Evaluating the risk of milling-induced polymorphism

Many pharmaceutical materials exhibit polymorphism, a phenomenon in which a material exists in more than one crystal form. Polymorphic forms can differ in many physicochemical properties, resulting in changes to drug efficacy, processibility, and bioavailability. Polymorphism can occur through various conditions, e.g., milling. Milling is the process of grinding or crushing coarse particle to produce finer particulates for manufacturing. To evaluate the risk of milling-induced polymorphism we have investigated the transitions, mechanism, and stability of two model systems: sulfamerazine and indomethacin. We have found that both systems proceed through an amorphous intermediate, a noncrystalline solid, while the mill provided increased temperatures driving the recrystallizations of both systems to a "metastable" form. Understanding these parameters will help provide insight into protecting against unwanted polymorphic conversions via milling.