PHARMACOLOGY
only the ability to reach said concentration that is impor-
tant, but the duration of time that the concentration can be
achieved). mulations. The same can be said if a different form of
the active (e.g. different salt, different size of molec-
ular, different polymorph, different isomer) is in use.
As one can see, since the drug concentration at the recep-
tor site is important, and that the drug pharmacokinetics
determines the drug concentration in the body, these the
two process must interact to produce a drug effect. More
importantly this principle states that if two drugs achieve the
same concentration in the plasma, they should be equally
as effective. As a given rule, no two formulations are identical un-
til proven i.e. simply being told that formulation has
the same active as another product is not sufficient to
assume efficacy. This would need to be proven with
validate methodology such as bioequivalence testing.
Another important factor to be consider is the po-
tential for the inactive and active to interact with one
another with resultant inactivation, or change in tab-
letting pressure that precludes the release of the ac-
tive ingredient in the same period of time, or even the
incorrect pH which can cause pain and tissue damage
on administration.
The formulation
Medication that are sold commercially, are sold as a mixture
of ingredients that all interact to allow the said drug to have
its effect. The formulation is there to ensure that the drug
is adequately absorbed into the circulation and it can also
control the rate of absorption. To place this into perspec-
tive, the formulation controls the time to a drug’s first effect,
the degree of effect and thus the degree of side effects. The
formulation has a number of potential components, which
all fulfil different roles in allowing the active ingredient to be
absorbed, as well as the shelf-life of the drug (Table 1).
Another important feature of the formulation is the actual
chemical properties of the active ingredient, which also has
an impact on drug absorption, chemical stability, interaction
with excipients and at times even activity. For the latter it's’
important to note that the active ingredient can also occur
in different forms (e.g. amorphous versus crystalline) with
some chemical forms being ineffective. The same can apply
for chirals (L and D Isomers) with some isomers being inac-
tive, more act ive or even toxic (e.g. dexmedetomidine is the
active chiral of medetomidine).
Since we know that the formulation effect is extreme-
ly important, drug manufacturers have to ensure that
their formulations are as uniform as possible. Most try
and keep their drugs within a 5% variation of the ex-
pected from batch to batch (e.g a 5mg tablet may have
4.75 to 5.25 mg therein), which is lower than natural
variation which can be as high as 10%. This process
of control is known as Good Manufacturing Practice
(GMP), and involves standardising as many factors as
possible, from how the chemicals are sourced to how
the equipment is handled, serviced and calibrated. It
expects the manufacturer to undertake routine assays
of their formulation at various steps in manufacture as
well to ensure that staff are adequately trained.
From numerous pharmaceutical studies, we know that a
change in the excipients or a change in the ratio of ingredi-
ents can result in different absorption profiles between for- Other important aspects include the source and pu-
rity of the chemicals in use e.g. what's the purity, is
it free of endotoxins, it is free of contaminants, it is
free of bacteria, etc. While this process does add to
the costs of production, it is well known that without
these control measures the variation in the formula-
tion can result in unpredictable variations in plasma
concentrations, which could translate to ineffective
treatment, treatment being toxic or even inconsistent
treatment where one dose works and another fails.
Figure 1 Figure 2: Interaction of the formulation effect, pharmacokinet-
ics and pharmacodynamics of the drug. The figure shows the
importance of the formulation in controlling the subsequent
pharmacokinetic profile of the drug and its effect concentration
achieved at the biophase. PK=Pharmacokinetics. PD= Pharma-
codynamics.
In the formulation, the actives and inactives will interact with
one another to control absorption (Figure 2).
Issue 03 | JUNE 2017 | 17