Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To get a better understanding of how functional particles are formed with respect to process and formulation parameters, it is indispensable to offer a comprehensive overview of critical aspects of the droplet drying and particle formation process. This review therefore closely relates single droplet drying to pharmaceutical applications. Although excellent reviews exist of the different aspects, there is, to the best of our knowledge, no single review that describes all steps that one should consider when trying to engineer a certain type of particle morphology. The findings presented in this article have strengthened the predictive value of single droplet drying for pharmaceutical drying applications like spray drying and electrospraying. Continuous follow-up of the particle formation process in single droplet drying experiments hence allows optimization of manufacturing processes and particle engineering approaches and acceleration of process development.

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The aim of this paper was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) were studied as a model system. First, the low crystallization tendency of the model drug in MeOH was evaluated and confirmed. In a next step, a drug loading screening was performed on casted films and coated beads in order to define the highest possible MIC loading that still results in a one-phase amorphous system. These results indicate that film casting is not suitable for phase behavior predictions of ASDs coated on beads. Therefore, a setup for coating a solid surface was established inside the drying chamber of a spray dryer and it was found that this surface coating technique could predict the phase behavior of MIC-PVP-VA systems coated on beads, in case an intermittent spraying procedure is applied. Finally, spray drying was also evaluated for its ability to manufacture high drug-loaded ASDs. The highest possible drug loadings that still result in a one-phase amorphous system were obtained for bead coating and its predictive intermittent surface coating technique, followed by spray drying and finally by film casting and the continuous surface coating technique, thereby underlining the importance for further research into the underexplored bead coating process.

The phenomenon of solvatomorphism in drugs always has its significance in the pharmaceutical industry and in the area of crystal engineering for various reasons. An old antifungal drug, 1-[2-(2,4dichlorophenyl)-2-[(2,4-dichlorophenyl)-methoxy]ethyl]-1-H-imidazole (Miconazole), with no earlier crystal structure reported in the neat form, is observed to exhibit solvatomorphism in the solid state. The first report of the crystal structure of Miconazole, along with the structure of its three solvates, ethanol solvate, methanol solvate, and hydrate, is presented. Their crystal packing is discussed in detail, with input from energy calculations (partitioned into its Coulombic, polarization, dispersion, and repulsion contributions), by the analysis of electrostatic potential mapped on the Hirshfeld surface, three-dimensional (3D)-deformation density map, and two-dimensional (2D)-fingerprint plot by CrystalExplorer. The crystal structure of the hemihydrate of Miconazole has been reported earlier and recognized to have a different molecular packing from hydrate. Noticeably, the hemihydrate water molecule utilizes both its hydrogens in the formation of strong O−H•••N hydrogen bonds in connecting the two Miconazole molecules in the asymmetric unit (Z′ = 3). However, interestingly, only one hydrogen atom of the water molecule participates in hydrogen bonding to connect a Miconazole molecule in the case of hydrate (Z′ = 2) and behaves similarly in the crystal packing as solvent molecules in other solvates of Miconazole. Except for hemihydrate, all other solvates of Miconazole crystallize in the triclinic space group P1̅ and display a similar layer of molecules (2D isostructurality) in the crystal packing. Comparison of the crystal packing of all solvates revealed the presence of similar molecular chains (one-dimensional (1D) similarity), which involve a weak C−H•••Cl hydrogen bond along with a type II C− Cl•••Cl−C halogen−halogen interaction in connecting the molecules and observed to provide similar stabilization (∼15 kJ/mol) in all crystal structures. Such a molecular chain was not observed in the crystal structure of Miconazole. Moreover, weak C−H•••Cl hydrogen bonds and C− Cl•••Cl−C halogen interactions in hydrate, ethanol, and methanol solvates were observed to be involved in the formation of a similar molecular packing motif in their respective crystal structures. In all structures, the presence of a σ-hole and charge depletion region was detected opposite to the C−Cl σ bond (manifesting polarization of electron density around the Cl atom in the crystal) by the analysis of electrostatic potential mapped on the Hirshfeld surface and 3D-deformation density plots. The type II C−Cl•••Cl−C halogen−halogen interactions in all structures were observed to be attractive in nature (interaction energy is being approximately −4 kJ/mol) and characterized as a halogen bond. Furthermore, hydrogen atoms were observed to direct toward the charge concentrated region (perpendicular to the C−Cl bond) on the chlorine atom in the formation o...