Biomedical Engineering Reference
In-Depth Information
5.1 INTRODUCTION
The proportion of drugs marketed as individual stereoisomers has rocketed over the last decade,
a fact that reinforces the importance of the link between chirality and drug design and develop-
ment. In this chapter, the reasons for this newfound focus in the marketing of chiral drugs will be
discussed. First, in this chapter a brief overview of the fundamental principles of stereochemistry
will be given. We will then focus on the underlying reasons why individual stereoisomers may have
different pharmacological activities. The major challenges in bringing chiral drugs to market are in
the production of single stereoisomers on a large scale and in i nding methods to assess their purity.
Therefore, the i nal sections of this chapter concentrate on these two important aspects.
5.2 WHAT IS CHIRALITY?
Isomers are compounds with the same molecular formula but with a different arrangements of the
atoms. Of the different types of isomers, optical isomers will be the focus of this chapter. A mol-
ecule is chiral when it cannot be superimposed upon its mirror image. Hence, a compound and its
nonsuperimposable mirror image are two different isomers termed enantiomers. Optical isomer-
ism is a result of this different spatial arrangements of atoms in a molecule. The lack of symmetry
can arise from four different substitutions around a tetrahedral carbon atom (stereogenic center),
although atoms such as phosphorous may also act as stereogenic centers. For example, lactic acid
has a stereogenic center and therefore can exist in two enantiomeric forms. However, propanoic acid
possesses a symmetry plane and so is achiral (i.e., the molecule can be superimposed on its mirror
image) (Figure 5.1). Enantiomers are identical except for two properties: their optical activity and
the way in which they interact with other chiral molecules. The optical activity of an enantiomer is
the ability to rotate the plane of polarized light (i.e., light that oscillates in a single plane). A 50:50
mixture of two enantiomers is called a racemic mixture and its optical rotation is zero. The degree
of rotation caused by a single enantiomer is measured using a polarimeter. If a molecule rotates
plane polarized light anticlockwise it is labeled as
laevorotatory
, abbreviated “l” or (−), or if it is
clockwise it is called
dextrorotatory
, “d” or (+).
Specii c rotation is an intrinsic property of an optically active molecule that can be used to
quantify the amount and purity of a single enantiomer. This value is dependent on the wavelength
of light used, the length of the sample tube through which the light is passed, temperature, solvent,
and sample concentration. The light source most often used for such determinations is that emit-
ted by a sodium lamp at 589 nm (the so-called D line). In order to compare data, these parameters
should be specii ed when quoting the specii c rotation, [a]
D
. Optical purity (usually expressed as a
percentage) can be dei ned as the ratio of the specii c optical rotation of the enantiomeric mixture
and the specii c optical rotation of the pure enantiomer.
The observed optical rotation (d or l) was the earliest method of distinguishing between
enantiomers, but this method gives no indication as to the actual spatial geometry of a molecule
Mirror plane
Central carbon atom
is the stereogenic center
H
H
H
H
H
HO
OH
CH
3
H
3
C
CO
2
H
2
C
H
H
CO
2
H
Propanoic acid—has a plane
of symmetry
The two enantiomers of lactic acid
FIGURE 5.1
The two enantiomers of lactic acid are mirror images of each other. However, propanoic acid is
achiral as it has a plane of symmetry through the center of the molecule.
