| 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 (API) through crystal doping. This, in turn provides the ability to tie functionality to API's at early stages of drug discovery and synthesis. The rapid expansion of supercritical solution (RESS) process was evaluated for these purposes. Pure and co-solvent modified supercritical fluid CO2 was used as the recrystallizing solvent. The supercritical region investigated for these studies included pressures from 1071–9000psi and temperatures ranging from 31–100°C. The pharmaceutical solids studied included α-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), thermal analysis (DSC, mDSC, TGA and thermomicroscopy) and HPLC. Selective extraction and a reduction in crystallinity were consistently seen in all of the drug-impurity mixtures co-crystallized by RESS process. In 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 API's using supercritical fluid crystal doping. Comparative evaluation studies indicated RESS to be superior to organic solvent-based recrystallizations in crystal doping. In summary, RESS offers great promise as a hybrid technique to control both the crystalline and the particle morphologies of APIs in a single stage. |
