Monitoring the influence of additives on the crystallization processes of glycine with dynamic nuclear polarization solid-state NMR.

Crystallization is fundamental in many domains, and the investigation of the sequence of solid phases produced as a function of crystallization time is thus key to understand and control crystallization processes. Here, we used a solid-state nuclear magnetic resonance strategy to monitor the crystallization process of glycine, which is a model compound in polymorphism, under the influence of crystallizing additives, such as methanol or sodium chloride. More specifically, our strategy is based on a combination of low-temperatures and dynamic nuclear polarization (DNP) to trap and detect transient crystallizing forms, which may be present only in low quantities. Interestingly, our results show that these additives yield valuable DNP signal enhancements even in the absence of glycerol within the crystallizing solution.

Exploring mechanochemical parameters using a DoE approach: Crystal structure solution from synchrotron XRPD and characterization of a new praziquantel polymorph.

A rotated Doehlert matrix was utilized to explore the experimental design space around the milling parameters of Praziquantel (PZQ) polymorph B formation in terms of frequency and milling time. Three experimental responses were evaluated on the resulting ground samples: two quantitative responses, i.e. median particle size by Laser Light scattering (LLS) and drug recovery by HPLC, and one qualitative dependent variable, i.e. the obtained PZQ crystalline form, characterized through X-Ray Powder Diffraction (XRPD) and confirmed by Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Temperature inside the jars was kept under constant control during the milling process by using temperature sensor equipped jars (thermojars), thus allowing evaluation of the obtained solid states at each experimental point, considering the specific temperature of the process. This explorative analysis led to the finding of a novel PZQ polymorph, named "Form C", produced without degradation, then fully characterized, including by means of Synchrotron XRPD, Polarimetric, FT-IR, SS-NMR, ESEM and saturation solubility. Crystal structure was solved from XRPD data and its geometry was optimized by DFT calculations (CASTEP). Finally, Form C and Form A activity against adult schistosoma mansoni were compared through in vitro testing, and Form C's physical stability checked. The new polymorph, crystallizing in space group I2/c, physically stable for approximately 2 months, showed a m.p. of 106.84 °C and displayed excellent biopharmaceutical properties (water solubility of 382.69±9.26 mg/l), while preserving excellent activity levels against adult schistosoma mansoni.

A Strategy for Probing the Evolution of Crystallization Processes by Low-Temperature Solid-State NMR and Dynamic Nuclear Polarization.

Crystallization plays an important role in many areas, and to derive a fundamental understanding of crystallization processes, it is essential to understand the sequence of solid phases produced as a function of time. Here, we introduce a new NMR strategy for studying the time evolution of crystallization processes, in which the crystallizing system is quenched rapidly to low temperature at specific time points during crystallization. The crystallized phase present within the resultant "frozen solution" may be investigated in detail using a range of sophisticated NMR techniques. The low temperatures involved allow dynamic nuclear polarization (DNP) to be exploited to enhance the signal intensity in the solid-state NMR measurements, which is advantageous for detection and structural characterization of transient forms that are present only in small quantities. This work opens up the prospect of studying the very early stages of crystallization, at which the amount of solid phase present is intrinsically low.