Role of thermodynamic, kinetic and structural factors in the recrystallization behavior of amorphous erythromycin salts

• Crystallization kinetics of amorphous erythromycin salts was assessed.
• Contribution of thermodynamic, kinetic and structural factors was evaluated.
• Role of counterions on physical stability of amorphous salts was investigated.
• Implications of the study: In rationalizing stabilization approach for amorphous form.

Amorphous form has become an important drug delivery strategy for poorly water soluble drugs. However, amorphous form has inherent physical instability due to its tendency to recrystallize to stable crystalline form. In the present study, amorphous forms of erythromycin free base (ED) and its salts namely, stearate (ES), phosphate (EP) and thiocyanate (ET) were generated by in situ melt quenching and evaluated for their crystallization tendency. Salts were characterized for kinetic, thermodynamic and structural factors to understand crystallization behavior. Kinetics of crystallization followed the order as ES > EP > ET > ED. Fragility and molecular mobility does not completely explain these findings. However, configurational entropy (Sconf), indicative of entropic barrier to crystallization, followed the order as ET > EP > ES > ED. Lower crystallization tendency of ED can be explained by its lower thermodynamic driving force for crystallization (Hconf). This correlated well with different structural parameters for the counter ions.

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