Effect of Additives on Preferential Crystallization for the Chiral Resolution of Citrulline: Experimental, Statistical, and Molecular Dynamics Simulation Studies

Abstract

The molar fraction solubilities of L-, D-, and DL-citrulline were first determined in aqueous solutions with different concentrations of (R)-1,3-butanediol from 283.15 to 328.15 K under 101.3 kPa using the gravimetric method. Then, based on solidstate characterizations such as powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, thermal gravity analysis (TGA), differential scanning calorimetry (DSC), and ternary phase diagram, the nature of crystalline DL-citrulline was considered to be a racemic compound. Then, the rates and parameters of primary nucleation of three species in mixtures of water and (R)-1,3-butanediol were experimentally derived through the classical nucleation theory (CNT). After that, topological electrostatic potentials and radial distribution functions were analyzed for exploring the intermolecular interactions between the molecules, and the Yasuoka−Matsumoto (YM) method was employed to simulate the nucleation process. However, the calculated nucleation rates by YM were shown to be 2 orders of magnitude greater than those derived through CNT. Finally, the effect of additives on the appearance probability (P) of racemic and enantiomeric nuclei from the same DL-citrulline solutions at a supersaturation ratio of 2.63 was statistically investigated from 140 nucleation experiments. It was interestingly found that there was only a minor difference between the appearance probabilities of both enantiomeric crystals among 20 batches of nucleations in the absence of additives; however, in the presence of additives, enantiomeric crystals with the same chirality as the additives were totally inhibited, which were utilized for the chiral enrichment of the studied racemic system. By coupling the addition of additives and seeds, L-citrulline or D-citrulline crystals with optical purity above 99% can be produced with a yield up to 25.4% through chiral enrichment from an initial ee of 88%.

Enhanced Direct Crystallization Resolution of Racemates Mediated in Chiral Ionic Liquid Cosolvent Mixtures: Experimental, Statistical, and QM Simulation Studies

“…However, in CCM-0.3, the randomness is completely absent, and P is ascertained as 1, accompanied by the significantly increased absolute ee values (Figure b,c,e,f) . Specifically, the direction of ee values in CCM is uniformly controlled, that is, in l -IL CM-0.3, all ee values of the nuclei are more than zero, while they are all less than zero in d -IL CM-0.3.…”

“…However, in CCM-0.3, the randomness is completely absent, and P is ascertained as 1, accompanied by the significantly increased absolute ee values (Figure 6b,c,e,f). 70 Specifically, the direction of ee values in CCM is uniformly controlled, that is, in L-IL CM-0.3, all ee values of the nuclei are more than zero, while they are all less than zero in D-IL CM-0.3. The results confirm that CCM-0.3 can suppress the nucleation of the enantiomeric crystal with the opposite chirality to them, leading to the preferential nucleation of enantiomeric crystals with the same chirality.…”

Uncovering the Coupling Mechanism of Enhanced Growth of Acephate by Additives: Experiments and Molecular Dynamics Simulations

“…In recent years, more and more methods have been used to regulate crystal growth. Due to the advantages of simplicity, effectiveness, and low cost, the additives method has been extensively studied in all kinds of crystallization processes, − including the regulation of crystal growth. Generally, additives play an inhibitory role among these studies, while promoting crystal growth through additives is less studied and reported .…”

Development and Validation of a Raman Spectroscopy Concentration Calibration Model to Enhance Crystallization Kinetic Model-Based Control: A Case Study of dl-methionine

“…6−9 Lu et al used solid-phase characterization by infrared spectroscopy to distinguish chiral amino acid crystals with different rotational properties. 10,11 In addition, by comparing the experimental IR spectroscopy and simulated IR spectroscopy, a new high-precision quantitative method has been developed to study the solidstate transformation process. 12,13 Zhou et al used Fourier transform infrared (FTIR) spectroscopy to conduct online concentration monitoring and supersaturation control of the antisolvent crystallization process of paracetamol.…”

“…In recent years, a multitude of PAT tools have been developed for application in the regulation of crystallization operating parameters . Spectroscopy, such as infrared (IR) spectroscopy and Raman spectroscopy, has been widely applied to monitor solute concentration changes in crystallization processes. − Lu et al used solid-phase characterization by infrared spectroscopy to distinguish chiral amino acid crystals with different rotational properties. , In addition, by comparing the experimental IR spectroscopy and simulated IR spectroscopy, a new high-precision quantitative method has been developed to study the solid-state transformation process. , Zhou et al used Fourier transform infrared (FTIR) spectroscopy to conduct online concentration monitoring and supersaturation control of the antisolvent crystallization process of paracetamol . Mark et al utilized in situ attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy to monitor the concentration of benzoic acid in solution to control the degree of supersaturation, which improved product growth and particle size .…”