(198o) The Role of Water in the Formation of Crystal Structure: A Case Study of Valnemulin Hydrochloride

In this work, to better understand the role of solvents during formation of solvate/hydrate and the effect of existence of solvent molecules on the properties of the host molecule, valnemulin hydrochloride (VH) was used as model compound to investigate the effect of water on formation of crystal structure. Valnemulin hydrochloride is a new semisynthetic pleuromutilin derivative. It is mainly used to prevent and cure mycoplasma disease and Gram-positive bacterial infection in pigs, cattle, sheep and poultry ^[1-4]. At present, amorphous valnemulin hydrochloride is mainly used as commercial material. The amorphous form has many shortcomings, such as low stability, strong hygroscopicity, low bulk density and heavy irritating taste^[5]. Many efforts have been made to prepare crystalline product of valnemulin hydrochloride. However, only two kinds of crystalline solvates, methanol-water solvate(VHWMS) and ethanol-water solvate (VHWES), have been successfully developed and characterized^[6]. Although the hygroscopicity of these two solvates are better than those of amorphous valnemulin hydrochloride, the thermal stability of them are still not ideal and they will loss some associated solvents continuously at around 40 ^oC, which limits its application.

In this study, one new form of valnemulin hydrochloride, valnemulin hydrochloride dihydrate (VHW), was devoloped for the first time and was characterized. Since water molecules are involved in all obtained crystal forms of valnemulin hydrochloride, it is speculated that water plays a key role in the crystal formation of valnemulin hydrochloride. Therefore, the single crystal structures of different crystals are determined and analyzed to explore the role of water in the stabilization of these structures. At the same time, the change of molecule conformation in different forms was also analyzed. The transformation process of VHW to VHWMS and VHWES was investigated by infrared and Raman spectroscopy and discussed in detail. The results show that, in addition to stacking similarity, the conformation may also have significant impact on the crystallization kinetics.

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