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David J.W. Grant, Principal Investigator

Effects of Impurities, Polymorphism, Solid-State Solution, and Salt Form on the Crystal Properties of Some Therapeutic Agents

Trace amounts of impurities present in the crystallization medium exert profound effects on the nucleation, growth, morphology, and properties of the crystals obtained. Structurally related impurities may be incorporated into the crystal lattice leading to changes in the crystal properties. The objectives of the present research are to investigate the effects of a diastereomeric impurity on the crystal properties of a chiral compound, the influence of structurally related impurities on the stability of hydrates and on their solid-state reactivity, and the influence of crystallization conditions on impurity uptake and their subsequent effects on crystal properties of the host. The observed effects of incorporated impurities on the properties of the host are related to the molecular interaction in the solid-state between the host molecule and the impurity molecule. The molecular modeling tool is applied in these studies to view crystal structures and hydrogen bond networks and to calculate lattice energy and intermolecular interaction energies.

Another project is looking at the effects of salt form and crystal habit on tableting. Tableting is an important yet very complex process in the pharmaceutical field. This project is studying the effects of salt form and crystal habit on the tableting properties of some pharmaceutical compounds. The cerius2 program is employed for analyzing the crystal structure and for calculating the attachment energy, theoretical powder X-ray diffraction patterns, crystal shape, crystallographic planes, and for identifying the slip plan, an important factor in the control of the mechanical (tableting) properties of powders.

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A further project is looking at eprosartan mesylate and its phases and transitions. Eprosartan mesylate is used in the treatment of hypertension and exists as an anhydrate, monohydrate, and dihydrate. The single crystal structures of the anhydrate and dihydrate are visualized, and various interatomic distances and intermolecular energies are calculated in order to assist in understanding, and ultimately in visualizing, the physicochemical properties and phase transitions of eprosartan mesylate.

In an additional project, these researchers are studying the effects of polymorphism on the tableting properties of the drug, sulfamazerine. Cerius2 software is being used to visualize the structural differences between the polymorphs. Information obtained from this kind of molecular simulation provides a fundamental understanding of the different mechanical properties relevant to tableting of these two polymorphs of sulfamazerine. Moreover, knowledge of the crystal structures may enable prediction of the tableting behavior of the powder forms and may facilitate the appropriate choice of crystal form for the prevention of unexpected problems during the formulation of tablets.

In the final project, these researchers are examining the molecular conformations, the molecular packing, and the conformational polymorphism of dipeptide sweeteners, using Cerius2 software, with the ultimate objective to predict certain properties of the crystals. This work is being done in collaboration with Professor Eric J. Munson of the Chemistry Department at the University of Minnesota.

This information is available in alternative formats upon request by individuals with disabilities. Please send email to alt-format@msi.umn.edu or call 612-624-0528.

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