Characterizing the Impact of Hydroxypropylmethyl Cellulose on the Growth and Nucleation Kinetics of Felodipine from Supersaturated Solutions

The use of amorphous drugs to generate supersaturated solutions that have the potential to enhance oral drug delivery is currently an area of intense interest. From an in vivo performance standpoint, inhibiting crystallization from these supersaturated systems is extremely important. In this study the ability of a polymer, hydroxypropylmethyl cellulose (HPMC), to inhibit nucleation and crystal growth of felodipine from supersaturated solutions was investigated. Nucleation and bulk crystal growth rates, in the absence and presence of seed crystals, were estimated from de-supersaturation curves. It was found that the presence of ppm levels of predissolved HPMC could inhibit both nucleation and growth of felodipine crystals. Empirical and mechanistic models were used to quantify the magnitude of inhibition. Crystal growth shifted toward an integration-controlled mechanism in the presence of HPMC where the overall impact on the growth rate was found to be strongly dependent on the extent of supersaturation. As predicted by theory, the polymer became less effective as a growth inhibitor with increases in supersaturation. The nucleation rate at similar supersaturations was significantly reduced in the presence of HPMC. A direct comparison of the impact of HPMC on nucleation and growth demonstrated that delaying nucleation was much more crucial to the stabilization of a supersaturated solution than hindering crystal growth.