Critical Influence of Water on the Polymorphism of 1,3-Dimethylurea and Other Heterogeneous Equilibria

Abstract

It is shown that the presence of hundreds of ppm of water in 1,3-dimethylurea (DMU) powder led to the large depression of the transition temperature between the two enantiotropically related polymorphic forms of DMU (Form II → Form I) from 58 °C to 25 °C, thus explaining the reported discrepancies on this temperature of transition. Importantly, this case study shows that thermodynamics (through the construction of the DMU-water temperature-composition phase diagram) rather than kinetics is responsible for this significant temperature drop. Furthermore, this work also highlights the existence of a monohydrate of DMU that has never been reported before with a non-congruent fusion at 8 °C. Interestingly, its crystal structure, determined from X-ray powder diffraction data at sub-ambient temperature, consists of a DMU-water hydrogen bonded network totally excluding homo-molecular hydrogen bonds (whereas present in forms I and II of DMU).

Keywords: crystal structure determination; hydrate; phase diagrams; phase transitions; polymorphism.

Figure 1

Molecular structure of 1,3-dimethylurea (DMU). Color code: carbon, nitrogen, oxygen and hydrogen atoms are in grey, blue, red and white, respectively.

Figure 2

Impact of the presence of an impurity on the temperature of polymorphic transition. (a) B is a neutral impurity, (b) C is an impurity which drops the temperature of transition because it has more affinity with the high-temperature Form I than with the low-temperature Form II, and (c) D is an impurity which increases the temperature of transition because it has more affinity with the low-temperature Form II than with the high-temperature Form I. Glossary: ss = solid solution, sat. sol. = saturated solution, T_F = melting temperature, and T_tr = temperature of the reversible solid–solid transition. Dashed lines represent metastable equilibria.

Figure 3

DMU Form II to Form I phase transition observed by (a) DSC (the melting peak is also observed at ca. 106.1 °C) and (b) TR-XRPD.

Figure 4

In-situX^® diffraction analyses of DMU in suspension in n-heptane with different molar fractions of water: (a) 0.15%, (b) 0.39%, and (c) 12%. The experimental XRPD patterns of pure Form II (ssII), pure Form I (ssI) and the domain of coexistence ssI + ssII are represented in black, blue and red, respectively. For (a–c), temperature increases from bottom to top in a step of 2 °C from the initial temperature (12 °C or 18 °C) and the first temperature of occurrence of each phase domain is indicated.

Figure 5

Result of the Rietveld fit of the crystal structure of the DMU monohydrate. The experimental XRPD pattern is in red dots (molar composition in water: 51%; temperature: −20 °C), the calculated one in black, the difference between both in blue and green bars represent the positions of Bragg reflections. The two black arrows point to reflections that do not belong to the XRPD pattern of the DMU monohydrate and that were thus not included in the crystal structure determination procedure. Inset is a zoom (ten times magnified) on the high angle 2θ region [41–55°].

Figure 6

Portion of a molecular chain of (a) anhydrous DMU Form II and (b) the DMU monohydrate.

Figure 7

DSC curves of DMU–water mixtures of various compositions in water (expressed in molar fraction of water) (a) before and (b) after two hours annealing at −10 °C. The onset temperature given for each invariant transition corresponds to the mean value of the onset temperatures measured from the corresponding peaks observed for the mixtures shown.

Figure 8

Solubility curve of DMU in water determined by the refractometry method.

Figure 9

TR-SHG analyses of DMU—H₂O mixtures of (a) 70% and (b) 70.5% molar compositions in water. SHG Intensity is normalized to the maximum intensity measured. U.sat.sol. stands for undersaturated solution.

Figure 10

Schematic DMU–water binary phase diagram. Experimental points obtained from DSC (blue dots), refractometry (black dots) and TR-SHG (red dots—open symbols: metastable eutectic temperature; filled symbols: ssII liquidus temperature) analyses are represented. The inset shows a magnification of the DMU-rich side of the phase diagram with the phase domains labelled. In particular, the compositions 0.15%, 0.39% and 12% in molar fraction of water which have been analyzed by In-situX^® measurements are highlighted in purple, green and black, respectively. Vertical dashed lines starting from the latter compositions (with the same respective colors) emphasize the phase domains they exhibit as a function of temperature along the ssII to ssI phase transition.