Molecular structure polymorphic nucleation

Keywords BPT derivatives, crystallization, crystallographic analysis, molecular structure, polymorphic nucleation... 

Effect of Molecular Structure on Polymorphic Nucleation of BPT Derivatives... 

We reported in the previous papers [8, 9] that the effect of the operational factors such as temperature and solvents on the polymorphic crystallization of a thiazole derivative - 2-(3 -Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-car-boxylic acid (BPT) - which is an enzyme inhibitor. In this paper, we synthesized the esters of BPT and studied the effect of the molecular structure on polymorphic nucleation systemically, and at the same time we also examined the solvent effect on the polymorphic nucleation of the ester. 

The majority of the crystallization literature deals with inorganic crystals, and the organic chemistry literature mainly covers small organic molecules with few degrees of freedom such as glutamic acid, phenytoin, or paracetamol. The reality in the pharmaceutical industry is often much more complicated— molecular weights above 1000 g/mole are common, and complex molecular structures have an effect on nucleation and growth kinetics as well as on the likelihood of polymorph formation. 

There are a number of MHC class I and class II polymorphic molecules, all with substantially the same basic structure. The MHC class I molecule is a dimer consisting of a glycoslylated transmembrane peptide of molecular weight 45 kDa covalently linked to a 12 kDa peptide it is found on the surface of most nucleated cells within the body. It is believed that the polypeptide backbones fold in such as way as to form a platform of -pleated sheet structures to support a peptide binding cleft in which the antigen fragments are held and presented to the T cells. 

Some experimental evidence for the presence of different aggregates in solution leading to polymorphic structures has been presented recently by Nather et al. (1996a,b), and there have been attempts to relate nucleation rates with proposed structures in solution based on molecular modelling (Petit et al. 1994). The number of studies of this nature is sure to increase with increasing sensitivity and sophistication of both experimental and computational tools those are the kinds of investigations that can provide answers to Powers challenge. 

Diphenyl-2,5-cyclohexadienone 3 exists as four polymorphs, labeled A-D, whose crystallographic details are summarized in Table 3-2 [14]. Polymorphs A-D are conformational polymorphs since they have different molecular conformers in their crystal structures. They are also concomitant polymorphs because they crystallized simultaneously from the same flask and under identical crystal nucleation and growth conditions. Forms B-D with multiple molecules in the asymmetric unit Z > ) may also be classified as conformational isomorphs. Such polymorph clusters with different molecular conformations, crystal packing and C—H - O... 

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