Molecular crystals, structural trends

The statistical thermodynamic method discussed here provides a bridge between the molecular crystal structures of Chapter 2 and the macroscopic thermodynamic properties of Chapter 4. It also affords a comprehensive means of correlation and prediction of all of the hydrate equilibrium regions of the phase diagram, without separate prediction schemes for two-, three-, and four-phase regions, inhibition, and so forth as in Chapter 4. However, for a qualitative understanding of trends and an approximation (or a check) of prediction schemes in this chapter, the previous chapter is a valuable tool. 

Cadmium clusters have been treated by Baetzold (47) using EH and CNDO calculations. With atomic valence electron configuration 4dl05s25p, the clusters are calculated to be weakly stable. Linear geometry is more stable than symmetric three-dimensional geometries or even the bulk crystal structure for small Cd clusters. Poor stability is a consequence of the closed atomic 5s shell in Cd. Unstable antisymmetric 5s molecular orbitals are filled in the small clusters, but the amount of bonding by 5p orbitals increases with size. This leads to the trend of increasing stability with size as observed in Table VIII. Compari-... 

The most obvious conclusion from the above (admittedly selective) survey is that solid state reactions are sensitive to the chemical properties of all the constituents and the crystal structure of the reactant. The trends in behavioin discerned, however, provide only limited insights into the factors controlling thermal stability. The observations are difficult to interpret at the levels of molecular, or ionic, interactions and rate determining bond redistributions. More precise, detailed and systematic comparative studies are required to advance understanding of the interface chemistry. 

The overriding conclusion from the extensive data available in the CSD is clear. In order to convince two different discrete chemical species to coexist in a molecular co-crystal there needs to be some specific molecular-recognition based reason for their solid-state union [93]. Although individual structures that defy rationalization will appear from time to time, there is no doubt that the important big picture reveals structural trends, patterns of behavior, and reproducible motifs that, when combined, can be developed into a library of high-yielding supramolecular reactions. 

The crystal structure of (Me4N)2[(l,6-C2B,oHioMe2)2Ti] has been determined. The molecular structure is similar to that found for CPC0C2B10H12, but the Ti—C (2.181,2.468 A) and Ti—B (2.399 A) bonds are much longer than the equivalent ones in the Co species. This complex is the most electron-deficient metallocarbaborane yet investigated, but there are insufficient data as yet to discern any regular trends in molecular parameters of such complexes. 

Quantitative and even qualitative information on impurity incorporation in pharmaceutical crystals is quite limited in the open literature, but the general trends are expected to follow the behaviors described in Chapter 3. Given that the molecular size of most biological compounds are larger than inorganic substances the resulting crystal structures are rather more open and better able to accommodate interstitial impurities including solvent. 

The arguments just provided detail the potential issues around hydrates in the development process. The other consideration is the frequency with which hydrates are encountered in real life. Focusing on active drug substances, it is estimated that approximately one-third of the pharmaceutical actives are capable of forming crystalline hydrates [3]. A search of the Cambridge Structural Database (CSD) shows that approximately 11% of all the reported crystal structures contain molecular water [4]. This represents over 16,000 compounds. If organometallic compounds are excluded, this number drops to approximately 6,000 (3.8%), and the breakdown of these according to hydration number is shown in Fig. 1. This shows the expected trend in which monohydrates are most frequently encountered, and where the frequency decreases almost exponentially as the hydration number increases. The hemihydrate stoichiometry occurs approximately as frequently as the trihydrate, which should serve as a caution to explore fully the occurrence of fractional hydration. That is, an apparent stoichiometry of 0.6 water molecules could be a partially dehydrated monohydrate, or it... 

The identification, structural and thermal characterization of new polymorphs is an important topic in solid-state chemistry and requires a battery of techniques that includes X-ray diffraction and spectroscopic methods, in addition to thermal analysis methods and dissolution techniques to determine solubility trends. Such studies are described by Caira in Chapter 16, as well as more recent theoretical techniques aimed at the prediction of the crystal structures of new polymorphs. Crystal polymorphism is particularly important in pharmaceutical products, so there is an emphasis on this area. Systems displaying solvatomorphism (the ability of a substance to exist in two or more crystalline phases arising from differences in their solvation states) molecular inclusion and isostructurality (the inverse of polymorphism) are also given due attention in this chapter. 

During the Stone Age, the material research was limited to the mechanical treatment of natural products. When Dalton discovered atomicity and Mendeleev revealed the periodic table, the research trends drastically changed in the intervening period and research was focussed on fundamental principles of basic molecular structure and simple chemical reactions. During the late twentieth century and the early twenty-first century, an exciting revolution in chemistry has taken place, with multidisciplinary approaches in nanoscience and nanotechnology to the creation of molecules with pre-specified complex structures to perform novel functions, hi the present century, research is focussed on control of crystal structures, nanostractures and microstructures with distinct mechanical, electrical, optical and magnetic properties [1-5]. 

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