Nanoindentation is a technique for measuring the elastic modulus and hardness of small amounts of materials. This method, which has been used extensively for characterizing metallic and inorganic solids, is now being applied to organic and metal-organic crystals, and has also become relevant to the subject of crystal engineering, which is concerned with the design of molecular solids with desired properties and functions. Through nanoindentation it is possible to correlate molecular-level properties such as crystal packing, interaction characteristics, and the inherent anisotropy with micro/macroscopic events such as desolvation, domain coexistence, layer migration, polymorphism, and solid-state reactivity. Recent developments and exciting opportunities in this area are highlighted in this Minireview.

Nanoindentation is applied to the two polymorphs of aspirin to examine and differentiate their interaction anisotropy and shear instability. Aspirin provides an excellent test system for the technique because: (i) polymorphs I and II exhibit structural similarity in two dimensions, thereby facilitating clear examination of the differences in mechanical response in relation to well-defined differences between the two crystal structures; (ii) single crystals of the metastable polymorph II have only recently become accessible; (iii) shear instability has been proposed for II. Different elastic moduli and hardness values determined for the two polymorphs are correlated with their crystal structures, and the interpretation is supported by measured thermal expansion coefficients. The stress-induced transformation of the metastable polymorph II to the stable polymorph I can be brought about rapidly by mechanical milling, and proceeds via a slip mechanism. This work establishes that nanoindentation provides ''signature'' responses for the two aspirin polymorphs, despite their very similar crystal structures. It also demonstrates the value of the technique to quantify stability relationships and phase transformations in molecular crystals, enabling a deeper understanding of polymorphism in the context of crystal engineering.

The nanoindentation technique has been employed to relate the mechanical properties of saccharin single crystals with their internal structure. Indentations were performed on (100) and ( 011) faces to assess the mechanical anisotropy. The load-displacement (P-h) curves indicate significant differences in the nature of the plastic deformation on the two faces. The P-h curves obtained on the (011) plane are smooth, reflecting homogeneous plasticity. However, displacement bursts (pop-ins) are observed in the P-h curves obtained on the (100) plane suggesting a discrete deformation mechanism. Marginal differences exist in the hardness and modulus on the two faces that may, in part, be rationalized, although one notes that saccharin has a largely three-dimensional close-packed structure. The structural origins of the fundamentally different deformation mechanisms on (100) and ( 011) are discussed in terms of the dimensionality of the hydrogen bonding networks. Down the (100) planes, the saccharin dimers are stacked and are stabilized by nonspecific van der Waals interactions mostly between aromatic rings. However, down the (011) planes, the molecules are stabilized by more directional and cross-linked C-H 3 3 3 O hydrogen bonds. This anisotropy in crystal packing and interactions is reflected in the mechanical behavior on these faces. The displacements associated with the pop-ins were found to be integral multiples of the molecule separation distances. Nanoindentation offers an opportunity to compare experimentally, and in a quantitative way, the various intermolecular interactions that are present in a molecular crystal.

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Structural information on the solid forms of efavirenz, a non-nucleoside reverse transcriptase inhibitor, is limited, although various polymorphic forms of this drug have been patented. We report here structural studies of four new crystal formsa pure form, a cyclohexane solvate, and cocrystals with 1,4-cyclohexanedione and 4,4′-bipyridine. Temperature dependent single-crystal to single-crystal phase transitions are observed for the pure form and for the cyclohexane solvate with an increase in the number of symmetry independent molecules, Z′, upon a lowering of temperature. Other issues related to these solid forms, such as thermal stability, conformational flexibility, and high Z′ occurrences, are addressed by using a combined experimental and computational approach.

Nanoindentation studies on α,ω-alkanedicarboxylic acids reveal that the elastic modulus, E, shows an odd-even alternation in exactly the same manner as the melting temperature, Tm. These results are consistent with the hypothesis that the strained molecular conformations in the odd diacids are the reasons for these alternations in Tm. The same packing features that lower Tm in the odd acids lead to easy accommodation of the deformation during nanoindentation and hence their low E.

Thirteen host−guest compounds of 3,5-dihydroxybenzoic acid (DHBA) have been structurally characterized. Water molecules occupy the peripheries of a hexagonal void, created with DHBA molecules, and act as “hooks” to connect the guest molecules with the host-framework via hydrogen bonding. The “water hook” is an OH group acting as a donor. Consequently, the guest molecules were chosen so that they contain good hydrogen bond acceptor functionalities. A number of multicomponent hydrates were isolated with stoichiometries (DHBA) x (H2O) y (guest) z . Of these, compounds with the following as guests were obtained as crystals that were good enough for single crystal work: ethyl acetate (EtOAc), diethyl oxalate, dimethyl oxalate, di(n-propyl) oxalate, diethyl malonate, diethyl succinate, chloroacetonitrile, N,N-dimethyl formamide (DMF), acetone, dimethyl sulfoxide (DMSO), 1-propanol, and 2-butanol. From 2-butanol, a hemihydrate, (DHBA)2(H2O), was also obtained concomitantly. Further to guest stabilization, water acts as a good mediator of effective crystal packing and also determines the topology of the host framework. In the present series of compounds, the role of water is wide ranging, and it is not easy to classify it specifically as a host or as a guest.

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