Quantitative analysis of the inhibitory effect of HPMC on felodipine crystallization kinetics using population balance modeling

Abstract

In the present paper, the effect of the polymer additive, hydroxypropylmethyl cellulose (HPMC), on inhibiting the nucleation and growth of felodipine from supersaturated aqueous solutions was investigated. To characterize the growth and nucleation kinetics, seeded and unseeded desupersaturation experiments were carried out, respectively. A mathematical model for the batch crystallization of felodipine was constructed by using empirical expressions for nucleation and growth, a population balance equation, and a material balance. An optimization algorithm was employed to obtain the kinetic parameters in the nucleation and growth expressions by fitting the simulated results to the experimental data. Population balance modeling successfully allowed for the decoupling of the separate effect of HPMC on the nucleation and growth rates. In both the absence and presence of polymer, the growth mechanism of felodipine was determined to be intermediate between mass diffusion and surface integration controlled growth. HPMC was able to inhibit nucleation and growth at very low polymer concentrations (0.2 μg mL⁻¹). However, the inhibitory impact was much greater on nucleation as opposed to growth. At a concentration of 3.5 μg mL⁻¹, HPMC was found to decrease felodipine nucleation by up to eight orders of magnitude while it only decreased the rate of crystal growth by a factor of two. Furthermore, at high concentrations, the inhibitory impact of HPMC on growth reached a plateau and any further increases in polymer concentration were ineffective.