The
cocrystal formation potential of itraconazole, a potent antifungal
drug, with C2–C10 aliphatic dicarboxylic acids has been investigated.
Using two experimental screening techniques (solvent-assisted grinding
and evaporation-based crystallization), the cocrystals of itraconazole
with C2–C7 dicarboxylic acids have been successfully synthesized
and characterized by powder X-ray diffraction, solid state nuclear
magnetic resonance, Raman spectroscopy, and thermal analysis. The
characterized multicomponent compounds include anhydrous cocrystals
(malonic, succinic, glutaric, and pimelic acids), a cocrystal hydrate
(adipic acid), and cocrystal solvates with acetone and tetrahydrofuran
(oxalic acid). This study is the first to demonstrate the diversity
in itraconazole cocrystals with a range of aliphatic dicarboxylic
acids of variable carbon chain lengths.
Abstract. Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology. An analysis of the molecular arrangements along the three dominant crystal faces [(002), (011), and (101)] was carried out using molecular simulation and thus the nature of the host-additive interactions was deduced. The crystals with modified habit showed improved compaction properties as compared with those of unmodified crystals. Overall, the results of this study proved that crystal morphology engineering is a valuable tool for enhancing tabletting properties of active pharmaceutical ingredients and thus of utmost practical value.
Thermal stress that pharmaceutical solids are exposed to during manufacturing can induce various phase transitions in bulk drug substances or excipients, resulting in altered dosage form performance. This paper reports on the thermally induced transformations of a macrolide antibiotic, erythromycin A dihydrate, investigated in situ by variable temperature powder X-ray diffractometry and hot-stage Raman spectroscopy. Erythromycin A dihydrate undergoes dehydration to isomorphic dehydrate, which then melts and recrystallizes to anhydrate. Raman spectroscopy was able to distinguish the two isomorphs of erythromycin A, the dihydrate and the dehydrate, thus offering a potential tool for in-process control of the drying process. The model fitting approach did not provide insight into the solid-state dehydration mechanism. However, the reaction mechanism was presented on the basis of crystal chemistry.
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