Structure-Activity Relationship Studies in Drug Development by NMR Spectroscopy

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Drug discovery is still a process which involves screening of a large number of chemical compounds against a defined biological target. However, this approach is now being gradually replaced by more ...
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Evaluation of Host/Guest Cyclodextrin Complex by NMR in Drug Product Development

Pp. 156-183 (28)

Giorgio Zoppetti

Abstract

The application of NMR technology in drug development is generally adopted to describe the structure of a drug substance and its degradation products under standard stressed conditions. As far as drug products are concerned, standard stability conditions are recommended by international health authorities (ICH conditions), while the stability profile of a drug substance can be defined by non-standard protocols. Both proton and carbon NMR spectroscopic technologies are powerful methods for the determination of a drug substance chemical structure and related degradation products. Unconventional use of NMR in drug development is described in this section, namely NMR applications in the development of drugs containing cyclodextrin inclusion complexes. Cyclodextrins (CD) are cyclic oligosaccharides whose lipophilic cavity and hosting capacity make them ideal for forming inclusion complexes with lipophilic drugs. Generally, this complexation involves the inclusion of a ‘guest’ molecule into the cavity of a CD ‘host’ molecule, with no covalent bonding. Inclusion and/or molecular dispersion of a drug in cyclodextrin are made possible by the partitioning of the dissolved drug between the aqueous phase and the hydrophobic cyclodextrin cavity followed by specific molecular interactions, including hydrogen bonding and hydrophobic interactions between the drug and cyclodextrin. Proton NMR is used to confirm the host/guest inclusion by the chemical shift of the cyclodextrin internal protons, which are disturbed by the lipophilic guest. Examples of approved drug products containing cyclodextrins and two detailed case studies involving NMR applications in the development of water soluble diclofenac sodium and progesterone for parenteral use are reported in this article.

Keywords:

Drug development, heparin, cyclodextrin, progesterone, diclofenac, NMR.

Affiliation:

R&D Pharma Department, IBSA Institut Biochimique SA –Via al Ponte 13-6903 Lugano 3 (CH), Switzerland.