**6. References**

86 Current Trends in X-Ray Crystallography

approximately 120°C. At 164ºC melting and decomposition take place. TGA for forms α and β reveals that there is no mass loss before 120°C, confirming the absence of water in both

The new 1:1:1.25 hydrate has shown to be as stable on shelf as form α for eighteen months and water slurry experiments revealed that it as a thermodynamically stable form. It has also shown to have a similar dissolution profile (Figure 22) as the commercially available

A probable reason for this is the enhanced stability provided by the presence of the water molecules linking the erbumine-perindopril double chains. Analysis of crystal structure has again proven to be quite important for the establishment of the intermolecular interactions responsible for the supramolecular arrangement and thus the physicochemical properties of

Over the last two decades crystal engineering, a key tool for the design of new crystal forms, has made possible the synthesis of novel pharmaceutical materials as well as molecular level control of crystallization and phase transformations. Advances in crystal engineering and supramolecular chemistry invite us to consider new perspectives and perhaps definitions of the various solid-state forms that the same and/or different molecules may adopt in terms

Pharmaceutical co-crystals have proven to offer potential benefits of superior efficacy, solubility and stability in drug formulation. It seems reasonable to assert that co-crystal approaches should be considered routinely as part of a broader set of form and formulation explorations to achieve the best possible drug products. Although the interest in co-crystals and polymorphs and their utility is obvious, identifying and implementing an efficient

The authors acknowledge Fundação para a Ciência e a Tecnologia, MCTES, Portugal, for funding the Project POCI/QUI/58791/2004, PEst-OE/QUI/UI0100 /2011, and the Ph.D.

drug and to be slightly more soluble in water than the α form40.

Fig. 22. Dissolution profile for the 1:1:1.25 hydrated form.

these forms.

APIs.

**4. Concluding remarks** 

**5. Acknowledgements** 

Grant SFRH/40474/2007 (V.A.).

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**4** 

*China* 

**Intramolecular N**−**H···X (X = F, Cl, Br, I, and S)** 

Hydrogen bonding (H-bonding) has recently been defined by IUPAC as "an attractive interaction between a hydrogen atom from a molecule or a molecular fragment X–H in which X is more electronegative than H, and an atom or a group of atoms in the same or a different molecule, in which there is evidence of bond formation". In most cases, the strength of an H-bond increases with the increase of the electronegativity value of the acceptor atom (Pauling, 1960). This is exactly the case for oxygen and nitrogen atoms. The H-bonds formed between them and the NH and OH groups are usually strong, which play essential roles in studies in supramolecular, crystal engineering, materials, and life sciences (Scheiner, 1997; Jeffrey,1997). As s result of their growing applications in supramolecular chemistry and crystal engineering, in the past two decades, the critical assessment of the weaker H-bonds has also become an important topic (Desiraju & Steiner, 2001). In this context, organic halogen and sulfur atoms, C-X (X = F, Cl, Br, I, S), have all been demonstrated to be weak H-bonding acceptors (Dunitz & Taylor, 1997), although their electronegativities (Pauling scale: 3.98, 3.16, 2.96, 2.66, and 2.58, respectively) are all higher than that of hydrogen (2.20). Indeed, over years it has been accepted that organic fluorine ''hardly ever accepts hydrogen bonds (Dunitz, 2004),'' presumably due to its low polarizability and tightly contracted lone pairs. For other organic heteroatoms, the increased van der Waals radius and decreased electronegativities may also weaken their capacity of forming the intramolecular electrostatic interaction, i.e., H-bonding, with the amide hydrogen and lose the competition with the amide oxygen of another molecule which forms the intermolecular N−H⋅⋅⋅O=C H-bonding. In contrast, the halogen anions are capable of forming strong intermolecular H-bonding with NH, OH or even CH protons (Harrell &

This chapter summarizes recent progresses in the assessment of the weak intramolecular six- and five-membered H-bonding patterns formed by aromatic amides bearing the above five atoms. Theoretical investigations show that similar intermolecular H-bonding patterns can be formed by fluorine in DNA or RNA base analogues (Frey et al., 2006; Koller et al., 2010; Manjunatha et al., 2010), although they are difficult to be confirmed in solution

McDaniel, 1964; Simonov et al., 1996; Del Bene & Jordan, 2001).

**1. Introduction** 

**Hydrogen Bonding in Aromatic** 

**Amide Derivatives - The X-Ray Crystallographic Investigation** 

*Department of Chemistry, Fudan University, Shanghai* 

Dan-Wei Zhang and Zhan-Ting Li

