5.2 The constituents
of a medicine‘A drug is not a drug is not a drug’ because, when
administered to a human being, in the general case,
it contains
active compound at a dose that is precise and
within a limited tolerance (sometimes as a
racemate);
manufacturing impurities;
one or more excipients;
degradants of the active compound;
degradants of the impurities;
degradants of the excipients.
Impurities
An impurity is defined as a compound which is the
by-product of the manufacturing process used for
the active compound that has not been removed
prior to formulation. Impurities can have their own
toxic potential, and control of impurity content is
therefore a highly important feature in any NDA.
Excipients
Anexcipientis defined as a material that is delib-
erately incorporated into the formulation to aid
some physicochemical process, for example for a
tablet, integrity, dissolution, bioavailability or
taste; excipients are typically chosen from among
many compounds without pharmacological prop-
erties (e.g. lactose), although there are examples
where pharmacokinetics change with the excipient
used. There are specialized examples of excipients,
for examplepropellantsare excipients that assist in
the delivery of inhaled drugs to the respiratory
tract. For intravenous infusions or ophthalmic pro-
ducts, the excipients are usually pH buffers or
preservatives, and for dermatological products,
they may include emollients and solvents.Degradants
Adegradantis defined as a compound that cumu-
lates during the storage of bulk drug or finished
formulation. For example, the vinegar-like odor of
old aspirin tablets is due to acetic acid, which is a
degradant due to hydrolysis of acetylsalicylate,
which is an ester.Formulation-associated intolerability
Many tablets carry printed identification markings
or are color coated; dyestuffs are special excipi-
ents, and allergies to them have been documented.
Formulations also have more subtle, but nonethe-
less differential characteristics such as whether the
tablet was compressed at a higher or lower pres-
sure. Lastly, differential efficacy exists among dif-
ferently colored placebos, and this should therefore
also be expected for active formulations.
Impurities and degradants may possess their
own toxicological properties. Early in develop-
ment, the structures of these impurities and degra-
dants may be poorly characterized. Typically, both
bulk drug and finished product become more
refined as clinical development progresses. Thus,
in order to preclude any new toxicology problems
developing later during clinical development, it is
common practice to use theless purebulk drug for
toxicology studies. This is commonly accom-
plished by using drug removed from the production
process before the last step, for example before the
last recrystallization. This usually guarantees that a
lower purity, that is mixture with greater molecular
diversity than the drug of interest, will be tested
toxicologically than that to which patients will
actually be exposed.
The evasion of formulation and toxicological
testing by ‘herbal medicine’ manufacturers is com-
pletely illogical in this context. For example, the
Butterbur (or Bog Rhubarb;Petasites hybridus)
contains well-characterized carcinogens. Butter-
bur extract tablets are sold as chronic oral therapies52 CH5 PHARMACEUTICS