CNT effective interfacial energy and pre-exponential kinetic factor from measured NaCl crystal nucleation time distributions in contracting microdroplets.

Nucleation, the birth of a stable cluster from a disorder, is inherently stochastic. Yet up to date, there are no quantitative studies on NaCl nucleation that accounts for its stochastic nature. Here, we report the first stochastic treatment of NaCl-water nucleation kinetics. Using a recently developed microfluidic system and evaporation model, our measured interfacial energies extracted from a modified Poisson distribution of nucleation time show an excellent agreement with theoretical predictions. Furthermore, analysis of nucleation parameters in 0.5, 1.5, and 5.5 pl microdroplets reveals an interesting interplay between confinement effects and shifting of nucleation mechanisms. Overall, our findings highlight the need to treat nucleation stochastically rather than deterministically to bridge the gap between theory and experiment.

Evaporation Dynamics of Sessile Saline Microdroplets in Oil.

The occurrence of concentration and temperature gradients in saline microdroplets evaporating directly in air makes them unsuitable for nucleation studies where homogeneous composition is required. This can be addressed by immersing the droplet in oil under regulated humidity and reducing the volume to the picoliter range. However, the evaporation dynamics of such a system is not well understood. In this work, we present evaporation models applicable for arrays of sessile microdroplets with dissolved solute submerged in a thin layer of oil. Our model accounts for the variable diffusion distance due to the presence of the oil film separating the droplet and air, the variation of the solution density and water activity due to the evolving solute concentration, and the diffusive interaction between neighboring droplets. Our model shows excellent agreement with experimental data for both pure water and NaCl solution. With this model, we demonstrate that assuming a constant evaporation rate and neglecting the diffusive interactions can lead to severe inaccuracies in the measurement of droplet concentration, particularly during nucleation experiments. Given the significance of droplet evaporation in a wide array of scientific and industrial applications, the models and insights presented herein would be of great value to many fields of interest.

Separation of Etiracetam Enantiomers Using Enantiospecific Cocrystallization with 2-Chloromandelic Acid.

Chirality plays an important role in the pharmaceutical industry since the two enantiomers of a drug molecule usually display significantly different bioactivities, and hence, most products are produced as pure enantiomers. However, many drug precursors are synthesized as racemates, and hence, enantioseparation has become a significant process in the industry. Cocrystallization is one of the attractive crystallization approaches to obtain the desired enantiomer from racemic compounds. In this work, we propose a chiral resolution route for an antiepileptic drug, S-etiracetam (S-ETI), via enantiospecific cocrystallization with S-2-chloro-S-mandelic acid (CLMA) as a coformer. The experiments indicate that the system is highly enantiospecific; S-2CLMA cocrystallizes only with S-ETI but not with R-ETI or RS-ETI. Therefore, the chiral purification of S-ETI can be achieved efficiently with a 69.1% yield and close to 100% enantiopurity from the racemic solution. Additionally, structural simulations of the S-ETI:S-2CLMA cocrystal reveal that the cocrystal structure has higher thermodynamic stability than that of R-ETI:S-2CLMA by about 5.5 kcal/mol (per cocrystal formula unit), which helps to confirm the favorability of the enantiospecification in this system.

Nucleation in sessile saline microdroplets: induction time measurement via deliquescence-recrystallization cycling.

Induction time, a measure of how long one will wait for nucleation to occur, is an important parameter in quantifying nucleation kinetics and its underlying mechanisms. Due to the stochastic nature of nucleation, efficient methods for measuring large numbers of independent induction times are needed to ensure statistical reproducibility. In this work, we present a novel approach for measuring and analyzing induction times in sessile arrays of microdroplets via deliquescence/recrystallization cycling. With the help of a recently developed image analysis protocol, we show that the interfering diffusion-mediated interactions between microdroplets can be eliminated by controlling the relative humidity, thereby ensuring independent nucleation events. Moreover, possible influence of heterogeneities, impurities, and memory effect appear negligible as suggested by our 2-cycle experiment. Further statistical analysis (k-sample Anderson-Darling test) reveals that upon identifying possible outliers, the dimensionless induction times obtained from different datasets (microdroplet lines) obey the same distribution and thus can be pooled together to form a much larger dataset. The pooled dataset showed an excellent fit with the Weibull function, giving a mean supersaturation at nucleation of 1.61 and 1.85 for the 60 pL and 4 pL microdroplets respectively. This confirms the effect of confinement where smaller systems require higher supersaturations to nucleate. Both the experimental method and the data-treatment procedure presented herein offer promising routes in the study of fundamental aspects of nucleation kinetics, particularly confinement effects, and are adaptable to other salts, pharmaceuticals, or biological crystals of interest.

Influence of Ostwald's Rule of Stages in the Deracemization of a Compound Using a Racemic Resolving Agent.

The stereoisomeric system of rac-2-phenylglycinamide (PGA) and rac-N-acetyl tryptophan (NAT) is significant in the application of chiral resolution because it has been shown that this system can be used for enantioseparation of PGA and/or NAT using a novel deracemization route of the conglomerate salt formed. However, it was also found that the conglomerate salt eventually converted into different crystal forms that limited the time available for the separation. Herein, we try to understand the phase conversion occurring in this system using DSC, PXRD, and SC-XRD. The related structures of the salt (two polymorphs of the more stable homochiral (dd- and ll-) salts and one polymorph of the less stable heterochiral (dl- and ld-) monohydrate salts) are demonstrated and discussed relating to their relative stabilities. The successful deracemization was demonstrated using the heterochiral (dl- or ld-) monohydrate salts. However, following Ostwald's rule of stages, only limited time is available for the deracemization before the metastable compound converts into the more stable homochiral (dd- and ll-) pair. Moreover, the occurrence of the (dd- and ll-) phase always coincides with the formation of yet another phase of the racemic compound containing four components in a crystal. Ostwald's rule of stages here thus involves three steps and phases and is highly significant during the deracemization of the homochiral species.

Bandgap Modulation in Zr-Based Metal-Organic Frameworks by Mixed-Linker Approach.

Metal-organic frameworks (MOFs) have been a promising material for many applications, e.g., photocatalysis, luminescence-based sensing, optoelectronics, and electrochemical devices, due to their tunable electronic properties through linker functionalization. In this work, we investigate the effect of mixed organic linkers on the bandgap modulation of polymorphic zirconium-based MOFs, UiO-66 and MIL-140A using density functional theory (DFT) calculations. We show that the electronic properties of both MOFs are in contrast to Vegard's law for semiconductors, that is, mixed-linker systems exhibit bandgaps not intermediate within the range of single-linker systems. Calculations of the total and partial density of states revealed the formation of mid-gap states in mixed-linker MOFs, causing the bandgap reduction. Interestingly, although both MOFs have similar composition, the effect is more significant in MIL-140A than in UiO-66. This is due to the presence of π-π stacking interactions in MIL-140A, which does not occur in UiO-66. The simulation results reveal a direct relationship between the strength of π-π interactions and the bandgap. This illustrates that distinct structural features, particularly the orientation of organic linkers can give rise to different consequences in bandgap modulation. Moreover, this computational work highlights the possibility to engineer the electronic properties of MOFs through a mixed-linker approach.