(68d) Surface Interactions and Microstructural Characterization of API Subjected to Cryogenic Milling

Poor water solubility of many drugs has lead to creative solubilization strategies to provide adequate dissolution hence bioavailability for therapeutic effectiveness. One common practice has been reducing the particle size of drugs or active pharmaceutical ingredients (API) by micronization. The benefit to this approach is that there is an increase in dissolution by increasing the surface area of the materials. However, during micronization molecular compounds are subjected to high energy impacts leading to several perturbations with significant chemical changes and physical instabilities. One main concern is that reproducibility of the milled material not only rest on obtaining similar particle size but also on the physicochemical, surface interactions and microstructural properties for ensuring functionality and storage. In this research, felodipine (FDP), nifedipine (NDP) and ketoconazole (KCZ) were chosen as the model drugs and three common excipients used in food and pharmaceutical industries: lactose (LAC), fructose (FRU) and mannitol (MAN). All samples were cryo-milled at 10 and 30 min and the milled material was stored at low relative humidity in desiccators. Thermal and surface free energy mapping of the FDP, NDP and KCZ, as well as the microstructure of all milled materials was investigated. All samples were compared with their respective counterparts of un-milled (crystalline), milled (defects) and amorphous (quench melt). Some milled materials showed a typical X-ray diffraction (PXRD) pattern of an amorphous material, however, differential scanning calorimetry (DSC) suggested the presence of defected material not amorphous. Optical microscopy has indicated the presence of crystallinity in some of the milled samples. Inverse gas chromatography (IGC), a surface characterization technique, indicated that there are three surface energetic regions when materials are crystalline, defected or amorphous. The information and understanding of the uncontrolled materials is necessary to take adequate measurements upon processing (surface interactions) and storage (bulk stability).