Impact of tert-butyl alcohol on crystallization kinetics of gemcitabine hydrochloride in frozen aqueous solutions

The effect of tert-butyl alcohol (TBA) on isothermal crystallization kinetics of gemcitabine hydrochloride (GHCl) in frozen aqueous solutions was assessed by cold-stage microscopy. Addition of TBA (0%-5%, w/w) increased the value of Johnson-Mehl-Avrami rate constant (1.3-33.3 h^-1) and reduced the Avrami exponent (2.5-1.0). Thermodynamic parameters [enthalpy (ΔH‡), entropy (ΔS‡), and free energy ΔG‡) of activation], calculated using Arrhenius and Eyring-Polanyi equations, established that TBA (2%, w/w) accelerated GHCl crystallization by reducing its ΔH‡ (53.9 cf. 96.5 kJ/mol^-1) and Δ‡(68.5 cf. 74.9 kJ/mol^-1). Further, to explore insights into the effect of TBA on nucleation and crystal growth of GHCl, crystallization kinetics data were deconvolved using Finke-Watzky model. This revealed that addition of TBA decreased ΔH‡ of nucleation and increased ΔS‡ of crystal growth, thereby reducing ΔG‡ of nucleation and crystal growth by 11.7% and 4.2%, respectively. Finkey-Watzky model also predicted a reduction in the crystal size upon TBA addition, which was confirmed by comparing particle size of GHCl lyophilized in the presence and absence of TBA. In conclusion, TBA reduces ΔG‡ of nucleation and crystal growth in a differential manner, thereby enhancing the crystallization kinetics of GHCl and affecting its morphological features.