannot
be synthesized, or can be synthesized only with unacceptably great effort, necessitates
creation of the natural starting-material, i.e. cultivation of the medicinal plant.
(2) The unreliability of supply of drug plants gathered from the wild
349 shows the need for their cultivation. The quantities available in the often widely
scattered gathering areas are limited. Expert collectors are becoming increasingly
difficult to find. All this results in the increasing occurrence of mistaken identity
and adulteration of
drug plant materials. (3)
The increased demands for safety of medicines in general have also led to
increasing demands for purity and quality of phytopharma-. ceuticals and of the
drug plant materials from which they are obtained. The fundamentally
heterogeneous composition of wild gathered medicinal plants does not meet the
demands for consis
tent and reproducible quality. (4)
Legal regulations such as the 1973 Washington Protection of Species Agreement and the
more recent 1980 West German Nature Protection Order will considerably hinder the
trade and processing of wild plants.
Franz draws the conclusion that not only should cultivation of medicinal plants be
intensified and renewed but also much more consideration should be given to the
factors affecting the quality of the product. Medicinal plants must be cultivated with
phytochemical aspects in view, as the success of such cultivation depends less on
the quantity of plants produced and much more on their quality. The active
substance content of a cultivated medicinal plant can be affected by various
factors: (a) Genetic variation and hereditary transmission of the secondary sub
stances, (b) Morpho- and ontogenetic variability, i.e. differences in the active
substance contents in various parts of the plant and during its growth, (C)
Environmental influences (location, fertilization).
Agricultural methods are now available which permit the grower to produce high quality
drug plants relatively quickly in large quantities. The reader is referred to Refs 6.9 and
6.10 for further considerations.
6.6. Stabilization and stability
The stabilization of a phytopharmaceutical preparation consists of measures. which
guarantee its keeping quality or stability. Stability means the unaltered state of the product
under customary or precisely defined storage ane transport conditions. Alterations which
reduce the quality and shelf-life ca he as a physical, chemical or microbial nature. They
can therefore be detecte
arininal state organoleptically (= sensorily):

Eddrugs should be put in a quarantine store, where they should remain until the
quality assurance laboratory releases them for 10
Store, like any other store, should be constructed so that no detrimental alterations
can occur to the produce during storage. Aargau
101 and suitable storage conditions must be ensured. Bundles of drug plants
which have become damp must be quickly dried out to prevent B of moulds.
Unchecked transfer from the quarantine store to the factory must be made
The goods inward' check extends to a series of pharmacognostic, physical
chemical and possibly biological and microbiological investigations, 1.C (1) Macro-
and microscopic examination for identity. (2) rossible thin-layer chromatographic
examination for identity.
Examination for foreign inorganic and organic impurities. Determination of drying
loss and water content.
Determination of ash. (6)
Determination of crude fibre. (7) Determination of extractable components.
Determination of the active substance(s) (insofar as they are known). (9)
Determination of microbial contamination and of the absence of
pathogenic bacteria. (10) Examination for pesticide residues. heavy metals.
(3) Sampling
All these assays require statistically trustworthy sampling. USP XX gives the following
directions for this. (a) It is recommended that samples of plant drug materials in powdered
or crushed form (or plant drug materials which in their natural state already exist as small
components, e.g. Umbelliferae fruits) which are available in large quantities, and the
components of which have a diameter of not more than I cm, should be taken with a
sampler which is pushed down from the top to the bottom of the container. It the total
weight of the amount of drug
material under investigation is less than 100 kg, at least two samples must be taken at
different points. At least 250 g must be taken in this way (if the total quantity of drug
material under examination comes from numerous containers, the number of containers
to be tested is shown in Table 2.13).
If the total weight is more than 100 kg, more samples should be taken by the method
described above, mixed and quartered. Remove two diagonally opposed quarters. They
will not be used for the analysis. The two remaining quarters are again mixed and
quartered repeatedly until two of these quarters