Enlarging crystal size of zoxamide by polymeric additives that modulate burst nucleation

Abstract

The fundamental understanding of how additives influence crystal nucleation and how to modulate nucleation in an explicit way by using target additives, remains considerable interests in the pharmaceutical science. Here, two polymeric additives, including polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), were adopted in the burst nucleation system to regulate the crystallization of zoxamide from both thermodynamic and kinetic perspectives. Nucleation rate and crystal growth rate were measured with and without PVP and PEG as a function of supersaturation, respectively. It was found that the existence of PVP could inhibit the nucleation and crystal growth of zoxamide, while PEG has a slight promoting effect on them. Furthermore, the kinetic parameter A and interfacial energy γ were calculated from the classical nucleation theory (CNT) fitting to elucidate the effect of polymeric additives on zoxamide nucleation process. The results indicated that PVP could reduce the attachment frequency of molecules and increase the interfacial energy, while PEG lower the nucleation energy barrier at high supersaturation. Finally, the concentration change during the cooling crystallization process was in-situ monitored and the mechanism for the larger crystal size was further proposed.