Solubility and crystallization of fentanyl in polyisobutylene films: Parameters that control the stability of a drug in adhesive system

The objective of this research was to investigate the crystallization of fentanyl from polyisobutylene films in order to find important parameters that determine the physical stability of a drug containing film. A model compound, fentanyl, was selected and the physicochemical properties relevant to nucleation and crystal growth were studied. The single crystal structure of fentanyl was determined and the data input in a molecular simulation program (Cerius 2) for visualization. Fentanyl crystals grown from heptane are monoclinic P2(1)/c, with the following cell parameters: a = 5.56Å, b = 25.42Å, c = 13.33Å, β = 101.2, Z = 4. The morphology of the crystals was predicted using Cerius2 and found to be comparable to the experimental morphology of crystals grown from heptane. Solvent systems and polymeric film formulations were then screened in order to find a system that would allow us to study crystallization. The solubility of fentanyl in polyisobutylene films with and without mineral oil was determined using kinetic release studies, equilibrium studies and by monitoring crystallization from adhesive films supersaturated with fentanyl. The equilibrium method with the solubility of 0.7% w/w was the most reliable. Solubility from kinetic release studies underestimates the solubility as opposed to obtaining solubility by monitoring crystallization, which overestimated the value. The effect of supersaturation of fentanyl in these films was investigated by studying the particle size and cluster distribution in the films visually and under the microscope. It was found that drug load concentrations greater than 4% resulted in homogeneous precipitation of fine, small needles. Films of 2% and 3% drug load resulted in fewer but bigger and more defined crystals that were clustered. Crystal size decreased as the supersaturation increased leveling off for drug load concentrations higher than 4% and keeping the aspect ratio of the crystals. This is due to nucleation taking over crystal growth. Furthermore, the effect of mineral oil on the crystallization of fentanyl was investigated. There was no change in morphology or size distribution in the presence of mineral oil, however the physical properties of the film changed and thermal analysis corroborates this change in the properties of the film.