Discovery and Formulation - Emerging Raman Applications and Techniques in Biomedical and Pharmaceutical Fields - page 212

chemistry coupled with X-ray crystallography and comparative molecular field
analysis (CoMFA) has been used to establish quantitative structure-activity
relationships (QSARs). However, limitations due to diculties in accurately
modelling molecular shape and charge have restricted its application.
Raman spectra can provide a complementary approach by providing a
three-dimensional molecular descriptor as a starting point for SARs eval-
uation [7]. Trending of band frequencies and intensity can help establish
structure-activity properties. There are many barriers for completing trend-
ing using the direct experimental approach. For example Raman analysis in
the presence of proteins is dicult due to a number of factors including matrix
effects, limited sensitivity, selectivity, spectral complexity and noise. There-
fore a two-step approach has been adopted that uses the Raman frequency
and intensity trends obtained from pure materials and correlating these to in-
dependent chemical/biological assays. Where these can be related to bioassay
binding anity values an insight into structural and electronic properties of
the chemical series can be obtained. This information can be used to indicate
molecular motifs that can enhance binding activity and hence improve the po-
tency of the drug candidate. This information is a key to the drug discovery
process. Pivonka has demonstrated the value of this approach by correlating
Raman shifts to the binding activity of isoflavone, coumarin and benzoxazole
within a human oestrogen receptor (ER- ) [8]. By identifying Raman spectral

shifts, he concluded that bonding activity was strongly influenced by electron
density of the pi-bonding system of the backbone scaffold for each series. By
relating the physical electronic state of molecular subcomponents within a
compound series involved in binding kinetics it was possible to identify and
optimise binding activity and potency.
The unique potential of Raman has also been used to establish SARS us-
ing an acyclic amide series [9]. Raman spectra were collected directly from
a naphthyl ring containing series of compounds, and trends in the band fre-
quency shifts of the nitrile vibration were observed. It was determined that
an increase in potency of this series could be correlated to a decrease in the
nitrile frequency. This was related to inductive effects resulting from variant
substitution on the naphthyl ring. Therefore the ring substitution enhanced
the electron density of the naphthyl aromatic system, increasing potency. This
type of information is critical for the discovery chemist and allows proactive
targeted structural molecule development to optimise potency and deliver a
compound suitable for commercialisation.

β

9.2 Selection and Characterisation of API
Form (Development)

When a compound moves from discovery into development it is critical that
the drug candidate's molecular properties are optimised in terms of bioavail-
ability (solubility), stability, processability, hygroscopicity, etc. The compound