New Co-Crystals of Betaine: Significant Improvements in Hygroscopicity

Abstract

To reduce the hygroscopicity of betaine (BET), three co-crystals were synthesized: betaine-3,5-dihydroxybenzoic acid (BET-3,5-DHB), betaine-2,4-dihydroxybenzoic acid (BET-2,4-DHB), and betaine-3-hydroxybenzoic acid (BET-3-HDB). BET, commonly present in natural products, is used to treat homocysteine methyltransferase and has additional benefits such as hepatoprotective and neuroprotective properties. However, BET is extremely hygroscopic. Three cocrystals are acquired to address the problem. Comprehensive characterization, such as X-ray diffraction analysis, spectral analysis and thermal analysis, were conducted for co-crystals and BET. Based on the evaluation results for dynamic vapor sorption, the three co-crystals, especially BET-3-HDB, significantly reduce BET’s hygroscopicity. At 90% RH, the weight changes of BET-2,4-DHB (0.36%), BET-3,5-DHB (1.79%) and BET-3-HDB (0.32%) are 306.9, 61.7, and 345.3 times greater than those of the raw material BET, respectively. Hygroscopicity results from BET’s ability to easily create hydrogen bonding interactions with water molecules due to its carboxylate ions. Nevertheless, carboxylate ions establish hydrogen bonds with CCFs in co-crystals, lowering BET’s hygroscopicity and minimizing the likelihood of contact with water molecules. The contributions of contacts in the co-crystals are shown by Hirschfeld surface analysis as follows: H-H > O-H > H-O. Coulomb forces are dominant in the co-crystals by 3D energy frameworks.