SOLUBILITY BEHAVIOR OF LAMIVUDINE CRYSTAL FORMS IN RECRYSTALLIZATION SOLVENTS

Lamivudine can be obtained as acicular crystals (form 1, 0.2 hydrate) from water or methanol and as bipyramidal crystals (form II, nonsolvat ed) from many nonaqueous solvents. Form II is thermodynamically favore d in the solid state (higher melting point and greater density than fo rm I) at ambient relative humidities. Solubility measurements on both forms versus solvent and temperature were used to determine whether en tropy or enthalpy was the driving force for solubility. Solution calor imetry data indicated that form I is favored (less soluble) in all sol vents studied on the basis of enthalpy alone. In higher alcohols and o ther organic solvents, form I has a larger entropy of solution than fo rm II, which compensates for the enthalpic factors and results in phys ical stability for form II in these systems. The metastable crystal fo rm solubility at 25 degrees C was estimated to be 1.2-2.3 times as hig h as the equilibrium solubility of the stable form, depending on the t emperature, solvent, and crystal form. Binary solvent studies showed t hat > 18-20% water must be present in ethanol to convert the excess so lid to form I at equilibrium.