Title

Quantitative indices for tuning the crystal morphology of carboxlic acids

Date of Completion

January 2008

Keywords

Chemistry, Physical

Degree

Ph.D.

Abstract

The control of crystal morphology in industrial crystallization is critical because it significantly affects efficiency of downstream processing (filtering, washing, and drying) and post-processing physicomechanical properties (bulk density, wettability and tableting behavior). In the case of pharmaceuticals, crystal morphology affects drug bioavailability and thus its therapeutic efficacy. Factors such as cooling rate, degree of supersaturation, agitation speed, agitation time, seeding and presence of impurities have been routinely used to engineer crystal morphology. However, the type of solvent chosen for a crystallization process tends to have the strongest influence. Identification of quantitative indices and associated software for tuning the crystal morphology of carboxylic acids were the main focus of this work. ^ The role of (i) inter-molecular hydrogen bonding (ii) intra-molecular hydrogen bonding (iii) steric hindrance resulting from solvent functional group position, and (iv) aromatic pi- intermolecular interactions, in determining the final crystal form were examined via a systematic and comprehensive series of cooling-crystallization experiments. Several carboxylic acids, including pharmaceutical compounds such as ibuprofen and aspirin, were crystallized from solvents with widely varying polarities. Optical Microscopy (OM) and Scanning Electron Microscopy (SEM) facilitated quantitative characterization of crystals. Powder X-Ray Diffraction (PXRD) patterns were used to rule out the potential for polymorph formation. Solvent-solute hydrogen bonding interactions was investigated using Fourier Transform Infrared (FT-IR) spectroscopy. Molecular modeling of the surface chemistry of succinic acid was also conducted to elucidate the relationship between directional hydrogen-bonding of molecules and observed crystal morphology. ^ Results revealed that crystallization from polar solvents with intramolecular hydrogen bonds or limited functional group accessibility due to steric hindrance yields needles instead of the expected plate-like morphology. Nonpolar solvents exhibiting aromatic pi- intermolecular interactions with the crystallizing compound yield plates instead of needles, These findings are novel and quantitative indices derived from these qualitative parameters found applications in the design and selection of solvents for crystallization processes. Finally, two powerful and user-friendly computer programs were developed to aid in selection of solvents for crystallization processes. ^ Keywords: Crystallization, Morphology, Carboxylic Acids, Hydrogen Bonding, Solubility Parameter, Surface Chemistry, Computer Program. ^