On the Polymorphism of l‑Citrulline: Crystal Structure and Characterization of the Orthorhombic δ Form

Solid-state properties of active pharmaceutical compounds are closely related to their dissolution behavior and bioavailability, and understanding their phase behavior leads to better control in the drug formulation process. l-Citrulline is an amino acid, which is known to exhibit polymorphism; however, only the structure of the α form is reported in the literature. The structure of the δ form has been elusive due to lack of good quality single crystals. It has been found to be orthorhombic P212121 with the cell parameters a, b, and c respectively 14.895(5) Å, 9.852(2) Å, and 5.353(2) Å. The unit cell contains four molecules, and its volume is 785.5(4) Å3. Both the α form and the δ form possess uniaxial negative thermal expansion along the direction of the charge exchange of the l-citrulline zwitterions. In mixtures containing solid and saturated aqueous solution, the α form quickly transforms in a dihydrate, whereas the δ phase persists for over three weeks. Although the evidence is not conclusive, the δ phase is most likely the more stable form and most suitable for storage.