Crystal doping aided by rapid expansion of supercritical solutions |
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Authors: | Vemavarapu Chandra Mollan Matthew J Needham Thomas E |
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Institution: | (1) Pharmaceutical Sciences, Pfizer Global R&D, 48105 Ann Arbor, MI;(2) Applied Pharmaceutical Sciences, University of Rhode Island, 02881 Kingston, RI |
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Abstract: | The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations
in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS
process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction
ranged from 45 to 100°C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II
involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity
of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder
diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization
from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion
to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies
revealed the formation of eutectic mixtures and solid solutions of CPD+urea. Formation of the solid solutions resulted in
the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these
results were the reductions in melting point (up to 9°C) and in the ΔHfvalues of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude
upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic
conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability
to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous
to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional
solvent-based cocrystallizations. |
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Keywords: | Rapid expansion of supercritical solutions RESS crystal doping cocrystallization chlorpropamide urea |
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