Amphiphilic block copolymers as crystal habit modifiers

This dissertation covers modification of the crystal habit of the antidiabetic drug tolazamide by an amphiphilic block copolymer. Tolazamide crystallizes in an acicular shape from an aqueous medium. Associated with this shape of the drug crystals are numerous problems that can give rise to difficulties in formulation design and in manufacturing processes. It was proposed that many of these problems could be overcome if the shape of the drug crystals could be changed by the use of additives. The additive studied was an amphiphilic block copolymer of poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA). A number of block copolymers belonging to this series were studied to evaluate their effectiveness in changing the shape of tolazamide crystals. It was determined by measurement of the aspect ratios of the crystals from images obtained using polarized light microscopy that crystals with a more regular size and plate shape were obtained in the presence of very small amounts of this additive. To confirm that the same crystal form of the drug was being obtained upon crystallization in the presence of this additive, powder x-ray diffractometry and differential scanning calorimetry were performed on the resulting crystals. Moreover, from proton nuclear magnetic resonance experiments it was determined that a small amount of the ABC was localized on the surface of the recrystallized solid. Additionally, by measurement of the induction time for crystallization in the presence of the ABC it was concluded that this additive was able to inhibit the nucleation and growth of tolazamide crystals without changing the underlying growth mechanism. Lastly, the mechanism of this habit modification was identified as being due to the existence of non-covalent forces between the poly(lactic acid) block of the ABC and the phenyl group exposed on certain faces of the tolazamide crystals.