Development Strategies of Polymorphs and Solvates for Enhancing Powder Properties: A Case Study of Thiothiamine

Abstract

Crystals with an acicular shape are a "nightmare" to many chemical engineers due to their poor powder properties, posing numerous challenges in purification, filtration, washing, and subsequent processing. However, these challenges may be circumvented by engineering new crystal forms with better morphology using a crystal engineering strategy. Herein, we demonstrated the validity of this strategy with the case of thiothiamine, an essential intermediate in the production of vitamin B1, which exhibits a needle-like crystal morphology in polymorph I. Another two polymorphs (forms II and III) and 14 solvates were discovered and developed using a combination of computational prediction and experimental screening with X-ray diffraction, IR spectroscopy, and thermal analysis. Crystal structures of form II and six solvates were fully determined for the first time by single crystal X-ray diffraction. First, compared to form I, form II exhibits a notably larger grain size. Furthermore, the desolvation of solvates can retain its original superior morphology. These optimization strategies targeting crystal morphology directly contribute to the enhancement of the powder performance. Specifically, the filtration time was significantly reduced by over 70%, and the flowability of the powder was also greatly improved. Crystal structure analysis reveals that inclusion of small solvent molecules in a disordered manner contributes to solvate formation, while hydrogen bonding interactions contribute to the formation of methanol solvate. This study can serve as a valuable reference for addressing filtration and flowability challenges in industry by using crystal engineering strategies to develop polymorph or solvate alternatives.

Solubility Determination and Data Correlation of 4-Methoxybenzoic Acid in 14 Pure Solvents at Temperatures from 283.15 to 328.15 K

“…The choice of solvent is crucial to ensure that unexpected phase transitions do not occur during the crystallization process. Different solvents may lead to polymorphic changes or the formation of solvates, thereby influencing the performance of the crystalline product. − To ensure the absence of phase transitions during the solubility determination process, PXRD analysis was conducted on the residual solid in the suspension, as depicted in Figure . The PXRD spectra of all remaining solids closely resembled those of the original material, affirming that no phase transitions occurred during the entirety of the solubility testing for 4-MBA.…”

Solid-Liquid Equilibrium Behavior and Data Correlation of Furosemide in 12 Pure Solvents from 283.15 to 323.15 K

“…In multicomponent solid–liquid equilibrium systems, different solvents may result in polymorphism transition or formation of solvates, which thereby affects the performance of the crystalline product of solute. − With the aim of estimating this possibility and eliminating the influence of polymorphic transformation on the solubility determination, the equilibrated solids in all investigated solvents, as well as the original material of furosemide, were characterized by the powder X-ray diffraction (PXRD) test. The PXRD patterns are depicted in Figure , it can be seen that all the spectra for the samples of equilibrated solids displayed the same angular positions of diffraction peaks on the patterns as that of raw material, locating at about 5.8, 11.9, 17.9, 21.2, 22.7 and 24.6° in 2θ.…”

New Findings on the Crystal Polymorphism of Imepitoin

“…In the pharmaceutical field [11], these difficulties constitute a barrier to the physicochemical and pharmaceutical characterizations essential for the development of the active ingredients from different points of view. In-depth knowledge of the polymorphic behavior of an active ingredient, indeed, is essential for choosing the most suitable crystalline form for the formulation, avoiding unpleasant inconveniences due to the appearance of new crystalline forms in advanced stages of the development of a drug, guaranteeing its maintenance during manufacturing and storage, and defending the patent [12][13][14][15][16][17][18].…”