Spatiotemporal control of l-phenyl-alanine crystallization in microemulsion: the role of water in mediating molecular self-assembly.

Water confined or constrained in a cellular environment can exhibit a diverse structural and dynamical role and hence will affect the self-assembly behavior of biomolecules. Herein, the role of water in the formation of l-phenyl-alanine crystals and amyloid fibrils was investigated. A microemulsion biomimetic system with controllable water pool size was employed to provide a microenvironment with different types of water, which was characterized by small-angle X-ray scattering, attenuated total reflectance-Fourier transform infrared spectroscopy and differential scanning calorimetry. In a bound water environment, only plate-like l-phenyl-alanine crystals and their aggregates were formed, all of which are anhydrous crystal form I. However, when free water dominated, amyloid fibrils were observed. Free water not only stabilizes new oligomers in the initial nucleation stage but also forms bridged hydrogen bonds to induce vertical stacking to form a fibrous structure. The conformational changes of l-phenyl-alanine in different environments were detected by NMR. Different types of water trigger different nucleation and growth pathways, providing a new perspective for understanding molecular self-assembly in nanoconfinement.

Formation and stabilization mechanism of mesoscale clusters in solution.

To understand the existence of complex meso-sized solute-rich clusters, which challenge the understanding of phases and phase equilibria, the formation and stabilization mechanisms of clusters in solution during nucleation of crystals and the associated physico-chemical rules are studied in detail. An essential part of the mechanism is the formation of long-lived oligomers between solute molecules. By means of density functional theory simulation and nuclear magnetic resonance experiments, this work showed that the oligomers in solution tend to be π-π stacking dimers. Clusters are formed under the combined effect of diffusion and monomer-dimer reaction. The physically meaningful quantities such as the monomer-dimer reaction rate constants and the diffusion coefficients of both species were obtained by reaction-diffusion kinetics and diffusion-ordered spectroscopy results. The evolution of cluster radius as a function of time, and the qualitative spatial distributions of monomer and dimer densities under steady-state were plotted to better understand the formation process and the nature of the clusters.

Unveiling the self-association and desolvation in crystal nucleation.

As the first step in the crystallization process, nucleation has been studied by many researchers. In this work, phenacetin (PHEN) was selected as a model compound to investigate the relationship between the solvent and nucleation kinetics. Induction times at different supersaturation in six solvents were measured. FTIR and NMR spectroscopy were employed to explore the solvent-solute interactions and the self-association properties in solution. Density functional theory (DFT) was adopted to evaluate the strength of solute-solvent interactions and the molecular conformations in different solvents. Based on these spectroscopy data, molecular simulation and nucleation kinetic results, a comprehensive understanding of the relationship between molecular structure, crystal structure, solution chemistry and nucleation dynamics is discussed. Both the solute-solvent interaction strength and the supramolecular structure formed by the self-association of solute molecules affect the nucleation rate. The findings reported here shed new light on the molecular mechanism of nucleation in solution.

Molecular evolution pathways during nucleation of small organic molecules: solute-rich pre-nucleation species enable control over the nucleation process.

Increasing evidence has shown that nucleation pathways involving disordered pre-nucleation species exist in the nucleation process of many types of solid state products, especially inorganic solid state products. Studying the thermodynamic and kinetic properties of these pre-nucleation species is crucial to understand and control the nucleation process of solid state products. In this work, the evolution pathway of molecular or supramolecular structures during the nucleation process was investigated by using 2-cyano-4'-methylbiphenyl (OTBN) as a model compound. In the resultant solutions, similar pre-nucleation clusters were analyzed and characterized by dynamic light scattering (DLS), small-angle X-ray scattering (SAXS) and nanoparticle tracking analysis (NTA). It was found that the clusters were disordered and liquid-like and did not represent any of the known OTBN condensed phases. They were of interest since they may be the key sites for the formation of new crystal nuclei of OTBN. It was demonstrated that the change in the solvation effect would drive the pre-nucleation clusters to exhibit very different structures. How the clusters vary with concentration and temperature, and how they differ before and after nucleation have been systematically studied. In addition, the molecular dynamics of the evolution of clusters, the effect of initial mixing process on clusters and the nucleation dynamics were also investigated. The results suggested that the pre-nucleation clusters played a key role in the process of crystallization of organic small molecules, indicating that the dynamics of nucleation could be regulated by changing the structure and size of the pre-nulceation clusters.

Manipulation of Pharmaceutical Polymorphic Transformation Process Using Excipients.

BACKGROUND: In the pharmaceutical field, it is vital to ensure a consistent product containing a single solid-state form of the active pharmaceutical ingredient (API) in the drug product. However, some APIs are suffering from the risk of transformation of their target forms during processing, formulation and storage. METHODS: The purpose of this review is to summarize the relevant category of excipients and demonstrate the availability and importance of using excipients as a key strategy to manipulate pharmaceutical polymorphic transformation. RESULTS: The excipient effects on solvent-mediated phase transformations, solid-state transitions and amorphous crystallization are significant. Common pharmaceutical excipients including amino acids and derivatives, surfactants, and various polymers and their different manipulation effects were summarized and discussed. CONCLUSION: Appropriate use of excipients plays a role in manipulating polymorphic transformation process of corresponding APIs, with a promising application of guaranteeing the stability and effectiveness of drug dosage forms.

Insight into the role of pre-assembly and desolvation in crystal nucleation: a case of p-nitrobenzoic acid.

As one of the most important phenomena in crystallization, the crystal nucleation process has always been the focus of research. In this work, influences of pre-assembly species and the desolvation process on the crystal nucleation process were studied. p-Nitrobenzoic acid (PNBA) was taken as a model compound to investigate the relationship between solution chemistry and nucleation kinetics in seven different solvents. One unsolvated form and four solvates of PNBA were obtained and one of the solvates was newly discovered. The nucleation behaviours and nucleation kinetics of PNBA in the seven solvents were studied and analyzed. Density functional theory (DFT) and solvation energy calculation were adopted to evaluate the strength of solute-solvent interactions. Vibrational spectroscopy combined with molecular simulation was applied to reveal the pre-assembly species in the solution. Based on these results, a comprehensive understanding of the relationship between molecular structure, crystal structure, solution chemistry and nucleation dynamics was proposed and discussed. It was found that the structural similarity between solution chemistry and crystal structure, the interaction between specific sites and the overall strength of solvation will jointly affect the nucleation process.

In Situ Monitoring and Modeling of the Solution-Mediated Polymorphic Transformation of Rifampicin: From Form II to Form I.

In this article, the solution-mediated polymorphic transformation of rifampicin was investigated and simulated in 3 solvents at 30°C. The solid-state form I and form II of rifampicin was characterized by powder X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, Raman spectroscopy, and Fourier transform infrared spectroscopy (FTIR). To explore the relative stability, solubility data of form I and form II of rifampicin in butan-1-ol were determined using a dynamical method. In addition, Raman spectroscopy and focused beam reflectance measurement were used to in situ monitor the transformation of rifampicin from form II to form I. The liquid state concentration of rifampicin was measured by UV spectroscopic method. To investigate the effect of solvent on transformation, the transformation experiments were carried out in 3 solvents. Furthermore, a mathematical model was built to describe the kinetics of dissolution, nucleation, and growth processes during transformation by using experimental data. By combination of experimental and simulation results, it was found that the transformation process of rifampicin is controlled by dissolution of form II in heptane, whereas the transformation in hexane and octane was firstly controlled by dissolution of solid-state form and then controlled by growth of form I.