Effect of process parameters on phase behavior and particle size of aspirin during freeze concentration

The present work investigated effect of process parameters on phase behavior of aspirin (ASP) solution and ASP particle size during freeze concentration. ASP solution (3% w/w in 40% w/w TBA in water) was studied using differential scanning calorimetry (DSC) and cold stage polarized light microscopy (CSPLM) at cooling rates of 0.1, 0.5, 1, 3, 5, 10, 20, and 30 °C/min. Significant reduction in D90 of ASP crystals (from 45.6 µm to 3.0 µm) was observed for ASP crystals in frozen solution with increase in cooling rate. Non-isothermal crystallization kinetics (NITC) of ASP in frozen solution using CSPLM revealed linear increase and an exponential increase in Avrami exponent and crystallization rate constant, respectively. NITC results indicated generation of higher nucleation sites and localized multidimensional crystallization with increase in cooling rate. Moreover, the high degree of supercooling and higher supersaturation achieved with increasing the cooling rate further supported the generation of more nuclei and smaller ASP crystals. Finally, the implication of phase behavior was established using lab scale freeze dryer, where particle size (D90) of 41.8, 14.8, and 7.1 µm was obtained with cooling rate of 1 °C/min, 15 °C/min and quench cooling, respectively. The proposed strategy can be applied for development of lyophilized product that can generate parenteral suspension upon reconstitution.