Evaluation of Host/Guest Cyclodextrin Complex by NMR in Drug Product Development
Pp. 156-183 (28)
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.
Drug development, heparin, cyclodextrin, progesterone, diclofenac, NMR.
R&D Pharma Department, IBSA Institut Biochimique SA –Via al Ponte 13-6903 Lugano 3 (CH), Switzerland.