David J. W. Grant, Principal Investigator

Effects of Impurities Incorporated During Crystallization on the Crystal Properties of Some Therapeutic Agents; Effects of Salt Form and Crystal Habit on Tableting

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. These researchers set out 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
• 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 were related to the molecular interaction in the solid-state between the host molecule and the impurity molecule. The molecular modeling tool was applied in these studies to view the crystal structures and hydrogen bond networks, and to calculate the lattice energy and intermolecular interaction energies.

A related area of study looked at trace amounts of impurities present in the crystallization medium. These 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.

Another body of research developed by the researchers involved the effects of salt form and crystal habit on tableting. Tableting is an important yet very complex process in the pharmaceutical field. This project studied the effects of salt form and crystal habit on the tableting properties of some pharmaceutical compounds. The CERIUS2 program was 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 planes, an important factor in the control of the mechanical (tableting) properties of powders.

These researchers also worked with eprosartan mesylate. This is used in the treatment of hypertension, and exists as an anhydrate, monohydrate, and dihydrate. The single crystal structures of the anhydrate and dihydrate were visualized and various interatomic distances and intermolecular energies were then calculated in order to assist in understanding, and ultimately in visualizing, the physicochemical properties and phase transitions of eprosartan mesylate.

Research Group and Collaborators

Rebanta Bandyopadhyay, Pharmacia, Kalamazoo, Michigan
Sarah M. Betterman, Supercomputing Institute Undergraduate Intern
Linna Chen, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan
Sharmistha Datta, Graduate Student Researcher
Zedong Dong, Graduate Student Researcher
Yushi Feng, Graduate Student Researcher
Chonghui Gu, Graduate Student Researcher
Suzanne Leung, 3M Pharmaceuticals, St. Paul, Minnesota
Jane Zheng Li, Process R and D, Pfizer Central Research, Groton, Connecticut
Jie Jennifer Sheng, Lilly Research Laboratories, Eli Lilly and Co., Greenfield, Indiana
Agam Sheth, Graduate Student Researcher
Changquan Sun, Pharmacia, Kalamazoo, Michigan
Geoff Zhang, Abbott Laboratories, Abbott Park, Illinois
Deliang Zhou, Graduate Student Researcher
Haijian Zhu, Glaxo Wellcome Inc., Research Triangle Park, North Carolina