Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? 2. Crystal Structure Prediction.

We report a multistage lattice energy minimization methodology for generating stable packing arrangements of cocrystals containing flexible molecules. In the first approximation, the intermolecular electrostatic interactions are modeled with atomic charges and the molecular deformation energy is interpolated over a set of precomputed quantum mechanical values. At subsequent stages, the accuracy is improved by first using analytically rotated and then conformation-dependent multipole moments, computed from the isolated-molecule charge density, and "on-the-fly" quantum mechanical calculations to compute the intramolecular deformation energy. This multistage approach increases the efficiency of the search and establishes the molecule-dependent error due to the atomic charge representation of the charge density and the neglect of the conformational dependence of atomic multipole moments. The methodology is used to study the lattice energy landscapes of the cocrystals of 4-aminobenzoic acid with 2,2'-bipyridine and 4-nitrophenylacetic acid, as well as the single-component crystals. All single-component, experimentally determined crystal structures within the scope of the search were found at, or very close to, the global minimum. The experimental cocrystal with 2,2'-bipyridine is also predicted to be among the most stable packing arrangements. On the contrary, the lattice energy landscape of the cocrystal with 4-nitrophenylacetic acid contains several low energy structures that are more stable than the experimentally observed form and have different hydrogen bonding motifs. Overall, the methodology can provide worthwhile crystal energy landscapes for multicomponent organic solids and thereby contribute to understanding cocrystal formation.

Marked insulin resistance in pregnancy: a case report and literature review.

Pregnancy is usually accompanied by insulin resistance; however, severe insulin resistance in pregnancy requiring massive doses of insulin is rare. We report a case of a 14-year-old with acanthosis nigricans and a strong family history of Type 2 diabetes who exhibited marked insulin resistance during pregnancy. Her treatment included terbutaline for pre-term labor and dexamethasone for fetal lung maturity. Shortly after these interventions, her insulin requirements escalated to 130 units per hour. Multiple insulin regimens were used in her treatment. Investigations were negative for antinuclear antibodies, islet cell IgG auto-antibodies (GAD65 Antibody assay) and insulin antibodies. Her thyroid-stimulating hormone was within normal limits and her C-peptide level elevated at 18 ng/dL [1.1-4.8 ng/L]. A week following cessation of the dexamethasone and terbutaline, her insulin requirements dramatically decreased. We conclude that in pregnant patients with underlying insulin resistance and strong family history of diabetes, the use of agents that antagonize insulin action, such as dexamethasone and terbutaline, can result in massive insulin resistance.