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.