Abstract
Crystal engineering has advanced the strategies for design and synthesis of organic solids with the main focus being on customising the properties of the materials. Research in this area has a significant impact on large-scale manufacturing, as industrial processes may lead to the deterioration of such properties due to stress-induced transformations and breakage. In this work, we investigate the mechanical properties of structurally related labile multicomponent solids of carbamazepine (CBZ), namely the dihydrate (CBZ·2H2O), a cocrystal of CBZ with 1,4-benzoquinone (2CBZ·BZQ) and the solvates with formamide and 1,4-dioxane (CBZ·FORM and 2CBZ·DIOX, respectively). The effect of factors that are external (e.g. impact stressing) and/or internal (e.g. phase transformations and thermal motion) to the crystals are evaluated. In comparison to the other CBZ multicomponent crystal forms, CBZ·2H2O crystals tolerate less stress and are more susceptible to breakage. It is shown that this poor resistance to fracture may be a consequence of the packing of CBZ molecules and the orientation of the principal molecular axes in the structure relative to the cleavage plane. It is concluded, however, that the CBZ lattice alone is not accountable for the formation of cracks in the crystals of CBZ·2H2O. The strength and the temperature-dependence of electrostatic interactions, such as hydrogen bonds between CBZ and coformer, appear to influence the levels of stress to which the crystals are subjected that lead to fracture. Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy. Structural defects within the crystal lattice, although highly influenced by the crystallisation conditions and which are especially difficult to control in organic solids, may also affect breakage.
Highlights
Our findings show that the appropriate selection of coformer in multicomponent crystal forms, targetting superior mechanical properties, needs to account for the intrinsic stress generated by molecular vibrations and not solely by crystal anisotropy
The case of CBZ$2H2O illustrates the effect of crystal anisotropy on the structural properties of organic solids resulting from mechanically-induced stress and stress resulting from dehydration
A comparison of CBZ$2H2O with 2CBZ$BZQ, CBZ$FORM and 2CBZ$DIOX, has shown that the source and the magnitude of tensile stresses acting on the’ weak planes of the crystals must be considered in determining the likelihood of breakage. This is part of the explanation as to why the dihydrate is more prone to the formation of cracks, it is structurally similar to the other crystal forms
Summary
Development of medicines: (i) the solid form diversity and (ii) the particle/surface properties of the materials.[2,6,7,8,9,10] While solid form diversity (e.g. polymorphism, hydrate/solvate formation) is extensively investigated, less attention is given to examining the possible variation in crystal surface characteristics and its impact on downstream processing.[11]. In this work we present a study of the breakage tendency of carbamazepine dihydrate (CBZ$2H2O) crystals and provide a possible explanation as to why the crystals have relatively poor mechanical properties and readily crumble into ne debris. This was previously observed in a study that involved the smallscale crystallisation of CBZ$2H2O.44. The current investigation presents a comparison of CBZ$2H2O with the cocrystal of CBZ with 1,4-benzoquinone (2CBZ$BZQ) and with the solvates of CBZ with formamide and 1,4-dioxane (CBZ$FORM and 2CBZ$DIOX, respectively) All these crystal forms are structurally related and present similar low index crystallographic planes of high atomic density (Fig. 2). We discuss the factors that contribute to the superior mechanical properties of 2CBZ$BZQ, CBZ$FORM and 2CBZ$DIOX in relation to CBZ$2H2O.§
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