Crystal Habits of Itraconazole Microcrystals: Unusual Isomorphic Intergrowths Induced via Tuning Recrystallization Conditions

Abstract

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.

In Situ Growth and Wrapping of Aminoanthraquinone Nanowires in 3 D Graphene Framework as Foldable Organic Cathode for Lithium‐Ion Batteries

“…In the XRD pattern of AAQ@G (Figure S1b), two peaks at 2 θ =11° and 14.3° are the same as those of AAQ but the peak at 14.3° becomes less intense. The same situation occurs in the multiple peaks located at 20–30°, which may be owed to different preferred orientation after antisolvent recrystallization in water . The peak of AAQ@G located at 24–30° results from the combination of a broad peak of RGO at 18–30° and several small peaks of AAQ in this range.…”

Tuning the Crystal Habits of Organic Explosives by Antisolvent Crystallization: The Case Study of 2,6-dimaino-3,5-dinitropyrazine-1-oxid (LLM-105)

“…Over the past several decades, the development of crystallization methods has been accelerated due to the increasing number of requests for crystals with specific properties [3]. As one of the most important crystal qualities, crystal habit (the characteristic external shape of a crystal) not only has a considerable impact on the physicochemical properties such as dissolution rate, bioavailability, solubility, and compressibility of crystal products, but also significantly affects the downstream operations such as filtration, drying, and milling [4][5][6]. For explosives, crystal habits are particularly important because they affect the mechanical and safety properties as well as the formulation and manufacturing processes, thus determining the further application of explosive crystals [7][8][9][10][11].…”

Intermolecular Interactions in Functional Crystalline Materials: From Data to Knowledge

“…Mugheirbi and Tajber analyzed the FIM hotspots around the itraconazole molecule to understand the molecular environment in the mesophase [260]. The itraconazole lacks any donors of strong H-donors but has a number of competing acceptors of H- This tool has been applied mainly for the analysis of strong hydrogen bonds [54,170,190,194,[248][249][250][251] in accord with the first test functional groups suggested within this tool, and the first paper published to describe it. Mutual disposition of hot spots can be used to find functional groups of the same molecule [245], co-formers [243,249,250], active sites in a binding pocket of a macromolecule [252], or surface inhibitors [170], which match a given pattern of interaction preferences.…”