Influence of water of crystallization on the ternary phase behavior of a drug and deep eutectic solvent

Henrik Palmelund, Ben J. Boyd, Jukka Rantanen, Korbinian Löbmann

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2 Citations (Scopus)


Deep eutectic solvents (DESs) are mixtures of two solid components that interact via hydrogen bonds causing a large melting temperature depression. DESs are promising drug carriers and solvents for drugs with poor aqueous solubility. The presence of water within DESs is reported to change physicochemical properties, which could influence molecular interactions with drugs. It is therefore essential to study the influence of water of crystallization within one of the DES components on the drug loading capacity. In this study the influence of water of crystallization on the properties of two DESs containing xylitol and betaine anhydrate or monohydrate was investigated. Furthermore, the binary and ternary phase diagrams as well as the interplay between acetylsalicylic acid and the DES components were characterized to identify the maximum drug loading and elucidate the solvation mechanism. The presence of water of crystallization did not change the phase behavior of the binary DES, which had a eutectic melting temperature of 35–36 °C. Betaine anhydrate and acetylsalicylic acid formed a co-crystal after ball milling for 5 min with a melting temperature of 78 °C. Betaine monohydrate and acetylsalicylic acid formed a eutectic mixture with a melting temperature of 35 °C. Due to different interactions between the two crystal forms of betaine, the ternary phase behavior was significantly influenced by water of crystallization. The highest drug loading for the betaine anhydrate containing DES was 10 n/n% and was found at the eutectic composition of the DES. For the betaine monohydrate containing DES, the highest drug loading was 39 n/n% at a non-eutectic composition of the DES. These results demonstrated the importance of investigating the ternary phase behavior and influence of water of crystallization.

Original languageEnglish
Article number113727
Number of pages7
JournalJournal of Molecular Liquids
Publication statusPublished - 1 Oct 2020


  • Co-crystal
  • Deep eutectic solvent
  • Pharmaceutical solvents
  • Ternary phase behavior
  • Therapeutic deep eutectic solvent
  • Water of crystallization

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