Principles and Practice of Pharmaceutical Medicine

then an anhydrous environment is needed for pro-
duct stability. This is most easily achieved as a
lyophilized powder in an evacuated and sealed
glass vial. This can be reconstituted with water or
saline immediately prior to injection. Lyophili-
zates in stoppered vials can also be subjected to
gamma irradiation to ensure sterility. Stability stu-
dies should include not only the range of tempera-
tures and humidities (see below) but also with the
vials inverted.
Rarely, adverse events are reported when an
apparently innocuous formulation is administered
via wrong route. Usually, these problems arise
because of excipients that the typical physician
takes little interest in. As one example, intravenous
remifentanil is formulated with glycine, and hence
it is not well suited for intrathecal administration.
The intravenous administration of liquid enteral diets
is occasionally achieved in spite of all precautions with
non-Luer equipped tubing and prominent labeling;
profound metabolic acidosis is the result.
The development of an injectate is often one
tactic used for obtaining a patent. Even though a
composition of matter patent (i.e. the structure of
the drug molecule itself) may be old, the develop-
ment of a nonobvious injectate and its method of
use for a new indication, may be sufficient to obtain
a further patent and thus extend effective proprie-
tary coverage. Such patents are usually stronger in
North American than in European jurisdictions.

Packaging

The selection of an inert package is an essential
part of the pharmaceutical development of a drug.
There are many standard stoppers, plastic and glass
bottles, and so on with which regulatory authorities
arevery familiar and for which drug master files are
already in place. Stability studies must be con-
ducted, of course, in the same sorts of packaging.
Packaging, nonetheless, degrades, and over a
period of months or years an apparently imper-
vious material may permit the ingress of water.
Foil wraps are generally available for all tablets
and are usually the most impervious of all materi-
als; however, these can be inconvenient for patients
with arthritis. PVC blister packs are at the other end

of the spectrum: Padfield (1985) has provided one

example where a 0.8% increase in tablet weight

within a PVC package occurred within 12 weeks.

Drugs, both investigational and prescription, are

today transported over great distances. Airlines

often advertise their cargo holds as pressurized

and temperature controlled, but even so require

special arrangements for the conveyance of live-

stock. The potential for condensation during

unloading at a humid airport, or degradation

because the pallet sat for several hours on the

unshaded tarmac in Dakkar, is great.

5.5 Stability testing

Stability testing of drugs is its own subspecialty.

In brief, it is the research pharmacist’s duty to

stress test drugs in storage using factorial combina-

tions of

low and high temperatures;

low and high humidity;

exceeding the labeled drug shelf life;

in contact with all feasible components of the

packaging (e.g. both the glass and the stopper of

a vial, the latter by inverted storage);

exposure to bright and subdued light (in some

case clear and amber glass bottles).

It is these data that justify approval and contin-

ued marketing of a drug that complies with

the ‘quality’ criterion of the oft-quoted triad

‘safety, efficacy, quality’. This is usually not a

trivial exercise.

5.6 Innovation in pharmaceutics

Innovation has always been a very visible activity

in pharmaceutics. As noted above, we very rarely

administer powders out of paper cones today.

Particular drugs have driven innovation, even

though the new formations later find broader use.

5.6 INNOVATION IN PHARMACEUTICS 59