Interpreting changes in nucleation and crystal morphology of carbamazepine dihydrate by probing the intermolecular interactions between additives and crystal surfaces.

The objective of this research was to characterize the intermolecular interactions between additives and the crystal faces of carbamazepine dihydrate (CBZ(D)) which led to changes in crystal morphology and inhibition of CBZ(D) nucleation. This was accomplished by comparing results from experiments designed to (1) measure the induction time for nucleation, (2) observe changes in crystal morphology, and (3) monitor the solution-mediated anhydrous to dihydrate carbamazepine transformation, with predicted binding energies between additives and crystal faces of CBZ(D). Additives were chosen based on their potential to interact with the molecular moieties present in the crystal faces of CBZ(D), with emphasis on their ability to form hydrogen bonds with the surface. These included bile salts (sodium cholate, glycocholate, glycodeoxycholate, glycochenodeoxycholate, and taurocholate), aliphatic surfactants (sodium lauryl sulfate and laurate), amino acids (phenylalanine and leucine), and aliphatic and aromatic amides (capramide and benzamide). Among the additives studied, the bile salts were found to significantly inhibit the nucleation of CBZ(D) and alter the crystal morphology by slowing the growth rate of the CBZ(D) {111} faces. Aliphatic anionic surfactants on the other hand promoted the nucleation while having no effect on the morphology. The comparison between surfactants is of importance since aliphatic surfactants are commonly used in in vitro dissolution studies of pharmaceutical compounds, whereas endogenous surfactants such as bile salts are encountered during in vivo dissolution in the gastrointestinal tract. These surfactants have quite different molecular and micellar structures which present a variety of possible intermolecular interactions with CBZ(D). The amino acids and amides had no apparent effect on either CBZ(D) nucleation or morphology. The basis of the intermolecular interactions were studied and interpreted by calculating the binding energies between the additives and the morphologically important crystal faces. The bile salts exhibited the strongest binding with the fastest growing faces of CBZ(D) (the {111} faces) while the other additives had binding energies of a similar magnitude or lower than the carbamazepine dimer. Molecular visualization of the interactions revealed that bile salts form hydrogen bonds with the carboxamide and water molecules in the CBZ(D) {111} faces, creating a formidable barrier that inhibited the further incorporation of growth units.Ph.D.Applied SciencesChemical engineeringPhysical chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132886/2/9990984.pd