Amorphous drug nanosuspensions. 3. Particle dissolution and crystal growth
Research output: Contribution to journal › Article
In the present paper, we have studied particle dissolution and crystal growth of the poorly water soluble drug felodipine, using fluorescence as a probe for the amount of crystalline material. Dissolution kinetics is essentially diffusion-controlled, while the rate of crystal growth is significantly slower compared to the diffusion-controlled limit. The deviation from diffusion control was characterized by the effective length, A, related to the kinetics of a surface integration process. Amorphous nanoparticles may be highly unstable in the presence of small amounts of crystalline particles. This is due to the fact that the molecular solubility from the amorphous nanoparticles often is at least an order of magnitude higher than the corresponding crystalline solubility. In a mixed system where crystalline nanoparticles have been added to an amorphous nanosuspension, the bulk will have a monomer concentration intermediate between the amorphous and crystalline solubilities, and is thus supersaturated with respect to the crystalline particles while being undersaturated with respect to the amorphous particles. As a consequence, the amorphous particles spontaneously dissolve, while crystalline particles grow, in a combined process which is similar to Ostwald ripening. By knowing the parameters describing dissolution and crystal growth, respectively, it was possible to simulate the outcome of controlled seeding experiments, where a small amount of crystalline nanoparticles was added to a dispersion of amorphous nanoparticles. A good agreement between model calculations and experiments was obtained including how the crystal growth rate varied with the amounts of added crystalline seeds.