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Control of organic polymorph formation: crystallization pathways in acoustically levitated droplets
(2017)
Theoretical and experimental studies indicate that crystal nucleation can take more complex pathways than expected on the ground of the classical nucleation theory. Among these pathways are the formation of pre-nucleation clusters and amorphous precursor phases. A direct in situ observation of the different pathways of nucleation from solution is challenging since the paths can be influenced by heterogeneous nucleation sites, such as container walls. Here, we provide insights into the crystallization process using the in situ combination of an acoustic levitator, Raman spectroscopy, and X-ray scattering. The contactless sample holder enables the observation of homogeneous crystallization processes and the detection of intermediates and final crystalline forms. We provide evidence for the existence of multiple pathways of nucleation based on the investigation of the crystallization of organic molecules from different solvents. Starting from a diluted solution, a supersaturation is reached during the experiment due to the evaporation of the solvent. The highly supersaturated solution reveals different pathways of crystallization. Depending on the degree of supersaturation either the thermodynamically stable or the metastable crystal form is observed.
The crystallization of a highly polymorphic compound was studied in situ by combined time-resolved X-ray diffraction and Raman spectroscopy. Any influences of solid surfaces, temperature, and humidity on the crystallization were omitted by the use of a specially designed acoustic levitator. Investigations of polymorphic phase transitions during the crystallization process in different solvents allowed a structure assignment from first crystalline assemblies to final crystalline form. For the first time, it was possible to yield pure phases of selected polymorphs of the model compound ROY (5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile) directly from solution. The influence of the solvent on the final products and transient phases during the crystallization process was elucidated.
An unusually fast crystallization of the organic glass former nifedipine has been observed. The crystallization process, starting from an amorphous film to crystalline material, was investigated by time resolved Raman microspectroscopy. The crystallization rates of the initially crystallizing metastable β-form are four orders of magnitude higher than those of previous studies.
The class of 2,5 disubstituted-1,3,4-oxadiazoles containing a biphenyl unit on one side is intensively used as electron transport materials to enhance the performance of organic light emitting diodes (OLEDs). In contrast to the ongoing research on these materials insights in their structure-property relationships are still incomplete. To overcome the structural tentativeness and ambiguities the crystal structures of 2-(4-biphenylyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole, that of the related compound 2-(4-biphenylyl)-5-phenyl-1,3,4-oxadiazole and of 2-(4-biphenylyl)-5-(2,6-dimethylphenyl)-1,3,4-oxadiazole are determined. A comparison with the results of GAUSSIAN03 calculations and similar compounds in the Cambridge Structural Database leads to a profound characterization.
The crystallization of nifedipine was studied by means of synchrotron-X-ray diffraction, single-crystal X-ray structural analysis, and Raman spectroscopy. The results of slow evaporation (24 h in minimum) using dimethyl sulfoxide (DMSO) are presented. Since fast crystallization processes (typically minutes) in different solvents always led to the final formation of the thermodynamically most stable α-polymorph of nifedipine, we observed a novel pseudo-polymorph due to slow crystallization from DMSO. The single-crystal X-ray structure of the solvated species nifedipine·DMSO (1:1) is reported for the first time. In addition, the crystallization process on surfaces was followed by means of light microscopy and environmental scanning electron microscopy (ESEM) coupled with energy-dispersive X-ray spectroscopy (EDS) analysis. Different diffractions pattern and Raman spectra were observed for crystals grown from stock solution and those obtained by drying the solution on soda lime silicate surfaces.
A combination of two analytical methods, time-resolved X-ray diffraction (XRD) and Raman spectroscopy, is presented as a novel tool for crystallization studies. An acoustic levitator was employed as sample environment. This setup enables the acquisition of XRD and Raman data in situ simultaneously within a 20 s period and hence permits investigation of polymorphic phase transitions during the crystallization process in different solvents (methanol, ethanol, acetone, dichloromethane, acetonitrile). These real time measurements allow the determination of the phase content from the onset of the first crystalline molecular assemblies to the stable system. To evaluate the capability of this approach, the setup was applied to elucidate the crystallization process of the polymorphic compound nifedipine. The results indicate the existence of solvent-dependent transient phases during the crystallization process. The quality of the data allowed the assignment of the lattice constants of the hitherto unknown crystal structure of the β-polymorph.
Crystallization processes under different conditions are of fundamental interest in chemistry, pharmacy, and medicine. Therefore, we have studied the formation of micro- and nanosized crystals using water-caffeine (1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione) solutions under ambient conditions as a relevant model system. When droplets of an aqueous caffeine solution evaporate and eventually dry on surfaces (glass, polystyrene, and polyester), stable coffee tabletop rings with a perimeter of typically 3 mm are formed after 20 to 50 min. Using a micro focus X-ray beam available at the BESSY µSpot-beamline, the fine structure of different caffeine needles can be distinguished. Unexpectedly, both crystal modifications (α- and β-caffeine) are present, but locally separated in these rings. Furthermore, AFM studies reveal the presence of even smaller particles on a nanometer length scale. To eliminate influences of surface irregularities from the crystallization process, acoustic levitation of liquid samples was employed. Such levitated droplets are trapped in a stable position and only surrounded by air. The solvent in an ultrasonically levitated drop evaporates completely, and the resulting crystallization of caffeine was followed in situ by synchrotron X-ray diffraction. In this case, the diffraction pattern is in accordance with pure α-caffeine and does not indicate the formation of the room temperature polymorph β-caffeine. Hence, our investigations open new vistas that may lead to a controlled formation of cocrystals and novel polymorphs of micro- and nanocrystalline materials, which are of relevance for fundamental studies as well as for pharmaceutical and medical applications.