Polymorphism in Crystalline Substances

Definition: Polymorphism is the ability of a single chemical substance to crystallize in more than one distinct crystal structure while maintaining identical chemical composition.
Variable Properties: Different polymorphs exhibit unique melting points, solubilities, densities, and stabilities due to variations in molecular packing, orientation, or conformation.

Packing Polymorphism: Molecules possess identical conformations but differ in their arrangement and orientation within the crystal lattice.
Conformational Polymorphism: Molecules adopt different shapes (e.g., torsion angles, ring puckering), leading to distinct crystal forms.
Synthon Polymorphism: Features different dominant supramolecular interaction motifs.
Tautomeric Polymorphism: Different structural isomers (tautomers) are fixed in the solid state, interconverting via proton movement and double bond shifts.

General Formula: $C_2H_5NO_2$ (amino acid zwitterion).
$\alpha$ -Glycine: Space group $P2_1/n$ (CSD refcode: GLYCIN29); head-to-tail layer arrangement; metastable.
$\beta$ -Glycine: Space group $P2_1$ (CSD refcode: GLYCIN31); open packing, low density; metastable.
$\gamma$ -Glycine: Space group $P3_1$ or $P3_2$ (CSD refcode: GLYCIN33); helical chains along the c-axis; thermodynamically most stable form.

Application: Drug used for epilepsy and nerve pain; features a flexible ring system and amide group.
Form I: Triclinic ( $P\text{-}1$ ), CBMZPN11; metastable.
Form II: Trigonal ( $R\text{-}3$ ), CBMZPN03; rare.
Form III: Monoclinic ( $P2_1/n$ ), CBMZPN02; stable hydrogen-bonded dimer; used in pharmaceuticals.
Form IV: Monoclinic ( $C2/c$ ), CBMZPN12; metastable.
Form V: Orthorhombic ( $Pbca$ ), CBMZPN16; very rare.

Synthon Polymorphism Example: 2 : 1 co-crystal of 4-hydroxybenzoic acid and 2,3,5,6-tetramethylpyrazine (ODOBIT and ODOBIT01).
Tautomeric Polymorphism Example: 2-Thiobarbituric Acid in Keto form (THBARB01) and Enol form (PABNAJ).
Concomitant Polymorphism: Simultaneous crystallization of multiple forms from a single experiment (e.g., mixtures of $\alpha$ , $\beta$ , and $\gamma$ glycine in polar solvents).
Disappearing Polymorphs: A stable form (lower Gibbs free energy $\Delta G$ ) emerges and dominates the nucleation landscape, acting as a seed that prevents the formation of earlier metastable forms.
Ritonavir Incident (1998): The unexpected appearance of stable Form II (less soluble) during manufacturing replaced Form I, leading to the drug's temporary market withdrawal.