Effects of the Ratio of Excipient and Solute on

Amorphous Particle and Unique Polymorph Formation

Victoria Karakis and Dr. Ryan C. Snyder

Department of Chemical Engineering, Bucknell University

In order to effectively deliver an Active Pharmaceutical Ingredient (API), pharmaceutical companies rely on specific particle properties to achieve the desirable drug performance. One very important attribute of a drug is that it must provide a reasonable amount of bioavailability, the fraction of drug that dissolves appropriately in the patient and is delivered to the system to provide relief of symptoms. Unfortunately, with the growing prevalence of more complex crystalline compounds, many drugs in development are poorly soluble in water and hence in the stomach; therefore, they are less bioavailable in their crystalline state. Thus, utilizing higher energy states than the most stable crystalline structure, specifically amorphous dispersions is one way to increase water solubility and hence increase bioavailability. While there is significant information concerning this method of improving bioavailability, the conditions that lead to the formation of amorphous particles are less understood. In this work, we utilize monodisperse droplet evaporation technology, which has shown to be a process that leads to the formation of less stable or amorphous structures. Additionally, metastable polymorphs, less stable crystal structures, of the pure organic acids used in this study are investigated.
Monodisperse droplet evaporation technology is implemented via a Vibrating Orifice Aerosol Generator (VOAG). The VOAG creates well dispersed droplets of solution in which the solvent rapidly evaporates during collection leaving the particles of interest. The solution includes the solute (model active ingredient), and an excipient (a polymer that prevents crystallization of the active ingredient). In this research, suberic acid is utilized as the solute and polyvinylpyrrolidone (PVP) as the excipient. In order to investigate the morphology and crystalline/amorphous structure of the particles, Scanning Electron Microscopopy (SEM) and an X-Ray Diffractometer (XRD) are used respectively. Structural results are confirmed with Differential Scanning Calorimetry (DSC). By varying the ratio of PVP:Suberic Acid in the solution, the amount of PVP needed in solution to create amorphous suberic acid is determined and compared to other solutes of interest. Additionally, X-ray diffraction tests of pure suberic acid without the addition of PVP lead to the formation of the metastable phase of suberic acid, denoted as β-suberic acid. Only one other report of this polymorph exists where it was formed on a nanoscale and solely at temperatures of 134°C and higher. Thus, this work further demonstrates the use of the VOAG as an effective method to investigate polymorphism.