Crystal Habits of Itraconazole Microcrystals: Unusual Isomorphic Intergrowths Induced via Tuning Recrystallization Conditions.
The external appearance of a crystal of active pharmaceutical ingredient (API), usually referred to as a crystal habit, has a substantial impact on the API's physicochemical and physiochemical properties and, subsequently, its pharmaceutical performance. In this work, we investigate the role of different parameters of antisolvent crystallization impacting on the itraconazole (ITR) crystal habit and how this crystal habit manipulation, including crystal intergrowth, can affect crystal interactions with water molecules. Three distinct isomorphic crystal habits of ITR, a twinned blade-shaped (CHtw), a plate-shaped (CHpl), and a flat sheet-shaped with dendritic ends (CHsh), were obtained by controlling crystallization conditions. A liquid-liquid crystalline phase separation was observed as an intermediate stage preceding crystal growth. The March-Dollase parameter was used as a quantitative description of the preferred orientation, where CHsh exhibited the highest preferred orientation. The three crystal habits were evaluated for their wettability and water vapor distribution, at 37 °C, using the Young-Nelson fitting model. CHtw crystals sorbed a statistically significantly higher amount of water than CHpl and CHsh, which was attributed to the presence of crystal defects due to the twinning boundary. On the other hand, the amount of water adsorbed on the surface of CHpl and CHsh crystals was comparable and it was about twice that adsorbed on CHtw crystals. This was related to the abundance of hydrophilic chemical functionalities on the (010) facet of CHpl and CHsh as supported by the full interaction map carried out using Mercury software. This study expands investigations of the impact of crystal habit manipulation on API's functional properties beyond the well-known solubility improvement approaches.
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
Naila A
NA
Mugheirbi
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin , Dublin 2, Ireland.
Lidia
L
Tajber
D003460:Crystallization; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry*; D017964:Itraconazole / Q000737:chemistry*; D050866:Liquid Crystals / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D017155:Wettability
D065692:Cytochrome P-450 CYP3A Inhibitors; D012997:Solvents; D014867:Water; D017964:Itraconazole
antisolvent crystallization; crystal habit; itraconazole; liquid−liquid crystalline phase separation; preferred orientation