Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences





First Advisor

Thomas E. Needham


This body of work is intended to serve as a proof of concept for the application of supramolecular chemistry in drug development. More specifically, this work is designed to evaluate crystal doping by recrystallization from supercritical media. The rapid nucleation and growth implicit to supercritical fluid based crystallizations were tested in doping drug crystals with structurally related impurities. The ultimate motive was to tailor the physicochemical properties of active pharmaceutical ingredients (APT) through crystal doping. This, in tum provides the ability to tie functionality to APl's at early stages of drug discovery and synthesis. Methods. The rapid expansion of supercritical solution (RESS) process was evaluated for these purposes. Pure and co-solvent modified supercritical fluid C02 was used as the recrystallizing solvent. The supercritical region investigated for these studies included pressures from I 07 l-9000psi and temperatures ranging from 31-100°C. The pharmaceutical solids studied included a-naphthalene acetic acid, aspirin, benzoic acid, caffeine, chlorpropamide, indomethacin, naproxen, phenytoin, piroxicam, salicylic acid, theobromine, theophylline, tolbutamide and urea. For comparison purposes, model chlorpropamide+urea system was also recrystallized from three liquid organic solvents using evaporative crystallization. The composition, morphology and the energetics of the crystals thus produced are characterized utilizing techniques such as microscopy (polarizing optical, SEM), thennal analysis (DSC, mDSC, TGA and thennomicroscopy) and HPLC. Results. Selective extraction and a reduction in crystallinity were consistently seen in all of the drug-impurity mixtures cocrystallized by RESS process. ln addition, a number of interesting phenomena were revealed. These include habit modification, solubility enhancement, particle size reduction, eutectic formation, amorphous conversion, hydrate formation and polymorph conversion. In viewing each of these phenomena from an application standpoint, this work serves as proof of concept for enhancing the physicochemical and mechanical attributes of APl's using supercritical fluid crystal doping. Comparative evaluation studies indicated RESS to be superior to organic so lventbased recrystallizations in crystal doping. In summary, RESS offers great promise as a hybrid technique to control both the crystalline and the particle morphologies of API's in a single stage. Conclusions. The presence of an impurity in the crystallization medium exhibits varied effects depending on the phase in which it is present prior to nucleation and its affinity to the host relative to the crystallizing solvent. This in turns dictates the rate at which it nucleates and grows in relation to that of the host. The domain of effects that these kinetics dictate on one extreme includes the fomrntion ofa solid solution or a solid dispersion of the impurity in the host lattice. On the other hand, selective extraction of each of the components with respect to time can also occur, the extent of which primarily depends on the resolution factor of the recrystallizing so lvent. While the former mechanism is largely aided by the rapid nucleation and growth implicit to supercritical fluid recrystallizations, the latter forms the scope of supercritical fluid chromatography. An optimal compromise between these extremes can be reached by utili zing the adjustable solvent power of supercritical fluids.



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