Title : Controlling the polymorphism of active pharmaceutical ingredients in confined thin films: A study on Biclotymol
Abstract:
Polymorphism—the ability of a compound to crystallize in more than one form—critically impacts the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs). Metastable polymorphs are particularly attractive due to their improved solubility and bioavailability. While extensively studied in bulk, polymorphism under geometric confinement, such as in thin films, remains underutilized despite its potential to control and stabilize desirable polymorphic forms for advanced drug formulations. This study investigates the crystallization behavior of Biclotymol (BCT), an antiseptic API, in confined thin film systems using spin coating and drop casting on glass coverslips and silicon wafers. These techniques revealed markedly different polymorphic behaviors compared to bulk. Temperature-dependent X-ray diffraction (XRD) and differential scanning calorimetry (DSC) showed that drop-cast films transition from Form I to an amorphous state upon melting and recrystallize as Form II during reheating. Spin-coated films, however, remained amorphous under thermal cycling but spontaneously evolved into Form II over several months—highlighting a time-dependent, single-step molecular reorganization pathway. Substrate-dependent crystallization rates further highlight the impact of surface properties and confinement geometry on polymorph selection. Notably, nucleation on glass substrates was slower than on silicon wafers, revealing a clear substrate-induced effect on crystallization kinetics. These phenomena were investigated through polarized light microscopy, dielectric spectroscopy, atomic force microscopy (AFM), scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy (FTIR), confirming the formation of distinct polymorphs and the influence of confinement. Overall, the study demonstrates that film preparation method, substrate type, and thermal history play critical roles in directing polymorphic outcomes. Thin films thus serve as powerful model systems for reproducibly controlling API solid forms. These insights into substrate-confinement interactions offer promising strategies for enhancing drug stability and efficacy in pharmaceutical development.
