Alvimopan is a drug compound which is known to act as a peripheral μ-opioid antagonist. The U.S. Food and Drug Administration (FDA) approved the drug for use in May 2008 as an aid to restoration of bowel function following surgery. Adolor Corporation and GlaxoSmithKline are collaborating on the development and marketing of the drug as Entereg. The crystal structure of Alvimopan is not currently publically available, but one can analyse the most likely hydrogen-bonding patterns to occur in the solid state based on the chemical structure (shown below). Alvimopan has four potential hydrogen-bonding functional groups, these are; carboxylate, carboxamide, phenol and protonated tertiary amino. The Solid Form module (Macrae et al. 2008) provides tools to determine which interactions are most likely to occur out of all the possible interaction pairs within this list.
The Motif tool in the Solid Form module was used to search the Cambridge Structural Database (CSD, Allen et al. 2002) and retrieve frequencies of occurrence for each interaction pair that could occur between these four functional groups. The frequency of occurrence in this case refers to the number of structures in which an interaction does occur as a percentage of the number of structures in which the interaction could occur. It can be seen from the table of hydrogen-bond frequencies of occurrence (below) that the most likely interaction is the charge-assisted carboxylate to amino hydrogen-bond. The next most likely contact is very difficult to predict, however, with the four interactions between the carboxamide and phenol donors and the carboxylate and carboxamide acceptors having high probabilities. Based on these figures, it is very difficult to predict which acceptors the carboxamide and phenol groups will interact with and there is a reasonable chance that this fine balance may be mirrored in the solid state behaviour of the compound. There may, for example, be multiple forms which exhibit different hydrogen-bonding patterns. We can also see, from the table, that there are a number of interactions that are not likely to occur (hydrogen bonds from the amino group to the carboxamide and phenol groups for example) and if these were observed in a solid form it may provide cause for concern about stability.
To further investigate the competition effects of the functional group, the CSD has been searched for structures containing one chemical component that exhibits only these strong hydrogen-bonding groups; carboxylate, carboxamide, alcohol and protonated tertiary amino groups. There are two structures that satisfy these criteria, these are CSD refcodes QILHIO & YUCSOE. Interestingly each of these structures exhibits a different network of hydrogen bonds (see figure below), which highlights the fine balance between these hydrogen-bonding interactions.
Another example of a drug compound with potential conflict between the hydrogen-bonding groups is Indomethacin (see chemical structure below), a non-steroidal anti-inflammatory drug with four functional groups of interest; carboxylic acid, carboxamide, methoxy and chlorophenyl groups. In this case the likelihood of forming a hydrogen bond from the carboxylic acid to the carboxamide is roughly the same as that of the carboxylic acid with itself (the homo-interaction).
The crystal structure of Indomethacin was first published by Kistenmacher & Marsh (1972) and this structure has a carboxylic acid dimer interaction around a crystallographic inversion centre. The high possibility for the carboxylic acid to carboxamide interaction to occur clearly makes this a good candidate for polymorphism and it turns out that there is another polymorph (Chen et al. 2002). This second polymorph contains both the carboxylic acid dimer and the carboxylic acid to carboxamide interaction in a Z'=3 crystal structure. The high Z' polymorph is thermodynamically less stable, but it can appear at higher relative humidities (Andronis et al. 1997) and thus could be a problem for the processing and marketing of a drug form.
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- Chen, X., Morris, K. R., Griesser, U. J., Byrn, S. R., Stowell, J. G. (2002). J. Am. Chem. Soc., 124, 15012-15019.
- Kistenmacher, T. J., Marsh, R. E. (1972). J. Am. Chem. Soc., 94, 1340-1345.
- Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst., 41, 466-470.