A disappearing metastable hydrate form of L-citrulline: Variable conformations in polymorphs and hydrates

Abstract

An unstable monohydrate crystalline form of l-citrulline was harvested during high throughput solid form screening and its crystal structure and hydrogen bonding patterns are elaborated. The crystal structures of the previously reported anhydrous polymorphs and dihydrate are analysed and compared their conformational flexibility. Periodic Density Functional Theory (DFT) approach was employed to unveil the relative stability of citrulline upon hydration and its microscopic interactions with water molecules. The relative binding energy suggests the order of stability as dihydrate > citrulline (anhydrous) > monohydrate. Metastable nature of the monohydrate is reasoned based on the presence of water molecules in the channel structure, less interactions with the citrulline molecules and lower crystal density compared to the other solid forms. Unlike the reported dihydrate form, monohydrate transformed to the anhydrous citrulline (Form II) on spontaneous dehydration at ambient conditions because of their similar conformational flexibility. First time, we report reproducible crystallization process of polymorphs, dihydrate and a novel metastable monohydrate of l-Citrulline.