Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril

McInnes, F.J. and Anthony, N.G. and Kennedy, Alan R. and Wheate, Nial J. (2010) Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril. Organic and Biomolecular Chemistry, 8 (4). pp. 765-773. ISSN 1477-0520

Abstract

The inclusion of the cardiovascular -blocker drug atenolol, the antidiabetic drug glibenclamide, the Alzheimer's NMDA glutamate receptor drug memantine and the analgesic/antipyretic drug paracetamol by cucurbit[7]uril (CB[7]) has been studied by 1H nuclear magnetic resonance spectroscopy, electrospray ionisation mass spectrometry, molecular modelling, fluorescence displacement assays and differential scanning calorimetry. All four drugs form 1:1 host-guest complexes with CB[7], but the exchange kinetics and location of the binding is different for each drug. Atenolol is bound over the central phenyl ring with a binding constant of 4.2 × 104 M-1, whereas glibenclamide is bound over the terminal cyclohexyl group with a binding constant of 1.7 × 105 M-1, and memantine is totally bound within the CB[7] cavity. Paracetamol is bound in two locations, over the central phenyl ring and over the methyl group, with the CB[7] molecule shuttling quickly between the two sites. Inclusion by CB[7] was shown by differential scanning calorimetry to physically stabilise all four drugs, which has applications preventing drug degradation and improving drug processing and formulation.

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